stereochemistry - PKU · Stereochemistry, Jian Pei, College of Chemistry, Peking University, Chirality is a fundamental properties of many three-dimensional objects. An object is

1

StereochemistryStereochemistry

裴裴坚坚

北京大学化学与分子工程学院北京大学化学与分子工程学院

2006 2006 年春年春

1985-1995, S. B., S. M., Ph. D

Peking University

1995-1998, Postdoctoral, National University of Singapore1998-2000, Postdoctoral, UCSB2000-2001, Associate Research Fellow,

Research FellowInstitute of Materials Research and EngineeringSingapore

2001.4 - Associate Professor, ProfessorPeking University

Jian PeiJian Pei

Stereochemistry, Jian Pei, College of Chemistry, Peking University,

The universe is dissymmetrical……

----- Louis Pasteur

The universe is dissymmetrical……

----- Louis Pasteur


Why

Preface IntroductionChapter 1 Basic Stereochemical Concepts

and VocabulariesChapter 2 Asymmetric Organic Reaction and

the ClassificationChapter 3 Type 1 Reactions: Reactions in Which

no New Chiral Centres Are CreatedChapter 4 Type 2 Reactions:Chapter 5 Type 3 Reactions:Chapter 6 Type 4 Reactions:

Preface IntroductionChapter 1 Basic Stereochemical Concepts

and VocabulariesChapter 2 Asymmetric Organic Reaction and

the ClassificationChapter 3 Type 1 Reactions: Reactions in Which

no New Chiral Centres Are CreatedChapter 4 Type 2 Reactions:Chapter 5 Type 3 Reactions:Chapter 6 Type 4 Reactions:

Contents


IntroductionIntroduction


History1. 1801, Haüy: quartz crystals exhibited hemihedral phenomena;2. 1809, Malaus: quartz crystals induced the polarization of light;3. 1812, Biot: quartz plate rotated the plane of polarized light …;4. 1815, Biot: difference between the rotation caused by…;5. 1822, Herschel: a correlation between hemihedralism and

optical rotation;6. 1846, Pasteur: tartaric acid;7. 1848, Pasteur: separated enantiomorphous crystals of sodium

ammonium salts of tartaric acid;8. 1874, J. H. van’t Hoff and J. A. Le Bel: Tetrahedron carbon

1. 1801, Haüy: quartz crystals exhibited hemihedral phenomena;2. 1809, Malaus: quartz crystals induced the polarization of light;3. 1812, Biot: quartz plate rotated the plane of polarized light …;4. 1815, Biot: difference between the rotation caused by…;5. 1822, Herschel: a correlation between hemihedralism and

optical rotation;6. 1846, Pasteur: tartaric acid;7. 1848, Pasteur: separated enantiomorphous crystals of sodium

ammonium salts of tartaric acid;8. 1874, J. H. van’t Hoff and J. A. Le Bel: Tetrahedron carbon

A clockwise direction: dextrorotatory molecule: (+) or d; A counterclockwise direction: levorotatory molecule: (-) or l;Enantiomers of a given molecule have specific rotations with the same magnitude but in oppsite directions.

A clockwise direction: dextrorotatory molecule: (+) or d; A counterclockwise direction: levorotatory molecule: (-) or l;Enantiomers of a given molecule have specific rotations with the same magnitude but in oppsite directions.



2

Emil Fischer:

COOH

Bu-tH

CONH2

COOCH3

Bu-tH

CONH2

CH2N2

HNO2

COOCH3

Bu-tH

COOH H2NNH2

CONHNH2

Bu-tH

COOHHNO2

CON3

Bu-tH

COOHCONH2

Bu-tH

COOH

(+)-1 [ ]Dα 20= + 50

(-)-1 [ ]Dα 20= -45



CA

B

D

E

CD

B

A

E



Because of their similarity in structure, diastereoisomers often have very similar chemical and physical properties. Consequently, separation of diastereoisomer mixtures will usually be more difficult than separation of constitutional isomers. Enantiopure materials have been important for the synthesis of natural products since the latter almost always are found in nature as a single enantiomers.In some cases, one enantiomer may be completely inactive; in others this enantiomer may be active in another deleterioussense, leading to undesirable side-effects of the drug.

Because of their similarity in structure, diastereoisomers often have very similar chemical and physical properties. Consequently, separation of diastereoisomer mixtures will usually be more difficult than separation of constitutional isomers. Enantiopure materials have been important for the synthesis of natural products since the latter almost always are found in nature as a single enantiomers.In some cases, one enantiomer may be completely inactive; in others this enantiomer may be active in another deleterioussense, leading to undesirable side-effects of the drug.

SignificanceSignificance


HO

HO COOH

HH2N

(L)-dopa

HO

HO COOH

NH2H

(D)-dopa



NMe

HOH

Me

(-)-benzomorphia(ease pain, unhabituational)

(+)-benzomorphia( faintly pain-easing, habituational)

MeN

OH

H

Me

止痛，不成瘾弱止痛，成瘾



(-)-benzopyriyldiol(strong carcinogenicity)

HO

O

OH(+)-benzopyriyldiol(no carcinogenicity)

OH

O

OH

强致癌性无致癌性



3

SNN

N

O

ONHC(CH3)3

HO

(R)-timolol (adrenergic)

SNN

N

O

ONHC(CH3)3

HO

(S)-timolol (ineffective)

肾上腺素能阻断剂无活性



Basic Stereochemical Concepts and Vocabularies


Chapter 1Chapter 1

OutlineOutline

1.1. Selectivity1.2. Chirality1.3. Determining Enantiomer

Composition1.4 General Strategies for Asymmetric

Synthesis


Chemoselectivity

Regioselectivity

Diastereoselectivity

EnatioselectivityStereoselectivity

1.1. 1.1. SelectivitySelectivity


ChemoselectivityChemoselectivity

Chemoselctivity is the preferential reaction of one functional group over another under the reaction conditions employed.

MeOOCR

O

NaBH4

MeOOCR

H OH


HO OHMeOOCR

O

HOH2CR

O

MeOOCR

OO LiAlH4

Na2SO4 (aq.) H+/H2O

Function of the Protecting GroupFunction of the Protecting Group


4

RegioselectivityRegioselectivity

Regioselctivity is the preferential formation of one isomer of the product in a reaction in which one (or less commonly two) other isomer (s) may also be formed.

Regioselctivity is the preferential formation of one isomer of the product in a reaction in which one (or less commonly two) other isomer (s) may also be formed.

HBrH2O

BrHBrperoxide

CH2Br


Regioisomer is formed in a reaction may depend critically on the conditions under which it is carried out.

Regioisomer is formed in a reaction may depend critically on the conditions under which it is carried out.

Same Mechanisms

R

R'

R

R'

R R

Br

R

R

base R

R

R

R


RegioisomerRegioisomer

OH

R'

R R'

HO RR

R

O

R' R'R'

R

O

R R'

O

R R'

H+

Nu--O

R

R'

Nu

R

Nu

O-

R'

Control of regioselectivity in these cases is less easy although not impervious to changes in reaction conditions.


RegioselectivityRegioselectivityTwo or more identical but distinguishable functional

groups in one molecule:

COOH

COOH

HO CH3OH

H+O

H+

LiAlH4 Na2SO4(aq)CH2OH

CH2OH

HO

O

H+

CH2OHO

O

CH2OH

O

O

10 %

NaH, DMFPhCH2Br

CH2OBnO

OH+

CH2OBnHO

HO

MeSO2ClPyr

Base CH2OBnO


RegioselectivityRegioselectivity

StereoselectivityStereoselectivity

Stereoisomers are isomers which have the same atoms and bonds in common but different arrangementsin space.

Stereoisomers are isomers which have the same atoms and bonds in common but different arrangementsin space.

Chirality or Handedness

Come from the Greek word Chier, which means hand in English

Chirality or Handedness

Come from the Greek word Chier, which means hand in English


Conformational isomers: nonisolableEnantiomers: a special sort of stereoisomer where the two molecules in question have a mirror-image or enantiomeric relationship.

Diastereoisomers:Stereoisomers which do not have an enantiomeric relationship.A chiral molecule containing at least two chiral elements.Some achiral molecules can exist as diastereoisomers:The E/Z stereoisomers of alkenes are not enantiomers andtherefore diastereoisomers.

Conformational isomers: nonisolableEnantiomers: a special sort of stereoisomer where the two molecules in question have a mirror-image or enantiomeric relationship.

Diastereoisomers:Stereoisomers which do not have an enantiomeric relationship.A chiral molecule containing at least two chiral elements.Some achiral molecules can exist as diastereoisomers:The E/Z stereoisomers of alkenes are not enantiomers andtherefore diastereoisomers.


StereoisomersStereoisomers

5

Enatioselectivity: in a reaction, is either the preferential formation of one enantiomer of the product over the other or the preferential reaction of one enantiomer of the (usually racemic) starting material over the other.

Diastereoselectivity: is the preferential formation in a reaction of one diastereoisomer of the product over the other.

Note: in a diastereoselective reaction

The product may be either as a single enantiomer or as a racemate, or excess of one enantiomer over the other between these extremes.



c

y

b

xz-

a+ a cb

zyx

b

x

c

y

a

z

enant.

c

y

b

xz-

a+

Completely diastereoselective, but the product is bound to be racemic.

a cb

zyx

a cb

y xz-



Stereoselectivity:

Diastereoselectivity

Enatioselectivity

CompleteHigh (> 90 %)Moderatelow



Enatioselectivity:normally quoted as the enantiomeric excess (e.e.), which is the mole fraction of the major enantiomer expressed as a percentage , i.e. with an excess of the R or S form.

e.e. =mole fraction R - mole fraction S

mole fraction R + mole fraction S * 100 % = α[ ]obs

α[ ]max* 100 %


EnatioselectivityEnatioselectivity

d. r.: diastereoisomeric ratiod. r.: diastereoisomeric ratio

Diastereoselectivity:usually given as the diastereoisomeric excess (d.e.), which is the mole fraction of the major diastereoisomer D1 in a mixture of two diastereoisomers D1 and D2 against usually expressed as a percentage:

d.e. =mole fraction D1 - mole fraction D2

mole fraction D1 + mole fraction D2* 100 %


DiastereoselectivityDiastereoselectivity

Stereospecificity: a term reserved for the circumstance in which stereo-differentiated reactants give stereo-differentiated products and/or show different reactivity.

Stereospecificity: a term reserved for the circumstance in which stereo-differentiated reactants give stereo-differentiated products and/or show different reactivity.

ax

bcNu-

aNu

bcNu

a

cb x

a

cb

Nu-

y x

z

b a

cNu-

ba

yx y x

z

a b

cNu-

ab

yx


StereospecificityStereospecificity

6

1.2 Chirality1.2 Chirality


Chirality is a fundamental properties of many three-dimensional objects. An object is chiral if it cannot be superimposed on its mirror image. There is one property in which chiral compounds differ from achiral compounds and in which enantiomers differ from each other. This property is the direction in which rotate plane-polarized light, and this is called optical rotation or optical activity.

Chirality is a fundamental properties of many three-dimensional objects. An object is chiral if it cannot be superimposed on its mirror image. There is one property in which chiral compounds differ from achiral compounds and in which enantiomers differ from each other. This property is the direction in which rotate plane-polarized light, and this is called optical rotation or optical activity.


ChiralityChirality

C N P S S

O

AsymmetryAsymmetry

1. Compounds with an asymmetric carbon atom: chiral center;2. Compounds with another quaternary covalent chiral center

binding to four different groups that occupy the four corners of a tetrahedron: Si, Ge, N, Mn, Cu, Bi, and Zn;

3. Compounds with trivalent asymmetric atoms:

1. Compounds with an asymmetric carbon atom: chiral center;2. Compounds with another quaternary covalent chiral center

binding to four different groups that occupy the four corners of a tetrahedron: Si, Ge, N, Mn, Cu, Bi, and Zn;

3. Compounds with trivalent asymmetric atoms:


N

H

CH3

Cl

N

H

CH3ClO

N

Ph

CH3Ph

In a three-membered heterocyclic ring


AsymmetryAsymmetry

N

N

Me

Me

The bridgehead structure


AsymmetryAsymmetry

ChiralA molecule which is non-superimposable upon its mirror image.

ChiralityArises from the absence of some symmetry elements.

The chiral element is most usually a chiral centre or, as it is sometimes called stereogenic centre in the molecule.

The configuration at this chiral centre is the arrangement in space of the substituents responsible for its chirality.

The chirality of a molecule may be alternatively ascribed to the presence of a chiral axis.

ChiralA molecule which is non-superimposable upon its mirror image.

ChiralityArises from the absence of some symmetry elements.

The chiral element is most usually a chiral centre or, as it is sometimes called stereogenic centre in the molecule.

The configuration at this chiral centre is the arrangement in space of the substituents responsible for its chirality.

The chirality of a molecule may be alternatively ascribed to the presence of a chiral axis.


ChiralityChirality

7

a

b

c

d

a

bd b

a

d

cc

enant.

One chiral center


ChiralityChirality

a bc

xy z

Two chiral centers


ChiralityChirality

a cb

zyx a cb

yxz

a cb

zyx

b

x

c

y

a

zenant.

b

x

a

y

c

z

c ab

zyx

enant.

Stereoisomers


ChiralityChirality FischerFischer’’s Conventions Convention

Glyceraldehyde as the standard

C OHH

CHO

CH2OH

C HHO

CHO

CH2OH

C

OHH

HO C

HHO

HO

CH2OH

CHO

CH2OH

OHH

CH2OH

CHO

CH2OH

HHO

Advantages:1. Enables the systematic

stereochemical presentation of a large number of natural of natural products;

2. Still useful for carbohydratesor amino acids today.

Limitations:Do not resemble the model reference compound glyceraldehyde;difficult to correlate the terpene compounds with glyceraldehye


The The CahnCahn--IngoldIngold--PrelogPrelog ConventionConvention

In the system, atoms or groups bonded to the chiral center are prioritized based on the sequence rules.1) An atom having a higher atomic number has priority over

one with a lower atomic number; for isotopic atoms, the isotope with a higher mass precedes the one with the lowermass;

2) If two or more of the atoms directly bonded to the asym-metric atom is identical, the atoms attached to them will compared according to the same sequence rule.

In the system, atoms or groups bonded to the chiral center are prioritized based on the sequence rules.1) An atom having a higher atomic number has priority over

one with a lower atomic number; for isotopic atoms, the isotope with a higher mass precedes the one with the lowermass;

2) If two or more of the atoms directly bonded to the asym-metric atom is identical, the atoms attached to them will compared according to the same sequence rule.



3) For multiple bonds, a doubly or triply bonded atom is duplicated or triplicated with the atom to which it is connected.

4) For vinyl groups, a group having the (Z)-configuration precedes the same groups having the (E) configuration, andan (R)-group have precedence over an (S)-group for

pseudochiral centres.

3) For multiple bonds, a doubly or triply bonded atom is duplicated or triplicated with the atom to which it is connected.

4) For vinyl groups, a group having the (Z)-configuration precedes the same groups having the (E) configuration, andan (R)-group have precedence over an (S)-group for

pseudochiral centres.


8

CH2OH

OHH

CHO

D-Glyceraldehyde in Fischer's convention(R)-glyceraldehyde in the Cahn-Ingold-Prelog convention



A equals C

A

A

C

A equals C

A

A

A

C

C

C

C

CC

CC

CHCH

CH

HC

CH

Cequals

R originating from the Latin word rectus, which means right in English;S originating from the Latin word sinister, which means left in English.

R originating from the Latin word rectus, which means right in English;S originating from the Latin word sinister, which means left in English.



CenterCenter--ChiralChiral

x

z wy

x, y, z and w different substituents

The system Cxyzw has no symmetry when x, y, z, and w are different groups, and this system is referred to as a central chiral system.

The system Cxyzw has no symmetry when x, y, z, and w are different groups, and this system is referred to as a central chiral system.


a

b

c

d

if a>b>c>d, R


CenterCenter--ChiralChiral

Axial Axial ChrialityChriality

OHOH

R

For a system with four groups arranged out of the plane in paired about an axis, the system is asymmetric when the groups on each side of the axis are different. Such a system is referred to as an axial chiral system.

For a system with four groups arranged out of the plane in paired about an axis, the system is asymmetric when the groups on each side of the axis are different. Such a system is referred to as an axial chiral system.

NO2

COOH

Me

OMe


C C C

C C Cd

ca

bif a > b, c > d, (R)

c

d

a

bif a>b, c > d, (S)



9

N

N

O

CH2COOHPhH2Cc d

a b

BrCMe2OH

Br

But

Br

Br



CH3

HH

HOOC

H

H3C COOH

H



OO

old, obsolete method(R)-configuration

OO

Currently used method(S)-configuration

12

3 4 4

3

2

1

For chiral spirocyclic compounds


Axial Axial ChrialityChriality Planar Planar ChrialityChriality

Br

CH2

Planar chirality arises from the desymmetrization of a symmetric plane in such a way that chirality depends on a distinction between the two sides of the plane and on the pattern of the three determining groups.

Planar chirality arises from the desymmetrization of a symmetric plane in such a way that chirality depends on a distinction between the two sides of the plane and on the pattern of the three determining groups.


Chiral Plane “Pilot Atom”or Descriptor

Br

O

CH2Pilot atom

12

3 CH2H2C

CH2H2C

Br

Pilot atom

12

3pS pS


Planar Planar ChrialityChriality

Metallocene molecules:Replace the η6-π bond by six σ single bonds.

According to the CIP rules, treated as a central chiral system.

Metallocene molecules:Replace the η6-π bond by six σ single bonds.

According to the CIP rules, treated as a central chiral system.

CH3

CHO

Cr(CO)3

CH3

CHO

Cr(CO)3

the most preferred atom

1

2

3

4S


Planar Planar ChrialityChriality

10

Helical Helical ChrialityChriality

Helicity is a special case of chirality in which molecules are shaped as a right- or left-handed spiral like a screw or spiral stairs. The configurations are designed M and P, respectively, According to the helical direction.

Helicity is a special case of chirality in which molecules are shaped as a right- or left-handed spiral like a screw or spiral stairs. The configurations are designed M and P, respectively, According to the helical direction.

M: counterclockwise orientation P: clockwise helix

M


Octahedral StructuresOctahedral Structures

Extention of the sequence rule makes it possible to arrange an octahedral structure in such a way that the ligands are placed octahedrally in an order of preference.

Extention of the sequence rule makes it possible to arrange an octahedral structure in such a way that the ligands are placed octahedrally in an order of preference.

2 5

3 4

1

C

6

1

4 3

5 2C

Observer's place

S R


Pseudochiral CentresPseudochiral Centres

A Cabcd system is called a pseudochiral cnetre when a/b are pair of enantiomeric groups and c/d are different from a/b as well as different from each other.

A Cabcd system is called a pseudochiral cnetre when a/b are pair of enantiomeric groups and c/d are different from a/b as well as different from each other.

CH2OH

OHH

OHH

H OH

CH2OH

CH2OH

OHH

HHO

H OH

CH2OH

pseudochiral centre

s rNH

MeMe

Molecules that belong to Cnor Dn point groups are also chiral


HO

CH3

Symmetric face

perchiral carbon atom


Pseudochiral CentresPseudochiral Centres

Compounds with other atoms

N

N

Me

Me

N

NMe

Me

N

MeO

N

Me O


ChiralityChirality

OOSS OSS

O

N P

NMe2

HO

O

As

Me


ChiralityChirality

11

PC6H4OHPh

S

R R'R''

S

OR'RO

S

R'RO

S

S

O

OStereochemistry, Jian Pei, College of Chemistry, Peking University,

ChiralityChirality Double Bond Double Bond Prochirality Prochirality

Enantiofaces

H

Me H

Me

1. OsO4

2. H2O +HO OH

H MeMe H HO OH

H MeMe H

OEt

H1. MeMgI2. NH4Cl

resi Et

H Me

OH Et

H OH

Me+

NPh

Me R 1. LiAlH4

2. Na2SO4 (aq) Ph

Me H

NHR Ph

Me NHR

H+


c

a bRe Si

b a

c

a b

cRe Si

O

RHRe


Double Bond Double Bond Prochirality Prochirality

enantioface or enantiotopic faces

A colckwise ordering of the substituents on the double bond defines the face views as re, an anticlockwise ordering as si.

In the reaction with a prochiral double bond, an achiral reagent cannot distinguish between enantiofaces and the product, therefore, is always racemic.



Prochirality is not an inherent property of the double bond alone but only arises in its combination with reagent.

H

Me H

Me

Br2 +

Br+

H MeMe H Br+

H MeMe H

Br

Br

H

Me

Me

H

Identical or homotopic faces



The difference between the carbonyl group and carbon-carbon double bond:A configured prochiral double bond can give rise to contiguous chiral centres from attack on its two enantiofaces whereas a non-configured prochiral double bond can give rise to only one.

The difference between the carbonyl group and carbon-carbon double bond:A configured prochiral double bond can give rise to contiguous chiral centres from attack on its two enantiofaces whereas a non-configured prochiral double bond can give rise to only one.



12

H

Me H

Me

1. OsO4

2. H2O+

HO OH

H MeMe H HO OH

H MeMe H

OEt

H1. MeMgI2. NH4Cl

resi Et

H Me

OH Et

H OH

Me+



N

O2N

t-Bu

RCO3HN

t-BuH

O

O2N

The carbon-nitrogen double bond may also be configured but the addition product does not normally have an assignable configuration …..

The carbon-nitrogen double bond may also be configured but the addition product does not normally have an assignable configuration …..



MeOOC

COOMe

Me

MeOOCCOOMe

MeH

Me H

COOMe

COOMe

MeOOC

COOMeMe Me

H

MeOOC

COOMe

Enant.

The possession of enantiofaces isn’t restricted to isolated double bonds.

H Me

COOMe

COOMe


Double Bond Double Bond Prochirality Prochirality Prochiral Prochiral ((ProstereogenicProstereogenic) ) CentresCentres

H3COH

HHpro-R

pro-S

H3COH

HD

H3COH

DH

entantiotopic

CH2COOH

CH2COOH

H

HOMeOH/H+

CH2COOH

CH2COOMe

H

HO

CH2COOMe

CH2COOH

H

HO

pro-S

pro-R


Identification of the individual enantiotopic atoms or groups uses an obvious extension of Cahn-Ingold-Prelog convention:One or other of two atoms or groups is assigned priority over the other (e. g. by substituting D for H or 18O for 16O), but the priority of the remaining two substituents is not affected.

The resulting configuration (R or S) defines the atom or group promoted as pro-R or pro-S.

Identification of the individual enantiotopic atoms or groups uses an obvious extension of Cahn-Ingold-Prelog convention:One or other of two atoms or groups is assigned priority over the other (e. g. by substituting D for H or 18O for 16O), but the priority of the remaining two substituents is not affected.

The resulting configuration (R or S) defines the atom or group promoted as pro-R or pro-S.



HOOC COOHHH

HOOC COOHHD

HOOC COOHDH

Two enantiotopic atoms or groups in a molecule are not necessarily substituents on the same carbon atom:the two hydrogen atoms in the meso-diacid are also enantiotopic since…

Two enantiotopic atoms or groups in a molecule are not necessarily substituents on the same carbon atom:the two hydrogen atoms in the meso-diacid are also enantiotopic since…



13

Prochirality Prochirality ------DiastereofacesDiastereofaces

a

cb

[O]

a

cb

Oa

cb

O

diastereoisomers


- Δ G≠ = RTlnkΔ Δ G≠ = - [Δ G≠(1) - Δ G≠(2)] = RTln(k1 / k2)

If k1 / k2 = 100, Δ Δ G≠ = 11.5 kJ / mol

- Δ G≠ = RTlnkΔ Δ G≠ = - [Δ G≠(1) - Δ G≠(2)] = RTln(k1 / k2)

If k1 / k2 = 100, Δ Δ G≠ = 11.5 kJ / mol

a

cb [O]

a

cb

[O]


Prochirality Prochirality ------DiastereofacesDiastereofaces

DiastereotopicDiastereotopic Atoms or GroupsAtoms or Groups

diastereoisomers

a

cb

z HH

a

cb

z HD

a

cb

z DH

diastereotopic

Br

COOHF

Me

Cl

MeBr

COOHF

Ph

Cl

Ph


HOOC COOHH OH

H H HOOC COOHH OH

D H

HOOC COOHH OH

H D

a ac

RBRBRA RA

b

2 × RA and 2 × RB


DiastereotopicDiastereotopic Atoms or GroupsAtoms or Groups

Diastereotopic atoms or groups also are not necessarily bound to the same atom.

Diastereotopic atoms or groups also are not necessarily bound to the same atom.

Br

F

Me

H

H

Me

Br

F

Me

H

H

Et

Br

F

Et

H

H

Me


DiastereotopicDiastereotopic Atoms or GroupsAtoms or Groups Homotopic Homotopic Faces and GroupsFaces and Groups

COOMeCOOMe

OR1

H

OR1

HH

COOMe

OR1

H

OR1

H COOMeR

COOMe

OR1

H

OR1

H COOMe

H

R


14

HOH

H H

H HH H

H

H

HH

H

H

OH OH

Me MePhPh

OH OH

Ph MePhMe


Homotopic Homotopic Faces and GroupsFaces and Groups Reaction of Reaction of DiastereofacesDiastereofaces

a

cb [O]

a

cb

O

a

cb

OR R R R

S+

It has been pointed out above that, in principle, an achiral reagent can distinguish between two diastereofaces of a double bond.

It has been pointed out above that, in principle, an achiral reagent can distinguish between two diastereofaces of a double bond.


Asymmetric induction

(R) + (S)

either or

(R,R) + (S,S) (R,S) + (S,R)


Reaction of Reaction of DiastereofacesDiastereofaces

Intermolecular Asymmetric Introduction

Enantiofaces react at the same rate with achiral reagents since the two transition state energies involved are identical.

Enantiofaces react at the same rate with achiral reagents since the two transition state energies involved are identical.


Reaction of Reaction of EnantiofacesEnantiofaces

For one enantioface to react in preference to the other they must be converted into diastereofaces.

For one enantioface to react in preference to the other they must be converted into diastereofaces.

However, it is not mandatory that the two faces of the alkene are diastereofaces from the outset of the reaction.However, it is not mandatory that the two faces of the

alkene are diastereofaces from the outset of the reaction.



G

Reaction coordinate

H H

ba

x y*

y* x

H Ha b

y* x

a bHH

y* x

a bHH

Ha b

y* x

H



15

2

BHMe tBu

Me tBuH HB H

2

NaOH, H2O2, MeOH

Me tBuH H

HO H

R 76 %, 60 % ee



G

Reaction coordinate

b

a

x y

y x

ba

y* x

a b

y* x

a b

a

y* x

bS*

S*

S*

S*

S*



OHPh

Me

OPh

Me

Me2NNMe2

OMe

OMe

hv, 52%

OH

OH

MePh

MePh

Ph

MeO

OHPh

Me

OHMe

Ph

OHMe

Ph

meso-isomer

8.3 % e.e.



a

cb

[O]

a

cb

Oa

cb

O

diastereoisomers

Sharpless Sharpless OxidationOxidation


G

Reaction coordinate

b

a

x y*

b

a

b

ax y*

x y*

ba

x

y*

ba

xy*

x

ba

ba

x

more lessy*


Reaction of Reaction of EnantiofacesEnantiofaces Asymmetric InductionAsymmetric Induction

G

Reaction coordinate

b

a

bH

x y*

bax

H b

y*

bax

b H

y*

bax

H b

y*

bax

b H

y*

b

bHa

xb

Hba

x

y*

more less


in Reaction of Enantiotopic Atoms or Groups

16

1.3. Determining Enantiomer Composition

1.3. Determining Enantiomer Composition


Measuring Specific RotationMeasuring Specific Rotation

optical purityOne of the terms for describing enantiomer composition

Refers to the ratio of observed specific rotation to the maximumor absolute specific rotation of a pure enantiomer sample

Drawbacks:1) The specific rotation of the pure enantiomer;2) Affected by numerous factors;3) A large quantity of the sample;4) Chemically pure sample for measurement.

Many enantiomer compositions determined by this method in earlier years were incorrect


The NMR MethodThe NMR Method

1. Measured in a chiral solvent or with a chiral solvating agent

2,2,2-trifluoro-1-phenylethanol, 19F NMR in (-)-α-phenylethylamine

O

C3F7

O

Eu3



2. Measured with a chiral chemical shift reagent 2. Measured with a chiral chemical shift reagent

H

OH

S

H1. Me3OBF42. NaOH(10 %)

OH

H


3. Chiral Derivatizing Agents3. Chiral Derivatizing Agents

COOH

CF3

OCH3

COOH

CF3

OCH3

(R)-Mosher's Acid (S)-Mosher's Acid

CH2NH2

CF3

OCH3

CH2NH2

CF3

OCH3

(R)-Mosher's Amine (S)-Mosher's Amine



4. Other New Agents4. Other New Agents

HO

HO

COOR

COOR

PCl3 +COOR

COOROP

OCl R*OH

2 min

COOR

COOROP

OR*O

HO

31P NMR 1.5 ppm 0.7 ppm 1.5 ppm

MeOH

OH



17

4. Other New Agents4. Other New Agents

NP

N

CH3

CH3

N

CH3

CH3

+ R*OH S8N

PN

CH3

CH3

OR*

S

PO

OO

ClP

N

OPh

Z

Y

CH3

OOP

O Cl

NP

N

CH3

CH3

OR*

Z = S, O,Y = Cl, NHR*, OR*


The NMR MethodThe NMR MethodDetermining the enantiomer composition of

chiral glycol or cyclic ketonesDetermining the enantiomer composition of

chiral glycol or cyclic ketones

O

Pr

+

R

HO OH*

PrOO

R*

PrOO

R*

*

O

R

+

Ph

H2N NH2

Ph

*R

NHHN

PhPh13C NMR or chiral HPLC


Measurement of the EnantiomerMeasurement of the Enantiomer

1) Chromatographic methods using chiral colummnsa. Gas chromatographyb. Liquid chromatography

2) Capillary Electrophoresis with enantioselective supporting electrolytes

1) Chromatographic methods using chiral colummnsa. Gas chromatographyb. Liquid chromatography

2) Capillary Electrophoresis with enantioselective supporting electrolytes

Other MethodsOther Methods


Determining Absolute ConfigurationDetermining Absolute Configuration

1) X-Ray Diffraction Methods2) Chiroptical Methods3) The Chemical Interrelation Method4) Prelog’s Method5) Horeau’s Method6) NMR

1) X-Ray Diffraction Methods2) Chiroptical Methods3) The Chemical Interrelation Method4) Prelog’s Method5) Horeau’s Method6) NMR


General Strategies for Asymmetric SynthesisGeneral Strategies for Asymmetric Synthesis

1. Chiron Approaches

2. Acyclic Diastereoselective Approaches

3. Double asymmetric Synthesis

1. Chiron Approaches

2. Acyclic Diastereoselective Approaches

3. Double asymmetric Synthesis


Chiron ApproachesChiron Approaches

A great number of natural compounds have been employed as chiral starting materials for asymmetric syntheses.

A great number of natural compounds have been employed as chiral starting materials for asymmetric syntheses.

O

O

Me

Me

HO

MeHO

O

CHO

OH

HO

CHO

CH2OH

OH

OH

HO

OH

CHO(+)-exobrevicomin


18

H2NNH

N COOH

OH NH2 O CH3

COOH

H2N

OH

CH2NH2

.

.CH2OH

HO

OH

CHO

HO

OH

Naturally occurring chiral compounds provide an enormous range and diversity of possible starting materials.

Natural CarbohydratesAmino Acids

Naturally occurring chiral compounds provide an enormous range and diversity of possible starting materials.

Natural CarbohydratesAmino Acids

negamycin


Chiron ApproachesChiron Approaches AcyclicAcyclic Diastereoselective ApproachesDiastereoselective Approaches

1. Substrate-controlled methods;2. Auxiliary-controlled methods;3. Reagent-controlled methods;4. Catalyst-controlled methods.

1. Substrate-controlled methods;2. Auxiliary-controlled methods;3. Reagent-controlled methods;4. Catalyst-controlled methods.


SubstrateSubstrate--Controlled MethodsControlled Methods

The substrate-controlled reaction is called the first generation of asymmetric synthesis. It is based on intramolecular contact witha stereogenic unit that already exists in the chiral substrate.

The substrate-controlled reaction is called the first generation of asymmetric synthesis. It is based on intramolecular contact witha stereogenic unit that already exists in the chiral substrate.

S* P*R


AuxiliaryAuxiliary--controlled methodscontrolled methods

The auxiliary-controlled reaction is referred to as the second generation of asymmetric synthesis. This approach is similarto the first generation method in which the asymmetric control is achieved intramolcularly by a chiral group in the substrate.

The auxiliary-controlled reaction is referred to as the second generation of asymmetric synthesis. This approach is similarto the first generation method in which the asymmetric control is achieved intramolcularly by a chiral group in the substrate.

S + A* P-A*R P*


ReagentReagent--Controlled MethodsControlled Methods

The reagent-controlled reaction is called the third generation of asymmetric synthesis. It is based on an achiral substrate directly converted to the chiral product using a chiral reagent..

The reagent-controlled reaction is called the third generation of asymmetric synthesis. It is based on an achiral substrate directly converted to the chiral product using a chiral reagent..

S R*P*

S* R*P*


CatalystCatalyst--Controlled Methods.Controlled Methods.

The most significant advance in asymmetric synthesis in the pastthree decades has been the application of chiral catalysts to induce the conversion of achiral substrates to chiral products

The most significant advance in asymmetric synthesis in the pastthree decades has been the application of chiral catalysts to induce the conversion of achiral substrates to chiral products

S Cat*

P*

S Cat / L*

P*


19

Double Asymmetric SynthesisDouble Asymmetric Synthesis

Pioneered : Horeau, A. 1968;Reviewed: Masamune, S. 1985.

The idea involves the asymmetric reaction of an enantiomerically pure substrate and an enantiomerically pure reagent. There are also reagent-controlled reactions and substrate-controlled reactions in this category.

*A C(x) I *A

*B C(y)

II*A *C *C *B

(*Cn)-C(z)

III


HO

O

O

OCH3

H

HO

Re

Si

O OXR

O OXR

1:4.5



O HCH2Ph

OM

Re

Si

O

YR

OX

O

YR

OX

1:8

OCOCH2Ph

O HCH2Ph

OM

Si

Re



O HCH2Ph

OM

Re

Si

O

YR

OXR

O

YR

OXR

1:40

O HCH2Ph

OM

Si

Re

O

O

OCH3

H



QuestionsQuestions

Asymmetric and Dissymmetric

D / L and d / l

Racemic, meso, racemization, and scalemic

syn / anti and erythro / threo

Asymmetric and Dissymmetric

D / L and d / l

Racemic, meso, racemization, and scalemic

syn / anti and erythro / threo


Prochirality:

Pro-R and Pro-S:

Optical activity, optical isomer, and optical purity

Re and Si

Prochirality:

Pro-R and Pro-S:

Optical activity, optical isomer, and optical purity

Re and Si


QuestionsQuestions

20

x y

a

b

c

b

a

b

a

b

a

b

a

b

a

b

a


QuestionsQuestions

Asymmetric Organic Reactions and the Classification


Chapter 2Chapter 2

OutlineOutline

2.1. Common Classification2.2. Stereoselective Synthesis of Molecules

Having Two Chiral Centres2.3. New Classification

Classification of Stereochemical Reactions

2.1. Common Classification2.2. Stereoselective Synthesis of Molecules

Having Two Chiral Centres2.3. New Classification

Classification of Stereochemical Reactions


2.1. 2.1. Common ClassificationCommon Classification

2.1.1. α-Alkylation and Catalytic Alkylation of Carbonyl Compounds;

2.1.2. Aldol and Related Reactions;2.1.3. Asymmetric Oxidations;2.1.4. Asymmetric Diels-Alder and Other

Cyclization Reactions;2.1.5. Asymmetric Catalytic Hydrogenation and

Other Reduction Reactions;2.1.6. Enzymatic Reactions and Miscellaneous

Asymmetric Syntheses

2.1.1. α-Alkylation and Catalytic Alkylation of Carbonyl Compounds;

2.1.2. Aldol and Related Reactions;2.1.3. Asymmetric Oxidations;2.1.4. Asymmetric Diels-Alder and Other

Cyclization Reactions;2.1.5. Asymmetric Catalytic Hydrogenation and

Other Reduction Reactions;2.1.6. Enzymatic Reactions and Miscellaneous

Asymmetric Syntheses


αα--AlkylationAlkylation and Catalytic and Catalytic AlkylationAlkylationof Carbonyl Compoundsof Carbonyl Compounds

1) Preparation of Quaternary Carbon Centres;

2) Preparation of α-Amino Acids;

3) Nucleophilic Substitution of Chiral Centres;

4) Chiral Catalyst-induced Aldehyde Alkylation

5) Catalytic Asymmetric Addition of Dialkylzinc to Ketones;

6) Asymmetric Cyanohydrination

7) Asymmetric α-Hydroxyphosphonylation

1) Preparation of Quaternary Carbon Centres;

2) Preparation of α-Amino Acids;

3) Nucleophilic Substitution of Chiral Centres;

4) Chiral Catalyst-induced Aldehyde Alkylation

5) Catalytic Asymmetric Addition of Dialkylzinc to Ketones;

6) Asymmetric Cyanohydrination

7) Asymmetric α-Hydroxyphosphonylation


Preparation of Quaternary Carbon Preparation of Quaternary Carbon CentresCentres

NH2

OHR

HOOC

ON

O

O

R

1. LDA, THF

2. R'XN

O

O

R

R'

bucyclic lactamR = Me, Ph

endo : exo = 9-30 : 1for R = Ph1 -1.5 : 1 for R = Me

1. LDA, THF

2. R''XN

O

O

R

R''

R'

75-95 % de for R = Ph90-93 % de for R = Me

H2SO4 / BuOH

(R = Ph) Ph CO2Bu

O R'' R'

1. Red-Al2. Bu4NH2PO4 Me CHO

O R'' R' HO-

O

R'R''

-OH从下面进攻,由-iPr的构型诱导

R′从下面进攻,由-iPr和R的构型共同

诱导


21

N

OA B

O

Me

s-BuLiPhCH2Br-100 oC

N

OA B

OLi

Me

N

OA B

O

Me

CH2Ph

N

OA B

O

CH2Ph

Me

endo

exo

3169HH63070MeH52080Hi-Pr4298Phi-Pr3298Met-Bu2397Mei-Pr1

exoendoBA


Preparation of Quaternary Carbon Preparation of Quaternary Carbon CentresCentres Preparation of Preparation of αα--Amino AcidsAmino Acids

N

N

MeO

OMe

Me

Me1. BuLi

2. RX N

N

MeO

OMe

Me

Me

R

92-95 % de

H3O+

H2N

OMe

Me

R

O

N

N

MeO

OMe1. BuLi

2. RX N

N

MeO

OMe

R

> 98 % de

H3O+

H2N

OMe

H

R

O

R从上面进攻,由Me的构型诱导


NucleophilicNucleophilic Substitution of Chiral Substitution of Chiral CentresCentres

Me

O

R'

R''

O Me

Nu-

Bu2AlHEt2O, -78 oC64 - 95 % R' H

OR'' OH

77Mec-C6H13

96MePh92Mec-C6H11

de (%)R’’R’

R‘和R’‘的摆向由两者的相对大小决定,Nu-从直立键Me的背面进攻


Chiral CatalystChiral Catalyst--Induced Aldehyde Induced Aldehyde AlkylationAlkylation

H

O

Et2Zn

10 % Catalyst

Et

OH

N

O

ZnEt(R)-product, 38 % ee

NH2

OZnEt

(S)-product, < 5 % ee

N

OPh

Ph

EtZn

(S)-product, 100 % ee


N

OPh

Ph

EtZn ZnEt

EtOH

Ph

六元环椅式过渡态,iPr的摆向决定了Nu的进攻方向


Chiral CatalystChiral Catalyst--Induced Aldehyde Induced Aldehyde AlkylationAlkylation Catalytic Asymmetric Addition of Catalytic Asymmetric Addition of DialkylzincDialkylzinc to to KetonesKetones

R2R1

OZnPh2

toluene1.5 eq. MeOH

3.5 eqR2R1

HO Ph

Me2N

HO

Fu, G. C. Dosa, P. I. J. Am. Chem. Soc. 1998, 120, 445.Ramon, D. J.; Yus, M. Tetrahedron 1998, 54, 5651.

Tetrahedron Letter. 1998, 39, 1239.

Fu, G. C. Dosa, P. I. J. Am. Chem. Soc. 1998, 120, 445.Ramon, D. J.; Yus, M. Tetrahedron 1998, 54, 5651.

Tetrahedron Letter. 1998, 39, 1239.


22

Catalytic Asymmetric Addition of Catalytic Asymmetric Addition of DialkylzincDialkylzinc to to KetonesKetones

RPh

O ZnR'2toluene

Ti(OPri)RPh

HO R'

OH

H

SO2

NH

e.e. > 89 %


2.1.2. 2.1.2. AldolAldol and Related Reactionsand Related Reactions

1) Substrate-Controlled Aldol Reactions;

2) Reagent-Controlled Aldol Reactions;

3) Chiral Catalyst-Controlled Asymmetric Aldol Reactions;

4) Double Asymmetric Aldol Reactions;

5) Asymmetric Allylation Reaction;

6) Asymmetric Allylation and Alkylation of Imines

7) Henry Reactions

1) Substrate-Controlled Aldol Reactions;

2) Reagent-Controlled Aldol Reactions;

3) Chiral Catalyst-Controlled Asymmetric Aldol Reactions;

4) Double Asymmetric Aldol Reactions;

5) Asymmetric Allylation Reaction;

6) Asymmetric Allylation and Alkylation of Imines

7) Henry Reactions


SubstrateSubstrate--Controlled Controlled AldolAldol ReactionsReactions

ON

O

RO

ON

O

RO

Ph

Oxazolidones as chiral Auxiliaries

ON

O

ROB(Bun)2

NOR

OB(Bun)2O

Z-enolate


ON

O

R

OB(Bun)2

ON

O

RO

R2BOTf

i-Pr2NEt

R'CHO

O

BOH

R'R

Bun

Bun

N

O

O

ON

O

O

R'R

OH

MeO

O

R'R

OHMeONa



ON

O

ROB(Bun)2

PhO

N

O

RO

Ph R2BOTf

i-Pr2NEt

R'CHO

ON

O

O

R'R

OH

PhMeO

O

R'R

OHMeONa



ON

O

OB(Bun)2

OHCO

N

O

O OH

ON

O

O OH

1.75 : 1

无手性辅基诱导选择性较低



23

ON

O

ROB(Bun)2

Ph OHCO

N

O

O OHPh

ON

O

O OH

Ph

600 : 1


SubstrateSubstrate--Controlled Controlled AldolAldol ReactionsReactions PyrrolidinesPyrrolidines as chiral Auxiliariesas chiral Auxiliaries

NH

MOMO

MOMO

N

MOMO

MOMO

O

N

MOMO

MOMO

OM

RCHON

MOMO

MOMO

O OH

HO

O OH

非对映选择性类似Evans助剂


H

R

N

MOMO

OMOMH

Me OZrLn

O


PyrrolidinesPyrrolidines as chiral Auxiliariesas chiral Auxiliaries

N

MOMO

MOMO

RO

N

MOMO

MOMO

O

R'R

O

1. BuLi

2. R'COCl

Zn(BH4)2

KBEt3H

N

MOMO

MOMO

O

R'R

OH

N

MOMO

MOMO

O

R'R

OH

syn

anti

构型相反

构型相反

两手性中心构型相反


PyrrolidinesPyrrolidines as chiral Auxiliariesas chiral Auxiliaries

AminoalcoholsAminoalcohols as Chiral Auxiliariesas Chiral Auxiliaries

R*O OTMS

RCHOTiCl4

Me2N

TiOOPh

H H

ClCl

Cl

OH

Me

Me2N

TiOOH

Ph H

ClCl

Cl

OH

Me

anti-product 77% syn-product 23 %

E-enolate得到anti-product


AcylsultamAcylsultam Systems as Chiral AuxiliariesSystems as Chiral Auxiliaries

O

N(Ar)SO2Ph

OTBS

i-PrCHO

TiCl4 R*O

O

Me

OH

+ syn

O 2S

N

O

E t2B O Tfi-P r2N E t

S

N

O B E t2

R C H OTiC l4

R *N R

O HO

R *N R

O HO

a b

anti: syn = 93 :7


24

93/0/70.5TiCl4

97/0/31TiCl4

98/0/22TiCl4

78/0/222Et2BOTf27/37/362Et2AlCl

b/a/others

Mole equiv. of Lewis acid / EtCHO

Lewis acid


AcylsultamAcylsultam Systems as Chiral AuxiliariesSystems as Chiral Auxiliaries αα--SillylSillyl KetonesKetones

H3C

TBS

O

H3CO

R

OH

d.e. 92-98 %, e.e. > 98 %

H3C

TBS

OBBu2RCHO H3C

O

R

OH

TBS

d.e. 92-98 %, e.e. > 98 %

HBF4


R1 OR2

H

OM

R4

R3

R1 R4R2

OOH

R3

O

BO

R3

R4L

LHR1H

HR2

R1 R4R2

OOH

R3

O

BO

H

R4L

LHR1HR3

R2

R1 R4R2

OOH

R3

O

BO L

LH

R2

HR1R3

H

R4

R1 R4R2

OOH

R3

O

BO L

LH

R2

HR1H

R3

R4

R1 R4R2

OOH

R3

L

Re-attack;(Z)-enolate

Re-attack;(E)-enolate

Si-attack;(Z)-enolate

Si-attack;(E)-enolate


αα--SillylSillyl KetonesKetones ReagentReagent--Controlled Controlled AldolAldol ReactionsReactions

Aldol Condensations Induced by Chiral Boron Compounds

BOTf

BOTf

BN

O

Me

Ph

OMe


BOTf

O

N i-Pr2NEt2

B

O

N

1. RCHO2. 3N H2SO43. CH2N2

RCOOMe

OH

Me

RCOOMe

Me

OHsyn anti

RCHOn-PrCHO

c-HexCHO

n-BuCHO

e.e. % for anti7784

79

anti : syn

91: 995 : 594 : 6


ReagentReagent--Controlled Controlled AldolAldol ReactionsReactions

O

BN L

L

Me

O

H

R

O

BN L

LO

R

H

Me

H和R互换


ReagentReagent--Controlled Controlled AldolAldol ReactionsReactions

25

AldolAldol Reactions by CoreyReactions by Corey’’s Reagentss Reagents

Corey’s Reagents

BNN

Ph Ph

SO2ArArSO2

Br

a: Ar: p-CH3C6H4

b: Ar: p-NO2C6H4


AldolAldol Reactions by CoreyReactions by Corey’’s Reagentss Reagents

C6H5S

Oa

RCHO C6H5S

O

R

HO H

R = Ph, 91 % e.e.R = i-Pr, 83 % e.e.

C6H5S

Ob

RCHO C6H5S

O

R

HO H

H

R = Ph, 95 % e.e.R = i-Pr, 97 % e.e.

syn/anti = 98.3 : 1.7 syn/anti = 94.5 : 5.5

O

BOH

RR'

H

C6H5S N

N

Ph

Ph

ArSO2

SO2Ar

构型相反

Ph的构型促使ArSO2向内


AldolAldol Reactions by Miscellaneous ReagentsReactions by Miscellaneous Reagents

R1 R2

OH O

R1 R2

OH O

BOTf

OLi

OBut

TiDAGOO

ODAG

OBut

RCHO

R OBut

OH O

OO

O

O

OOH


Asymmetric Asymmetric AldolAldol Reactions by Chiral catalyst Reactions by Chiral catalyst

Mukaiyama’s Reactions

R'

ORRCHOL. A. R'

O

R

OH


NS

S O

Sn(OTf)2

NEt

N

Me

N NS

S OSnTfO

N N

RCHONS

S O OH



CHOTMSBnO

OPh

OTMSNCH3

NH

Sn(OTf)2SnO

OPhTMS

OH

OH

O

H27C13 OH

OH

NHBOC

87 % syn/anti = 97 : 3 91 % e.e. for syn

10 steps with 15 % overall yieldD- erythro-sphingosine (without BOC)



26

A Chiral A Chiral FerrocenylphosineFerrocenylphosine--Gold ComplexGold Complex

PPh2PPh2

NMeCH2CH2NR2

H

Fe

RCHO + CNCH2COOCH31 mol % [Au(c-HexCN)2]BF4

R: Me, Et

NO

R COOCH3

+ NO

R COOCH3

R = Ph, 90 % trans : cis = 89 : 11; trans e.e % > 90 %


Chiral Lewis AcidsChiral Lewis Acids

H

R

OM

XL1

L2

R

OX M

H

L1L2

OMO

H

R L1L2

H-binding stacking chelationπ-


NN

OO

R RCu

2+

2OTf-

R: CMe3; CHMe2; Ph; Bn

NN

OO

R RCu

2+

2SbF6-


2+

2OTf-


N

O

R

N

O

R

NCu

2+

2SbF6


N

O

R

N

O

R

NCu



BnOH

O OTMS

RBnO

R

OH O

RCHOOO

OTMS

2 mol %[CuF2((S)-Tol-BINAP] OO

OR

OH



Bimetallic Catalysts: Bimetallic Catalysts: ShibasakiShibasaki’’s Systems System

O

M1

O

O O

OOM2

M2

M2


Ba(OPri)2 OH

OMe DMEr. t.

i-PrOH

DME(R)-BaBM

RCHO + Ph

O (R)-BaBM5-mol %

DME , -20 oCPh

O

R

OH

R Y ie ld % e . e . %

t-B u 7 7 6 7P h C H 2(C H 3 )2C

c -C 6H 1 1

i-C 3 H 7

B n O C H 2 (C H 3 )2C

B n O (C H 3)2 C

7 78 7

9 18 3

9 9

5 55 4

5 06 9

7 0


Bimetallic Catalysts: Bimetallic Catalysts: ShibasakiShibasaki’’s Systems System

27

Double Asymmetric Double Asymmetric AldolAldol ReactionsReactions

MeOOC CHO

O

SPh

B MeOOCSPh

OH O

MeOOCSPh

OH O

3:2


R: PhCH2OCH2CH2: OB(n-C4H9); 28:1OB(C-C5H9); 100:1

R: (CH3)CH: OB(n-C4H9); >100:1OB(C-C5H9); no reaction

R: PhCH2OCH2CH2: OB(n-C4H9); 28:1OB(C-C5H9); 100:1

R: (CH3)CH: OB(n-C4H9); >100:1OB(C-C5H9); no reaction

O

t-BuMe2SiO H

B

R'CHO

R'

OH O

OSiMeBut

R'

OH O

OSiMeBut

R: PhCH2OCH2CH2; a:b = 16:1 (CH3)2CH > 100:1

a

b



BO

Me SCEt3

MeOOC CHO

O

O

COR

4,5-anti-matched case: 200 : 1

BO

Me SCEt3

MeOOC CHO

O

O

COR

4,5-syn-mismatched case: 55 : 1

O

BO

H

CH3R1H

Me

Et3CS

H

O

BO

H

SCEt3HR1H3C

H3CH



O

t-BuMe2SiO H

B

MeOOC CHO MeOOCR*

OH O

MeOOCR*

OH O

matched pair a:b > 100:1

a

b



O

t-BuMe2SiO H

B

MeOOC CHO MeOOCR*

OH O

MeOOCR*

OH O

mismatched pair a:b = 1:30

a

b


Double Asymmetric Double Asymmetric AldolAldol ReactionsReactions Asymmetric Asymmetric AllylationAllylation ReactionsReactions

Me M

M

Me RCHOR

OH

MeR

OH

Me

M: SiMe3, SnBu3, BR2, AlR2, MaX, Li, CrX2, TiCp2X, ZrCp2X, InBr


28

The Roush ReactionThe Roush Reaction

B O

O

COOR

COORB O

O

COOR

COOR B O

O

COOR

COOR


B O

O

COOR

COOR

B O

O

COOR

COOR

RCHO4 A molecular sieves R

OH

RCHO4 A molecular sieves R

OH


The Roush ReactionThe Roush Reaction

BO O

OCOOR

ORO

H

R'Me

Hfavored

O

B O

O

ORO

Me

H

H

R'

OR

O


The Roush ReactionThe Roush Reaction The Corey ReactionThe Corey Reaction

BNN

Ts Ts

Br

Ph Ph

BNN

Ts Ts

Ph Ph

BNN

Ts Ts

Ph Ph

RCHO

O

BN

N

Ts

Ts

Ph

Ph

R

H R

HO H


BNN

Ts Ts

Ph Ph

X

RCHO

O

BN

N

Ts

Ts

Ph

Ph

R

HX R

HO HX

X: Br, Cl

Catalytic Asymmetric Catalytic Asymmetric AllylationAllylation ReactionsReactions


R

HO HX

R

HO H

R

HO H

OO HR

H2C

R

H OCH2OCH3TMS

R

H OCH2OCH3

HO

R

H OCH2OCH3O

R

H OHO

R

H OCH2OCH3

SnBu3


AllylicAllylic CompoundsCompounds

29

Asymmetric Asymmetric AllylationAllylation and and AlkylationAlkylation of Iminesof Imines

H

NTMS B

21.

2. H3O+

H NH2

BNN

Ts Ts

Me Ph

H

NTMS

N

BN

N

Me

PhTs

Ph

HTMS

Ts Ph

NH2


Cat.R

PdCl

PdCl

R

N

R1 H

R2

SnBu3R1

NHR2


Asymmetric Asymmetric AllylationAllylation and and AlkylationAlkylation of Iminesof Imines

ON

PhBu3Sn LA

O

H

H

NLA

Ph

SnBu3

O

N Ph

H

H H


Asymmetric Asymmetric AllylationAllylation and and AlkylationAlkylation of Iminesof Imines The Henry ReactionThe Henry Reaction

OLiOLi

LaCl3NaOHH2O

optically active La catalyst

CHO CH3NO210 mol% NO2

OH

O CHO

CH3NO2La-(R)-BINOL

O NO2

OH

80 %, 92 % e.e.


2.1.3. 2.1.3. Asymmetric OxidationsAsymmetric Oxidations

R2

R1

R3

OH

"O"(S,S)-D-(-)tartrate(unnatural)

(R,R)-L-(+)tartrate(unnatural)

"O"


Characteristics• Simplicity: all the ingredients are inexpensive and

commercially available;• Reliability: It succeeds with most allylic alcohols,

although bulky substituents at R are deleterious;• High optical purity: optical purity of the product is generally

> 90 % e.e. and usually > 95 %;• Predictable absolute stereochemistry:•Relative insensitivity to preexisting chiral centers;•Versatility of 2,3-epoxy alcohols as intermediates.

Characteristics• Simplicity: all the ingredients are inexpensive and

commercially available;• Reliability: It succeeds with most allylic alcohols,

although bulky substituents at R are deleterious;• High optical purity: optical purity of the product is generally

> 90 % e.e. and usually > 95 %;• Predictable absolute stereochemistry:•Relative insensitivity to preexisting chiral centers;•Versatility of 2,3-epoxy alcohols as intermediates.


Sharpless EpoxidationSharpless Epoxidation ReactionsReactions

30

MechanismMechanism

TiOO

O

OO

OTiOO

O

O

OTiOO

O

OOTi

OO

O

O

HO

TiOO

O

O

HO

O

OOH

OH


OO OH

Ti(OPri)4

t-BuOOH

OO OH

O

OO OH

O+

no catalyst: a : b = 2.3 :1(+)-DET: mismatched a : b = 1 : 22;(-)-DET, matched a : b = 90 : 1

a b

Double Asymmetric Induced Double Asymmetric Induced EpoxidationEpoxidation ReactionsReactions


OH

OO (+)-DET

OH

OO

OOH

OO

O

30 : 1

OH

OO

(-)-DET

OH

OO

O OH

OO

O

3 : 2


Double Asymmetric Induced Double Asymmetric Induced EpoxidationEpoxidation ReactionsReactions

R'

+R''

O

L. A.R'

O

R''

exo

endo

exo

endo

Asymmetric DielsAsymmetric Diels--Alder ReactionsAlder Reactions


Chiral Chiral DienophilesDienophiles

O

OR*

R*

O

NR2*

O

Chiral Dienes

O

O

Ph

H OMe

There are few reports about chiral auxiliary-attached dienecomponents due, in part, tothe difficulty of the preparation of the modified dienes


Asymmetric Dipolar Asymmetric Dipolar CycloadditionCycloaddition

HNSO2

COCl

NSO2

ORCNO

NSO2

O

N OR

L-selectrideOH

N OR


31

R

NMe

O-

H

H

X

Cr(CO)3

H

R

NMe

O-

H

X

H

Cr(CO)3

H

endo-transition state (A) to cis

exo-transition state (A) to trans

N+

H

O- MeTMS

Cr(CO)3

Ph

CAN

R

TMS ONX

H3C

3R 5S

TMS

N+

H

O- Me

Ph

CAN

TMS

ONX

H3C

3S 5R

Cr(CO)3

Cerium ammonium nitrate

(-)-

(+)-


Asymmetric Dipolar Asymmetric Dipolar CycloadditionCycloaddition 2.1.5. 2.1.5. Asymmetric Catalytic Reduction ReactionsAsymmetric Catalytic Reduction Reactions


2.1.6. 2.1.6. Enzymatic Reactions and Enzymatic Reactions and

Miscellaneous Asymmetric SynthesesMiscellaneous Asymmetric Syntheses


2.2 2.2 Molecules with Two Chiral Molecules with Two Chiral CentresCentres

Racemic: relative configurationEnantiopure: absolute configuration

cb

a

p

q

ab

yxp

x z

y

p

ra

qx


To maximize the yield of compound 1 with, and to minimize the yiled of its diastereoisomer 1’, four method are empolyedTo maximize the yield of compound 1 with, and to minimize the yiled of its diastereoisomer 1’, four method are empolyed

cb

ap

x z

y

cb

ap

xy

z1 1'



Method A:Starting materials having chiral centres in 1 already in place

Method A:Starting materials having chiral centres in 1 already in place

OH

OH

HO

HO

HO

OH

HOHO H

OH

OH

OH

OHH

O

ZnCl2

H

OH

OHH

OO

O

O

1. MeSO2Cl, Pyr2. NaI, DMF, Zn

H HO

O

O

O1. Pd/C, H22. HOAc, H2O

HOHO H

OH

OHH

Tetraol



32

x z

y

cb

a1

cb

a

x z

y

px z

y

cb

a



tBuOOCNH

COOH

R 1H

HN COOM e

H R 2

DCC

tBuOOCNH

CO

R 1H

H 2N COOM e

H R 2

+



Method B:Starting materials having chiral centres in 1 already in place

Method B:Starting materials having chiral centres in 1 already in place



px

LG

z

cb

ay-

p

xzc

b

a y

p

xzc

b

a COR

mCPBA p

xzc

b

a OCOR

pc

b

a

zO

R2 R1

pc

b

a

zR2

R1

CHO

pc

b

a

zR2

LGR1

x-

pc

b

a

z

R2

R1

x



Method C:Creating both chiral centres in a reaction

Method C:Creating both chiral centres in a reaction

HO OH

b ya x

b y

xa

OsO4

+

H OH

b ya x

HO OH

b yxa

Br2

+H OH

b yxa

Br

yxBr

ba+Br

b a Br

yx

1. R2BH2. NaOH, H2O2


2.2 2.2 Molecules with Two Chiral Molecules with Two Chiral CentresCentresMethod D:Using a parent chiral centre in a precursor to control the configuration of newly created chiral centre

Method D:Using a parent chiral centre in a precursor to control the configuration of newly created chiral centre

a

b cp

y'

x z

a

b cp

y

zx

1' 1

a

b cp

y

xx

1''

x z

a

b cp

y

zx

1

a

b cp

1'' a

b cp

y

zx

1y'

zx



33

2.3 2.3 Classification of Classification of StereochemicalStereochemical Reactions Reactions

1) Type 0 Reactions; 2) Type 1 Reactions;3) Type 2 Reactions;4) Type 3 Reactions;5) Type 4 Reactions

1) Type 0 Reactions; 2) Type 1 Reactions;3) Type 2 Reactions;4) Type 3 Reactions;5) Type 4 Reactions


Reactions without no selectivityIn stereoselective synthesis, these reactions are carried out onsubstrates having one or more chiral centres, no new chiral centres are created and all bonds remain unbroken to the chiral centres which survive the reaction

Reactions without no selectivityIn stereoselective synthesis, these reactions are carried out onsubstrates having one or more chiral centres, no new chiral centres are created and all bonds remain unbroken to the chiral centres which survive the reaction

O

HSPh

1. PhMgBr

2. NH4Cl HPhHO

SPh

1. Me3O+BF4-

2. NaOH HPh

O

C10H21MgBr CuI

HPhHO

H23C11OH23C11

H O

Type 0 Reactions Type 0 Reactions


Reactions with either complete or retention of configuration at an existing chiral centre;

Reactions with either complete or retention of configuration at an existing chiral centre;

aX

bcNu- Nu

a

cb

inversiona

SnR3

bc

R1Li aLi

bc

R2Xa

R2

bc

overall retention

Type 1 ReactionsType 1 Reactions



Type 2 reactions involve the diastereoselective formation of a product containing at least two chiral centres from the reaction of one or more prochiral double bondscontained in one or more achiral starting materials using achiral reagents.

Cycoladdtions,Electrocyclic reactions

Sigmatropic rearrangementsAdditions to double bonds in which two chiral centres are created


x

y

a

b

[3,3]sigmatrpoicrearrangement

bx

y

a

+ enantiomer

y

ab

xcontotatory electrocyclic reaction

a

by

x

b

ax

yenantiomer

xa

b yRCO3H O

b ya x



Reactions involve the stereoselective formation of one or more additional chiral centres from the reaction of one or more prochiral double bonds contained in one or more achiral starting materials using achiral reagents;


Cycloaddition reactions;Electrocyclic reactionsSigmatropic rearrangementsAddition reactions to double bonds

Cycloaddition reactions;Electrocyclic reactionsSigmatropic rearrangementsAddition reactions to double bonds

Difference with Type 2:One and more existing chiral centres in the starting material, the reagents

or some part of the reaction ensemble.


34

2

BH t-BuMe

2

B H

Me Bu-tHH

NaOH

H2O2/MeOH

H

Me Bu-tHH

HO

R

99 % e.e.

76 %, 60 % e.e.



R1

R2 R3

OH(+)-diethyl tartrateCH2Cl2

Ti(OiPr)4, t-BuO2H(-)-diethyl tartrate

O OH

R3R2

R1

90 % e.e.

O

OH

R3R2

R1

90 % e.e.



Reactions are those which require the exercise of astereocontrol but do not involve the formation of

tetrahedral centres or other chiral elements;

i. Elimination from substrate containing two contiguous chiral centres;

ii. Addition to alkynes or allenes;iii. Substitution on a (usually already configured) double bond;iv. Sigmatropic rearrangement in which formation of

configured double bonds accompanies the loss of chiral centres;

v. Union of two functional groups with direct formation of the double bond;

vi. Addition-elimination using a molecule containing a double bond;



x

y

Oa

b

x

ya

bO

type II

x

y

Oa

b

c

d

x

ya

bO

c

d type III

O

c

d

O

c

d type IV

How to define the reaction having one chiral How to define the reaction having one chiral centrescentres??


QuestionsQuestions

ON

O

ROB(Bun)2

PhO

N

O

RO

Ph R2BOTf

i-Pr2NEt

R'CHO

ON

O

O

R'R

OH

PhMeO

O

R'R

OHMeONa

Please give the reasonable transition state of this reaction:


Type 0 Reactions:Reactions in Which no New Chiral

Centres Are Created


Chapter 3Chapter 3

35

OutlineOutline

1. Commercial Enantiopure Starting Materials;

2. Second-Rank Starting Materials;

3. Synthesis of Single Diastereoisomers Using Type 0 Reactions;

4. Bicyclic Compounds as Sources of Chiral Centres;

5. Readily Available Fissionable Bicyclic Compounds;

6. Fissionable Bridges;

7. Readily Available Fissionable Tricyclic Compounds

1. Commercial Enantiopure Starting Materials;

2. Second-Rank Starting Materials;

3. Synthesis of Single Diastereoisomers Using Type 0 Reactions;

4. Bicyclic Compounds as Sources of Chiral Centres;

5. Readily Available Fissionable Bicyclic Compounds;

6. Fissionable Bridges;

7. Readily Available Fissionable Tricyclic Compounds


Why?Why?

This type reaction necessary in this case will convert functional groups in the starting material into those required in the product.

This type reaction necessary in this case will convert functional groups in the starting material into those required in the product.

Starting materials:Readily available enantiopure having one, two, or more chiral centres.

Starting materials:Readily available enantiopure having one, two, or more chiral centres.


Since Type 0 reactions do not require stereoselectivity, it might be assumed that a synthesis consisting of only Type 0 reactions would not constitute a stereoselective one.

Since Type 0 reactions do not require stereoselectivity, it might be assumed that a synthesis consisting of only Type 0 reactions would not constitute a stereoselective one.

Stereoselective synthesis is now widely taken to be the synthesisof a single stereoisomer of the product by whatever means which include only Type 0 reactions if the chiral centres of the productare already in place in the starting materials.

Stereoselective synthesis is now widely taken to be the synthesisof a single stereoisomer of the product by whatever means which include only Type 0 reactions if the chiral centres of the productare already in place in the starting materials.


Why?Why?

The Type 0 reactions may also include the removal of superfluous chiral centres.The application of Type 0 reactions to a limited number of readily available enantiopure starting materials having one, two or more chiral centres is the means by which a much greater number of enantiopure products are made available.

The Type 0 reactions may also include the removal of superfluous chiral centres.The application of Type 0 reactions to a limited number of readily available enantiopure starting materials having one, two or more chiral centres is the means by which a much greater number of enantiopure products are made available.

These enantiopure products will often in turn be used for further transformations or they may be synthetic

targets themselves.

These enantiopure products will often in turn be used for further transformations or they may be synthetic

targets themselves.



Syntheses consisting of only Type 0 reactions will require a

knowledge of the availability of starting materials having

chiral cnetres in place with the correct relative or absolute

configuration for those required in the product.

Syntheses consisting of only Type 0 reactions will require a

knowledge of the availability of starting materials having

chiral cnetres in place with the correct relative or absolute

configuration for those required in the product.



NH

HO

NH2COOH

H

HOOC

(S)-glutamic acid

HNO2

OH

HOOCO 1. EtOH, H+

2. NaBH4

OH

HOH2CO 1. TsCl, Pyr.

2. NaN3, DMF OHO

N3

H2, Pd/C

NH

OHO BH3/THF

NH

HO



36

O

HSPh

1. PhMgBr

2. NH4Cl HPhHO

SPh

1. Me3O+BF4-

2. NaOH HPh

O

C10H21MgBr CuI

HPhHO

H23C11OH23C11

H O

OH23C11

H O


Type 0 ReactionsType 0 ReactionsHO

PhS

O Baker's yeast

OH

HHO

SPh

1. TsCl, Pyr2. NaOH H

O

SPh

SPh

OH

1. C10H21MgBr

2. H+

SPh

HO C11H23H

1. Me3O+BF4-

2. NaOH

O

C11H23H

HO C11H23H

O

O

10 % H2SO4

C11H23H

OHO

PCC

C11H23H

OO

O

O

CuMgBr)2



O

O H

HO

HO HO

CH2

CH2

CH2

H OH

HHO

CH2COCH3

CH3CH2OH

H OH

OHH

HHO

H OH

CHO

exo-Brevicomin



Glucose Me2CO

ZnCl2

O

OO

OH

HH

O

O 1. NaH, PhCH2Cl

2. H+, H2O O

OO

OBn

HH

HO

HO

1. MsCl, Pyr.2. I-

3. MeOH, HClO

OH

OBn

HH

OMe

1. NaH2. CS2

3. MeIO

OBn

HH

OMe

O

S

SMe

SnBu3OOBn

HH

OMeBu3SnH

OOBn

HH

OMe

1. AcOH, H2O2. Ph3PCHCOCH3

OHOBn

HH

O 1. H2, R-Ni

2. H2, Pd/C O

O

The BartonThe Barton--McCombieMcCombie MethodMethod


OHOBn

HH

O

HOO

HO H

O

O H


The BartonThe Barton--McCombieMcCombie MethodMethod

Readily available starting materials enantio- and diastereoisomerically pure.Readily available starting materials enantio- and diastereoisomerically pure.

What constitutes a readily available starting material?What constitutes a readily available starting material?

S

NO

H2N H

COOH


Readily available starting materialsReadily available starting materials

37

SecondSecond--Rank Starting MaterialsRank Starting Materials

O

H2O2

NaOH

O

OPhSNa

O

O-

PhS

PhS

ONa

RIR

O

PhS1. mCPBA

2.

R

O

H+, H2O orNaOH, H2O

O

反式消除


O

O3HOOC

HOOC

O

on Ca salt

Br2

OBr

BrNaOMe COOMe

NaOHCOOMe


Trans稳定



O

1. HCl2. NaOH

COOH

Citronellic acid


O Br2, HOAc O

BrBr2ClSO3H

O

Br

Br

ZnHBr

O

Br



O

Br

H+

Br

OH

Br

OH

H BrOH

(2,3)-exo Me shift

H BrOH

-H+

H BrOH

Br2

H BrOH

Br+

(2,3)-exo Me shift

H BrOH

Br

H BrOH

Br

H Br

Br

O

Br

Br

O



O

Br

KI, DMFO

I

NaCH(COOMe)2

O

MeOOC

NH2OHN

MeOOC

OH

1. TsCl, pyr

2. CF3COOH COOMe

CNH



38

O

Br

Br2, ClSO3HBr2, 95 % O

Br

Br

O

Br

Br

Br

Zn HBr

75 %O

Br


SecondSecond--Rank Starting MaterialsRank Starting Materials Synthesis of Single DiastereoisomersSynthesis of Single Diastereoisomers

O O

OH

H

Ph

OH

OH

H

Ph

COOH

OH

HOH

COOH

Ph

CH2OH

OH

HOH

COOH

OH

HO O

O O

OH

HO

OH

HO OH


OH

OHHO

R-Ni

OH

HO OH

2equiv. tBuPh2SiClTHF, imidaz.

PCC

OSiPh2But

tBuPh2SiO O

mCPBA MeOHH+

PCC PhCH2+PPh3Cl-

BuLi

Bu4N+F- AcOH

O

OH

H

Ph

O


Synthesis of Single DiastereoisomersSynthesis of Single Diastereoisomers BicyclicBicyclic Compounds as Sources of Chiral Compounds as Sources of Chiral CentresCentres

Unsubstituted bicyclic compounds can serve as usefulsources of monocyclic compounds whose relative or absolute configuration at two chiral centres is defined.

This requires that one of the bridges in the bicyclic compound can be cleaved without affecting the configuration at either chiral centre originating from the bridgehead positions.

Unsubstituted bicyclic compounds can serve as usefulsources of monocyclic compounds whose relative or absolute configuration at two chiral centres is defined.

This requires that one of the bridges in the bicyclic compound can be cleaved without affecting the configuration at either chiral centre originating from the bridgehead positions.


O3

COOH

COOH

H

HCOOH

COOH


BicyclicBicyclic Compounds as Sources of Chiral Compounds as Sources of Chiral CentresCentres The Schreiber ModificationThe Schreiber Modification

O3, MeOHNaHCO3

O3, MeOHpTsOH

CHOOH

CHO

OMe

Ac2OEt3N COOMe

CHO

CHOOH

CH(OMe)2

OMe

NaHCO3

Me2S CHO

CH(OMe)2

Et3NAc2O COOMe

CH(OMe)2


the Ozonolysis Reaction

39

COOH

NH2

COOH

CONH2

O

O

O

Completely Stereoselective ConversionCompletely Stereoselective Conversion


CC--C to CC to C--N BondsN Bonds

Readily Available Fissionable Readily Available Fissionable BicyclicBicyclic CompoundsCompounds

The use of made of bicyclic compounds for the preparation of disubstituted monocyclic compounds of the defined relative configuration by Type 0 reactions will depend upon their availability and on the ease with which one ring can be cleaved.

The use of made of bicyclic compounds for the preparation of disubstituted monocyclic compounds of the defined relative configuration by Type 0 reactions will depend upon their availability and on the ease with which one ring can be cleaved.

A large number of bicyclic compounds are readily available by a variety of Type 2 cycloadditions including the

Diles-Alder reaction.

A large number of bicyclic compounds are readily available by a variety of Type 2 cycloadditions including the

Diles-Alder reaction.


Readily Available Fissionable Readily Available Fissionable BicyclicBicyclic CompoundsCompounds

p q

x

a

p q

x

a

rp

qx

a

rp

qx

a


Fissionable BridgesFissionable Bridges

Any reaction which leads to bond breaking can be harnessed to bring about cleavage of a ring provided

that the atoms of the functional group involved can be incorporated into a ring.

Any reaction which leads to bond breaking can be harnessed to bring about cleavage of a ring provided

that the atoms of the functional group involved can be incorporated into a ring.

Lactones are particularly useful fissionable rings because they are cleaved under mild conditions to give two chemo-

differentiated functional groups.

Lactones are particularly useful fissionable rings because they are cleaved under mild conditions to give two chemo-

differentiated functional groups.



OmCPBA O

O

MeOH

H

OH

COOMeDIBAL

O

OH

Ph3PCHCO2Me

H

OH

CO2Me

取代多的R基优先迁移


O

OO

OBnO

1. LiCH2PO(OMe)2

2. H2O

O

OO

BnOOH

CH2P(OMe)2

O

NaOMe, MeOH

OO

BnO OH

CH2P(OMe)2

O

O

CrO3pyr

OO

BnO O

CH2P(OMe)2

O

O

K2CO3

18-crown-6

OO

BnOO

Wittg Reaction冠醚可以增强试剂的碱性



40

hv, O2MeOH, thiorea O

O

OH

OH

H

HOH

OH

NCOPh

O O

NCOPh Al/HgNHCOPh

HO



OAc

OAc

NN

MeO2CCO2Me

OAc

OAcN

NCO2Me

MeO2C

NHMeOH

NH2

OH

MeO

HO



O

O

O

1. LDA2. TMSCl

O

O

OTMS

1. O32. CrO3

CO2H

COOH

O

O

SN

O

H

H

ArR-Ni

SNHAr

OH

H

H

R-Ni NHArOH

H

H

酮的α-H酸性大于酯

过量的还原剂还原硫醚



O

O

1. PhSCl2. HOCH2CH2OH

H+

O

PhS

ClO

O

1. mCPBA2. DBUCHCl3

O

PhSO2 O

O

MeLi

O

PhSO2 O

O

O

OPhSO2

MeOH

AcOCN

O

成砜可以增强α-H的酸性

Li和O的络合作用使Me从上面进攻



Readily available Fissionable Readily available Fissionable TricyclicTricyclic CompoundsCompounds

The use of tricyclic compounds for the synthesis of bicyclic/monocyclic compounds is widespread.

The use of tricyclic compounds for the synthesis of bicyclic/monocyclic compounds is widespread.

The small number of commercially available tricyclic compounds of any complexity means that assembly of the required tricyclic

compound will almost always be necessary with substitution on one or more bridges appropriate for their cleavage as required.

The small number of commercially available tricyclic compounds of any complexity means that assembly of the required tricyclic

compound will almost always be necessary with substitution on one or more bridges appropriate for their cleavage as required.



Br2Br

Br

KOHdioxane

Br

O- O


41

N

Cl

dioxaneH2O

NH2O N

CHO

NaBH4 Ac2O, pyr

AcN

H

H

H

CH2OAc



O

CF3CO3HNa2HPO4

O

O

LiAlH4

OHCH2OH

Ph3CClpyr

CrO3 NH2OHH

H

H

CH2OCPh3NHO

AcN

H

H

H

CH2OAcTsClpyr

Al2O3 LiAlH4 HClCHCl3

Ac2Opyr

保护一级醇



SummarySummary

Synthesis using Type 0 reactions relies heavily on the availabilityand recognition of appropriate starting materials in which the chiral centre(s) in the target molecule must already be present.

Synthesis using Type 0 reactions relies heavily on the availabilityand recognition of appropriate starting materials in which the chiral centre(s) in the target molecule must already be present.

Although the most useful starting materials containing two chiral centres in Type 0 synthesis are those which are single enantiomers, racemic compounds may also be of use in the synthesis of target molecules in racemic form.

Although the most useful starting materials containing two chiral centres in Type 0 synthesis are those which are single enantiomers, racemic compounds may also be of use in the synthesis of target molecules in racemic form.


The number of cheap enantiopure compounds which are commercially available is small and their variety is limited. However, in the hands of a competent chemist working in a well-found laboratory this small number of compounds can

provide access to a much larger number of second-rankstarting materials, most of which are not commercially available.

The number of cheap enantiopure compounds which are commercially available is small and their variety is limited. However, in the hands of a competent chemist working in a well-found laboratory this small number of compounds can

provide access to a much larger number of second-rankstarting materials, most of which are not commercially available.

Bicyclic compounds are fertile sources of monocyclic and acyclic molecules having at least two chiral centres of defined relative or absolute configuration. The two chiral centres present at the bridgehead or ring junction positions of these bicyclic compounds are conserved in Type 0 reactions which open one or both rings.

Bicyclic compounds are fertile sources of monocyclic and acyclic molecules having at least two chiral centres of defined relative or absolute configuration. The two chiral centres present at the bridgehead or ring junction positions of these bicyclic compounds are conserved in Type 0 reactions which open one or both rings.


SummarySummary

Awareness of the existence of second-rank starting materialsand retrieval of methods for their preparation can be accomplished by chemical literature searching methods including computer-assisted searches. Ultimately, however, there is no substitute for familiarity with as wide a rangeof organic chemistry as possible and particularly with the chemistry of the compounds.

Awareness of the existence of second-rank starting materialsand retrieval of methods for their preparation can be accomplished by chemical literature searching methods including computer-assisted searches. Ultimately, however, there is no substitute for familiarity with as wide a rangeof organic chemistry as possible and particularly with the chemistry of the compounds.


SummarySummary

Type 1 Reactions


Chapter 4Chapter 4

42

Those Proceeding With Either Inversion or With Rentention of Configuration at a Single Chiral

Centre

Part 1Part 1


OutlineOutline

4.1. Inversion of Configuration;4.2. Stereoelectronic Control;4.3. Transition-state Geometry;4.4. Limitations of the SN2 Reaction in

Stereoselective Synthesis;4.5. Double Inversion --- Retention 4.6. 1,2-Rearrangements with Inversion of

Configuration at the Migration Terminus4.7. 1,2-Rearrangements with Retention of

Configuration at The Migration Terminus4.8. Substitution with Retention of Configuration

via Configurationally Stable Carbanions 4.9. Summary

4.1. Inversion of Configuration;4.2. Stereoelectronic Control;4.3. Transition-state Geometry;4.4. Limitations of the SN2 Reaction in

Stereoselective Synthesis;4.5. Double Inversion --- Retention 4.6. 1,2-Rearrangements with Inversion of

Configuration at the Migration Terminus4.7. 1,2-Rearrangements with Retention of

Configuration at The Migration Terminus4.8. Substitution with Retention of Configuration

via Configurationally Stable Carbanions 4.9. Summary


bc

a

Nu-

bc

a

NuX X Nua

bc

σ∗-orbital

4.1. 4.1. Inversion of ConfigurationInversion of Configuration

The bond changes which accompany the SN2 reaction take place concertedly: as the Nu-C bond is forming so the C-X bond is breaking and a single transition state separates the starting materials and products.

The bond changes which accompany the SN2 reaction take place concertedly: as the Nu-C bond is forming so the C-X bond is breaking and a single transition state separates the starting materials and products.


In Type 1 reactions, at least one bond to a chiral centre is broken and a new bond is formed completely stereoselectively.

In Type 1 reactions, at least one bond to a chiral centre is broken and a new bond is formed completely stereoselectively.

In concerted reactions such as the SN2 type, the orbitalswhich are involved in making new bonds have a defined spatial relationship to those orbitals which arise from the breaking of existing bonds.

In concerted reactions such as the SN2 type, the orbitalswhich are involved in making new bonds have a defined spatial relationship to those orbitals which arise from the breaking of existing bonds.

4.2. 4.2. StereoelectronicStereoelectronic ControlControl


Scheme illustrates the inversion of configuration which characterises an SN2 reaction


In SN2 reaction, the part of the σ∗-orbital shown is directed at the angle of 180o to orbitals comprising the C-X σ bond undergoing cleaving. Bond formation, therefore, which occurs by overlap of this empty σ∗ orbital with the filled orbital of the nucleophile, takes place with inversion of configuration.

In SN2 reaction, the part of the σ∗-orbital shown is directed at the angle of 180o to orbitals comprising the C-X σ bond undergoing cleaving. Bond formation, therefore, which occurs by overlap of this empty σ∗ orbital with the filled orbital of the nucleophile, takes place with inversion of configuration.

bc

a

Nu-

bc

a

NuX X Nua

bc

σ∗-orbital


When, as in the SN2 reaction, a specific spatial relationship exists between bonds made and broken, the reaction is said to proceed under stereoelectronic control.

When, as in the SN2 reaction, a specific spatial relationship exists between bonds made and broken, the reaction is said to proceed under stereoelectronic control.



43

4.3. 4.3. TransitionTransition--state Geometrystate Geometry

In SN2 reaction, the transition state is assumed to be as shown in scheme in which C-a, C-b and C-c bonds lie in a plane and the Nu-C and C-X bonds are colinear.

In SN2 reaction, the transition state is assumed to be as shown in scheme in which C-a, C-b and C-c bonds lie in a plane and the Nu-C and C-X bonds are colinear.

This transition-state geometry (TSG) is an idealized representation for most SN2 reactions. If, for example, C-X bond breaking runs ahead of Nu-C bond making, or vice versa, then this will result in a transition state in which C-a, C-b and C-c bonds deviate from coplanarity.

This transition-state geometry (TSG) is an idealized representation for most SN2 reactions. If, for example, C-X bond breaking runs ahead of Nu-C bond making, or vice versa, then this will result in a transition state in which C-a, C-b and C-c bonds deviate from coplanarity.


4.4. 4.4. Limitations of the SLimitations of the SNN2 Reaction 2 Reaction in Stereoselective Synthesisin Stereoselective Synthesis

Since the SN2 reaction is sensitive to steric effects, ideally this reaction requires attack by a non-bulky and highly polarisable nucleophile on a sterically unencumbered sp3-hybridised carbon atom bearing a good leaving group.

Since the SN2 reaction is sensitive to steric effects, ideally this reaction requires attack by a non-bulky and highly polarisable nucleophile on a sterically unencumbered sp3-hybridised carbon atom bearing a good leaving group.

The most widely used leaving group:Halides, OZ groups (esters of the hydroxyl group with strong acids:tosylates, mesylates, triflates

The best nucleophiles:CN-, N3

-, RS-, I-, etc



The stereoelectronic control present in the SN2 results in inversion of configuration in the product.

The stereoelectronic control present in the SN2 results in inversion of configuration in the product.

The complete stereoselectivity is impervious to the presence of the other chiral centres elsewhere in the molecule

The complete stereoselectivity is impervious to the presence of the other chiral centres elsewhere in the molecule

The SN1 reaction can occasionally also be highly stereoselective if the carboncation through which it proceeds is captured by a nucleophile predominantly from one face.



OOMe

Me

H

H H

C6H13Me2AlOAr O

OMe

Me

HH H

C6H13

Al Me

MeOAr

H+ OHOMe

Me

HH

H

C6H13Me

70 %, > 99 % retention, Ar = C6F5





If the latter does occur, it is invariably the result of the molecular environment in which the carboncation is generated as in ion-pair formation: unlike the SN2 reaction, the SN1 reaction is not an inherently stereoselective (stereospecific) reaction.

If the latter does occur, it is invariably the result of the molecular environment in which the carboncation is generated as in ion-pair formation: unlike the SN2 reaction, the SN1 reaction is not an inherently stereoselective (stereospecific) reaction.



Limitation the Usefulness of Limitation the Usefulness of Intermolecular SIntermolecular SNN2 Reactions2 Reactions

First, attack at tertiary centres is so sterically retarded that reaction, if it occurs at all, results in elimination and

alkene formation rather than substitution.

First, attack at tertiary centres is so sterically retarded that reaction, if it occurs at all, results in elimination and

alkene formation rather than substitution.

HX

Nu-+ NuH + X-


44

Second, although primary carbon centres are well suited for SN2 substitution, inversion of configuration is only apparent

when deuterium (or trituim) substitution is present.

Second, although primary carbon centres are well suited for SN2 substitution, inversion of configuration is only apparent

when deuterium (or trituim) substitution is present.

Nu- XR

HDNu

R

HD

+ X-

Nu- XR

HHNu

R

HH

+ X-



Third, attempted SN2 substitution at secondary centres is also often blighted by competitive elimination especially

when the nucleophile has any basic character.

Third, attempted SN2 substitution at secondary centres is also often blighted by competitive elimination especially

when the nucleophile has any basic character.

MeMeOHOTs

+MeO2C Ph

CO2MeMeMeOH

Ph

CO2Me

CO2Me

OO

H

( )-sarracenin



OR1

R2109oO

119o

In epoxides, the angle between the two exocyclic bonds is widened as a consequence of the higher s-character which these bonds contain.

This increased s-character is itself a consequence of the higher p-character which is required for formation of the ring bonds to accommodate the geometry of the small ring.



Widening of the bond angles allows easier ingress of the nucleophiles.

Complexation of the epoxide oxygen can assist in the ring opening such that the substitution has both

‘push’ form the nucleophile and ‘pull’ from the leaving group.

O

B F 3 .E t 2 OB u L i, -7 8 o C

+ O-B F 3

B u -

O H

B u

H OB u



The diminished basicity and increased nucleophilicity of carbonions when complexed with copper facilitates substitution at secondary centres and particularly those on epoxide rings.

The diminished basicity and increased nucleophilicity of carbonions when complexed with copper facilitates substitution at secondary centres and particularly those on epoxide rings.

Bu COOEt

OTfMe2CuLi, -70 oC Bu COOEt

Me

Me2CuLi

OO O

MeOBn

OO

MeOBn

OHMe



The epoxide is opened at the less hindered position highly regio-selectivity (11:1) and also completely stereoselectively.The epoxide is opened at the less hindered position highly

regio-selectivity (11:1) and also completely stereoselectively.

Me2CuLi

OO O

MeOBn

OO

MeOBn

OHMe



45

O

Me TMSHH

Li2CuCN(CH2TMS)2

2TMSCH2Li + CuCNMe

TMSHO

CH2TMS

H

H

Epoxide ring opening by nucleophiles does not necessarily occur at the sterically less hindered. In this case attack of the nucleophile is believed to take place initially by addition to the silicon substituent and is thence directed to the more hindered position on the ring.

Epoxide ring opening by nucleophiles does not necessarily occur at the sterically less hindered. In this case attack of the nucleophile is believed to take place initially by addition to the silicon substituent and is thence directed to the more hindered position on the ring.



SN2 substitution at secondary centres is also facilitated when steric congestion in the transition state is reduced in other ways.

This is the case when one or more of the substituents on Cα in the substrate is sp2- or sp-hybridised, i.e. a vinyl or ethynyl group.

A heteroatom substituent (C, N, O) is smaller by virtue of the lone pair(s) (rather than substituents) that it bears. Unfortunately, these unsaturated substituents and heteroatoms may also facilitate SN1 substitution (C+ stabilisation) with its only occasionally complete stereoselectivity.



CO2Me

H

N3

OHRH

O

H CO2MeHR

NaN3HO

N3H

CO2MeH

R +

Ring opening of the enantiopure epoxide with azide ion followed by reaction of two products with triphenylphosphine results in the formation of aziridine. In spite of the fact that the ring opening is not regiospecific, only a single enantiopureaziridine is obtained.

Ring opening of the enantiopure epoxide with azide ion followed by reaction of two products with triphenylphosphine results in the formation of aziridine. In spite of the fact that the ring opening is not regiospecific, only a single enantiopureaziridine is obtained.



O

H CO2MeHR

NaN3HO

N3H

CO2MeH

RPh3P

DMF, 80 oC

HO

NH

CO2MeH

R PPh3

NHP

O

HH CO2MeR

Ph3PO

CO2Me

H

H

R-N H

Ph3

NH

CO2MeHR H



CO2Me

H

N3

OHRH

O

H CO2MeHR

NaN3 Ph3PDMF, 80 oC

NH

CO2MeHR H

CO2Me

H

N

OHRH

Ph3P

H HR CO2Me

OPPh3

NCO2Me

H

HN-

ORH

PPh3

从两边进攻的最终产物相同



RO- also as the nucleophiles

Like carbanions, oxyanions (RO-) are also basic and the classic method for replacement of one C-O bond with inversion. This transformation can now be accomplished in better yield by making use of the Mitsunobu reaction followed by the hydrolysis.



46

H

H

HO

HTsCl, pyr.

H

H

TsO

H

HO-, DMF

H

H

HO

H

HO-

H

H

PhCOO

H

Ph3P, EtO2CNNCO2Et (DEAD)

PhCOOH, THF



The mechanism of the Mitsunobu reactionsThe mechanism of the Mitsunobu reactions

Widely used for converting a secondary alcohol directly into its inverted ester

Widely used for converting a secondary alcohol directly into its inverted ester

EtO2CNNCO2Et (DEAD) Ph3P EtO2CN NCO2Et

PPh3

R1COOH

EtO2CN NHCO2Et

PPh3

R2OH EtO2CN NHCO2Et

PPh3

OR2R1COO-H+

R1COOR2



This reaction can also be used for the construction of large-ring compounds as in the closure of compounds to the ring system.

This reaction can also be used for the construction of large-ring compounds as in the closure of compounds to the ring system.

S

SH11C5

OTHP1. BuLi2. O

Br3.

LiO

O

Li

4. MeOH, THF, H3O+

H11C5

OH

S

S

OH

O OH

Ph3PDEAD

H11C5

O

S

S

OH

O

只适用于醛



EtOOCCOOEt

OHO1. , H+;

2. LiAlH4;3. TsCl, pyr;4. NaBr, DMSO;5. HOAc, H2O

BrH2CCH2Br

OH

KOH

CH2BrO



OO

TsO OBn

1. KNO2, DMF2. H2O

OO

HO OBn

Other method for C-O to C-O conversion of configuration

Other methods for C-O to O-C conversion with inversion of configuration which minimise yields of alkene by-products:Some of these methods were developed for prostaglandin synthesis, where elimination to give alkene was a particular problem with existing methods.



tBuOTs

KNO2, DMSODME18-crown-6

tBu

OH

tBuOH

KNO2, DMSODME18-crown-6

tBu

OMs



47

The factors referred to above which limit the use of intermolecular SN2 reactions in stereoselective synthesis

are less serious in their intramolecular versions, particularly when three-, five-, or six-membered rings are being formed.

The factors referred to above which limit the use of intermolecular SN2 reactions in stereoselective synthesis

are less serious in their intramolecular versions, particularly when three-, five-, or six-membered rings are being formed.



OMe

MeO OBn

OH

O

Me

MsClpyr

OMe

MeO OBn

OMs

O

Me

Pd/CNaHCO3, EtOH

OMe

MeO O

O

H

Me

氢源



OMeO

OMe

MeOMe

OMe

1. CF3CO2H, H2O

2. NaBH43. MsCl, pyr (2 equiv.)4. NaN3

OMsMeO

OMe

MeOMe

N3

Pd/H2

OMsMeO

OMe

MeOMe

NH2NH2

MeO H

OMe

MsO H

OMe

N

MeO H

OMe

H

OMe

H

SN2 reactions

反式进攻



O

O

SnBu3

TiCl4CH2Cl2

OTiCl4

OSnBu3

O

OH

Appropriately sited carbon nucleophiles can also react in an intramolecular SN2-type reaction at secondary centres.


构想最小改变原理



O

O

SnBu3 no reaction under same conditions





OHO- O O

MeMeNaOH

dioxaneOHO

MeMeO

O-

OH

MeMeO

OH H

OH

OH

MeMeHO

OH H

OH

HO

enantiopure

meso

The mechanism of the reaction shows that an intramolecular SN2 reaction can take place even at a tertiary centre.

The mechanism of the reaction shows that an intramolecular SN2 reaction can take place even at a tertiary centre.



48

TsOCO2H

OH

OH

NaOEtEtOH

COO-

O-

O

O

HH

HO

O-

O

O

O

HHO

H

HO

Ac2OO

O

HAcO

H

AcO

Treatment of the enantiopure acid with sodium ethoxide followed by acetylation gave diacetate, whose relative and absolute configurations suggest that a Payne rearrangement is involved and inversion at both adjacent chiral centres has occurred.

Treatment of the enantiopure acid with sodium ethoxide followed by acetylation gave diacetate, whose relative and absolute configurations suggest that a Payne rearrangement is involved and inversion at both adjacent chiral centres has occurred.




1. Attack at teriary centres is so sterically retarded that reaction, if it occurs at all, results in elimination and alkene formation rather than substitution.

2. Although primary carbon centres are well suited for SN2 substitution, inversion of configuration is only apparent when deuterium (or trituim) substitution is present.

3. Attempted SN2 substitution at secondary centres is also often blighted by competitive elimination especially when the nucleophile has any basic character.

1. Attack at teriary centres is so sterically retarded that reaction, if it occurs at all, results in elimination and alkene formation rather than substitution.

2. Although primary carbon centres are well suited for SN2 substitution, inversion of configuration is only apparent when deuterium (or trituim) substitution is present.

3. Attempted SN2 substitution at secondary centres is also often blighted by competitive elimination especially when the nucleophile has any basic character.


4.5. 4.5. Double Inversion Double Inversion ------ Retention Retention

COOHNH2H

HOOC 1 M HClHNO2

COOHN2

+HC

HO

O

C

C

O

HOOH

OO

OH

HOOC

An intramolecular SN2 reaction with inversion and formation of an unstable α–lactone is followed by a second intramolecular substitution with inversion.

An intramolecular SN2 reaction with inversion and formation of an unstable α–lactone is followed by a second intramolecular substitution with inversion.


COOHMeH

H NH2

COOHMeH

H OHHNO2

1. Mitsunobu

2. hydrolysisCOOH

MeH

HO H

Three inversions and overall just inversion.Three inversions and overall just inversion.



Double inversion commonly results from neighboring group participation of which α- and then γ-lactone formation.

Double inversion commonly results from neighboring group participation of which α- and then γ-lactone formation.

NOBn

H

H

Me

COOMe

HI

Bu3NMeCN, H2O N

OBnH

H

Me

O

H OMe

NOBn

H

H

Me O OH

91 %

NMeH COOMe

I

HBnO

6 %

I-



NOBn

H

H

Me

O

H OMe NMe

H COOMe

I

HBnO

I-



49

MeO

MeONMe

HO

H

(CO)3Cr

HBF4CH2Cl2

< - 20oC

MeO

MeONMe

H

(CO)3Cr

MeO

MeO

NMe

H

(CO)3Cr

O2hvMeO

MeO

NMe

H

Cyclisation of this compound lacking the chromium tricarbonyl ligand gave rise to the product with only 6 % e.e.



OTsHOAc H

H

-OAc

OAc

a-OAc

ba

b

AcOAcO

H H

AcO- AcO-a b

The first inversion is the result of the intramolecular necleophilic displacement mediated by partial delocalization of the bond with the formation of a non-classical carbocation. The second substitution path a takes place by attack on this non-classical ion by the solvent acetic acid with the partially formed bond acting as a leaving group.

The first inversion is the result of the intramolecular necleophilic displacement mediated by partial delocalization of the bond with the formation of a non-classical carbocation. The second substitution path a takes place by attack on this non-classical ion by the solvent acetic acid with the partially formed bond acting as a leaving group.Stereochemistry, Jian Pei, College of Chemistry, Peking University,


R R

X

PdL2PdL2

R

H

R

H

Nu- R R

Nu

TMS Ph

OCOOMe

R PH

MeOOC COOMe

Pd(PBu3)n- CO2

Ph

H

TMS

HPd

Bu3P OMe

Net retention of configuration can also be accomplished at allylic secondary carbon centres by carbon nucleophiles using palladiumchemistry.

Net retention of configuration can also be accomplished at allylic secondary carbon centres by carbon nucleophiles using palladiumchemistry.



HO OAcPd(PPh3)4

HO

Pd+

Nu- HO Nu

Nu: CH(CO2Me)2 80 % PhS 86 %

N 74 %

O

O

Retention here is the result of two substitutions and although neither is the SN2 reaction, the overall stereochemistry is that which would obtain if this were the case.

Retention here is the result of two substitutions and although neither is the SN2 reaction, the overall stereochemistry is that which would obtain if this were the case.



4.6. 1,24.6. 1,2--Rearrangements with Inversion of Rearrangements with Inversion of Configuration at The Migration TerminusConfiguration at The Migration Terminus

The migration of a substituent from one carbon to an adjacent one is frequently accompanied by stereochemical changes.

The migration of a substituent from one carbon to an adjacent one is frequently accompanied by stereochemical changes.


The stereoelctronic requirementfor this rearrangement is anantiperiplanar disposition of the bonds to migrating group and leaving group as shown in both transitions.

The stereoelctronic requirementfor this rearrangement is anantiperiplanar disposition of the bonds to migrating group and leaving group as shown in both transitions.

OHc

a

OH

b

d

H+OH2

+

c

a

O

b

d

H

dO

ca

b

OH2+

d

a

O

b

c

H

cO

d ab

Loss of one chiral centre.



50

Pinacol rearrangement of acyclic diols is seldom regioselective although completely stereoselective.

A small rotation around the C-C bond in which migration of d is stereoelectronically preferred.

Protonation and ionisation of the other hydroxyl accompanied by migration of a or b can lead to other regioisomers.

Pinacol rearrangement of acyclic diols is seldom regioselective although completely stereoselective.

A small rotation around the C-C bond in which migration of d is stereoelectronically preferred.

Protonation and ionisation of the other hydroxyl accompanied by migration of a or b can lead to other regioisomers.



OHc

a

OH

b

d

H+OH2

+

c

a

O

b

d

H

dO

ca

b

OH2+

d

a

O

b

c

H

cO

d ab

Regioselectivity may be accomplished if migration of c is easier than d if it has a higher migratory aptitude.

Regioselectivity may be accomplished if migration of c is easier than d if it has a higher migratory aptitude.



O

O HO

MeMsO H

O H

Bu

Et3Al, CH2Cl2, - 42 oC

H

Me

BuO

1. BuCCLi, THF2. LiAlH4, THF3. pyrH+OTs-

4. MsCl, Et3N

> 99 % e. e.

Solved by selective mesylation of the secondary hydroxyl; this thenbecomes then better leaving group. Exclusive migration of the vinyl group occurs with retention of double bond configuration in the alkene and inversion configuration at the migration terminus.

Solved by selective mesylation of the secondary hydroxyl; this thenbecomes then better leaving group. Exclusive migration of the vinyl group occurs with retention of double bond configuration in the alkene and inversion configuration at the migration terminus.



OHc

a

OH

b

d

H+OH2

+

c

a

O

b

d

H

dO

ca

b

OH2+

d

a

O

b

c

H

cO

d ab

The migration of c or d in the rearrangement is promoted and assisted by the pull of the developing carbocation but the migration may be assisted as much by a push from a substituent on the migrationorigin.

The migration of c or d in the rearrangement is promoted and assisted by the pull of the developing carbocation but the migration may be assisted as much by a push from a substituent on the migrationorigin.



OOBn

H

H

C8H17O

1. CH2 CH2MgBr2. TMSCl, imidazole

OOBn

H

H

H17C8O

SiMe3

Cl-

Ti

H17C8 OBn

OHO

(iPrO)2TiCl2-78oC to -40oC

Driving force:The formation of the strong Si-Cl bond;The conversion of the resulting alkoxide anion into a carbonyl group long with relief of ring strain from opening of the epoxide.

Driving force:The formation of the strong Si-Cl bond;The conversion of the resulting alkoxide anion into a carbonyl group long with relief of ring strain from opening of the epoxide.



Commercially available enantiopure compounds containing a C-O bond at a chiral centre are more abundant than analogues containing C-C bonds.It is noteworthy, therefore, that the overall conversions in above two schemes fashion C-C bonds at the expense of C-Obonds and this is acoomplished diastereoselectively in spite of the fact that the substrates undergoing reaction are not necessarily single diastereoisomers.

Commercially available enantiopure compounds containing a C-O bond at a chiral centre are more abundant than analogues containing C-C bonds.It is noteworthy, therefore, that the overall conversions in above two schemes fashion C-C bonds at the expense of C-Obonds and this is acoomplished diastereoselectively in spite of the fact that the substrates undergoing reaction are not necessarily single diastereoisomers.



51

It is noted previously that intermolecular SN2 substitution using carbon-centred nucleophiles at secondary and tertiary centres is not generally synthetically useful.Above two scheme provide at least a partial solution to this problem: the nucleophile is added initially to a carbonyl group flanking the chiral centre and this is followed by intramolecular transfer to the chiral centre.

It is noted previously that intermolecular SN2 substitution using carbon-centred nucleophiles at secondary and tertiary centres is not generally synthetically useful.Above two scheme provide at least a partial solution to this problem: the nucleophile is added initially to a carbonyl group flanking the chiral centre and this is followed by intramolecular transfer to the chiral centre.


4.6. 1,24.6. 1,2--Rearrangements with Inversion of Rearrangements with Inversion of Configuration at The Migration TerminusConfiguration at The Migration Terminus WagnerWagner--MeerweinMeerwein Rearrangement ReactionsRearrangement Reactions

c

a

ed

bed

c abx

c

a

ed

b reaction with Nu-

(Type III reaction?)loss of +ve charged fragment(regiocontrol: Type IV reaction?)

daughter carboncation by further rearrangementX-

The 1,2-shift is a rearrangement in which a group c migrates with its σ-bonded pair of electrons to an electron-deficient centre.

The 1,2-shift is a rearrangement in which a group c migrates with its σ-bonded pair of electrons to an electron-deficient centre.

A

B


In general, a new more stable carboncation (B) is formed from that (A) formally derived by loss of a leaving group X. It is likely that the migration of c is already underway as X departs and that the carbocation (A) is not ‘fully developed’. A stable product is formed from (B) either by loss of a positively charged fragment (usually a proton) or by reaction with a necleophile.

In general, a new more stable carboncation (B) is formed from that (A) formally derived by loss of a leaving group X. It is likely that the migration of c is already underway as X departs and that the carbocation (A) is not ‘fully developed’. A stable product is formed from (B) either by loss of a positively charged fragment (usually a proton) or by reaction with a necleophile.


WagnerWagner--MeerweinMeerwein Rearrangement ReactionsRearrangement Reactions

Alternatively, further rearrangement can occur and this daughter carbocation can be stabilised in either of the above ways. In any event, further stereo- or regiocontrol may be required if a single product is to be formed

Alternatively, further rearrangement can occur and this daughter carbocation can be stabilised in either of the above ways. In any event, further stereo- or regiocontrol may be required if a single product is to be formed



The stereoelectronic requirement in these Wagner-Meerwein rearrangement is just the same as that obtaining in above two Schemes with the migrating groups acting as the nucleophile in an intramolecular SN2-like substitution of the leaving group.



TsO O-

O

O

CH3O-

O

O

CH2

H

O

OOH

Me

H

H

The most common and useful 1,2-shifts of this type are those that are constrained to take place in conformationally restricted molecules such that, stereoelectronically, one group is better disposed for migration over others, even though their inherent migratory aptitudes might be similar.

The most common and useful 1,2-shifts of this type are those that are constrained to take place in conformationally restricted molecules such that, stereoelectronically, one group is better disposed for migration over others, even though their inherent migratory aptitudes might be similar.



52

O

Br

H+

Br

OH

Br

OH

H BrOH

(2,3)-exo Me shift

H BrOH

-H+

H BrOH

Br2

H BrOH

Br+

(2,3)-exo Me shift

H BrOH

Br

H BrOH

Br

H Br

Br

O

Br

Br

O



Wagner-Meerwein rearrangements dominate the carbocation-mediated chemistry of strained bicyclic systems and, in particular, that of substituted bicyclo[2.2.1]heptanes including camphor).

Wagner-Meerwein rearrangements dominate the carbocation-mediated chemistry of strained bicyclic systems and, in particular, that of substituted bicyclo[2.2.1]heptanes including camphor).




Me

AgSbF6toluene

Cl-

N

O

H64 %

SiO

H H

MeN

Cl SiO

HH

MeN

H

Rearrangement ReactionsRearrangement Reactions

Neighboring group participation (NGP) can also result in rearrangement as in the conversion of this compound to the morphinane ring system; here there is NGP by nitrogen in formation of the aziridinium ion and NGP by the double bond in formation of addition ring and in both steps there is inversion of configuration.

Neighboring group participation (NGP) can also result in rearrangement as in the conversion of this compound to the morphinane ring system; here there is NGP by nitrogen in formation of the aziridinium ion and NGP by the double bond in formation of addition ring and in both steps there is inversion of configuration.


Rearrangement ReactionsRearrangement Reactions

OH

HO

H

H

MeSPh

H+ OHH

H

MeSPh

OHHMe

H SPhO

H

Me

SPh

H

Sulphur readily enters into NGP and migration of the sulphur substituent is often the result, particularly when a more stablecarbocation is generated thereby.

Sulphur readily enters into NGP and migration of the sulphur substituent is often the result, particularly when a more stablecarbocation is generated thereby.


Rearrangement ReactionsRearrangement Reactions 4.7. 1,24.7. 1,2--Rearrangements with Retention of Rearrangements with Retention of Configuration at The Migration TerminusConfiguration at The Migration Terminus

1,2-Rearrangement are not limited to those in which carbon is the migrating terminus.

1,2-Rearrangement are not limited to those in which carbon is the migrating terminus.

R1 R2

O HOO R

O

O

OR

O

O

HR1

R2

R1 OR2

O

The ease with which the O-O bond is broken, for example, facilitates migration from carbon to oxygen in the Baeyer-Villiger reactions.

The ease with which the O-O bond is broken, for example, facilitates migration from carbon to oxygen in the Baeyer-Villiger reactions.


53

R1 R2

O HOO R

O

O

OR

O

O

HR1

R2

R1 OR2

O

It is likely that this reaction includes an SN2 attack on oxygen by the migrating group R2 but this cannot be proved from inversion of configuration since oxygen cannot be a chiral centre.

It is likely that this reaction includes an SN2 attack on oxygen by the migrating group R2 but this cannot be proved from inversion of configuration since oxygen cannot be a chiral centre.


4.7. 1,24.7. 1,2--Rearrangements with Retention of Rearrangements with Retention of Configuration at The Migration TerminusConfiguration at The Migration Terminus

RCH2

Obc a

RCOOOHbc a

O

RCH2

O

However, if the migrating group R2 is chiral then the rearrangement will be a Type I reaction since a bond to a chiral centre is broken and a new one is made.

However, if the migrating group R2 is chiral then the rearrangement will be a Type I reaction since a bond to a chiral centre is broken and a new one is made.



Two factors happily conspire together to make the Baeyer-Villiger a valuable reaction in stereoselective synthesis.

1. The more substituted bond to the carbonyl group is the one that migrates to oxygen:tertiary alkyl > secondary alkyl > primary alkyl > methyl;

2. If the migrating α-carbon is chiral, the new carbon oxygenbond is formed with retention of configuration.

Two factors happily conspire together to make the Baeyer-Villiger a valuable reaction in stereoselective synthesis.

1. The more substituted bond to the carbonyl group is the one that migrates to oxygen:tertiary alkyl > secondary alkyl > primary alkyl > methyl;

2. If the migrating α-carbon is chiral, the new carbon oxygenbond is formed with retention of configuration.



The reluctance of methyl to migrate in the Baeyer-Villiger reaction is used in the Criegee sequence for conversion of a γ-lactone into a 1,3-diol.

The reluctance of methyl to migrate in the Baeyer-Villiger reaction is used in the Criegee sequence for conversion of a γ-lactone into a 1,3-diol.

O

H

O

MeLiOH

H

OMe

1. CH3CO3H2. Ac2O, DMAP3. LiAlH4

4. H+

OH

H

OH



a

c

b

d

R2BHa b

dc

BR2

HH2O2, OH-

a b

dc

BR2

H

OOH

a b

dc

OBR2

H

HO-a b

dc

OH

H

Hydroboration of an alkene followed by transformation of the C-C bond into a C-O bond is an invaluable route to alcohol.

Hydroboration of an alkene followed by transformation of the C-C bond into a C-O bond is an invaluable route to alcohol.



SiMe(OEt)2

30 % H2O2

KHF2, DMF OH

SiF3

DMFOH

mCPBA

100 % exo

95 % endo

Replacement of C-Si bonds by C-O bonds can now be reliable accomplished with retention of configuration at carbon.

Replacement of C-Si bonds by C-O bonds can now be reliable accomplished with retention of configuration at carbon.



54

Ph

O

(PhMe2Si)2CuLi

Ph

O

SiMe2Ph

HBF4

Ph

O

SiMe2

H

F-

Ph

O

SiMe2

FPh

O

OH



SiR

ArCOOO- Si

R

OO Ar

O

SiOR

ROH

These rearrangements are triggered by weakness of the O-O bond and mechanisms resembling that aboveScheme are operative.

These rearrangements are triggered by weakness of the O-O bond and mechanisms resembling that aboveScheme are operative.



NH2

O

cb

aKOH, Br2

Hofmann N

O

cb

a

Br

Cl

O

cb

aN3

-

CurtiusN

O

cb

a

N2

Nc

b

a CO

H2ONH2

cb

a

OH

O

cb

a

HN3 Schmidt Lossen

N

O

cb

a

OAc cb

a

NH

O

OAc

base



Migration from carbon to nitrogen occurs in the Hofmann, Schmidt, Curtius and Lossen rearrangements, all of which proceed via an intermediate isocyanate formed with retention of configuration in the migrating group.

Migration from carbon to nitrogen occurs in the Hofmann, Schmidt, Curtius and Lossen rearrangements, all of which proceed via an intermediate isocyanate formed with retention of configuration in the migrating group.



In stabilized carbanions, e.g. enolates, the carbanion is planar and achiral. Simple carbations are usually tetrahedral but have low barriers to invcersion. Consequently, the formation of a carbanion from an enantiopure precursor followed by reaction with an electrophile will in general give a racemic product because the carbanion is not configura-tionally stable.

In stabilized carbanions, e.g. enolates, the carbanion is planar and achiral. Simple carbations are usually tetrahedral but have low barriers to invcersion. Consequently, the formation of a carbanion from an enantiopure precursor followed by reaction with an electrophile will in general give a racemic product because the carbanion is not configura-tionally stable.

4. 8. 4. 8. Substitution with Retention of Configuration Substitution with Retention of Configuration via Configurationally Stable via Configurationally Stable Carbanions Carbanions

a

Hbc base a

bc fast

abc E+ a

Ebc

enantiopure racemicE+: electrophile



The situation here is analogous to that of tetrahedral sp3-hybridised (pyramidal) trivalent nitrogen, where inversion is so fast as to preclude the possibility of isolating enantiomers.

Na

bc

fastN

a

bc


55


One way in which the inversion barrier in sp3-hybridised amines can be raised is by having one or more of the substituents a, b or c as heteroatoms, e.g. O, N or halogen. The presence of non-bonding electron pairs on the heteroatom and/or its σ electron-withdrawing character raises the energy of the transition state for inversion relative to the ground state as compared with simple trialkylamines.

One way in which the inversion barrier in sp3-hybridised amines can be raised is by having one or more of the substituents a, b or c as heteroatoms, e.g. O, N or halogen. The presence of non-bonding electron pairs on the heteroatom and/or its σ electron-withdrawing character raises the energy of the transition state for inversion relative to the ground state as compared with simple trialkylamines.



Me H

HOPh

SnBu3

OMe BuLi, -78 oCTHF

Bu3SnI Me H

HOPh

Li

OMe

Me2CO

Me H

HOPh

OMeMe

MeHO

It was shown by Still and Sreekumar that the same inversion-retarding effect of heteroatom effect of heteroatom substitution could be applied to carbonions.

It was shown by Still and Sreekumar that the same inversion-retarding effect of heteroatom effect of heteroatom substitution could be applied to carbonions.

transmetalation



1. BuLi2. CO23. H+

iPr SnR3

OEtOH

(S)-BINAL-H iPr SnR3

H OH iPr2NEtBOMCl iPr SnR3

H OBOM

iPr COOH

H OBOM

93 %98 % e.e.

CH2N2

iPr COOCH3

H OBOM1. HNO2

2. CH2N23. BOMCl

iPr COOH

H NH2

O

OAl

H

OEt

Li+Converted into the hydroxy acid derivative with complete retention of configuration.

Converted into the hydroxy acid derivative with complete retention of configuration.



H

xy

bX

a

H H

xy

bH

a

From what has been said previously regarding the limitations ofthe SN2 reaction, it might appear that with abcX as a secondary centre there is little prospect of being able to carry out the transformation to form two adjacent carbon chiral centres of defined absolute configuration.

From what has been said previously regarding the limitations ofthe SN2 reaction, it might appear that with abcX as a secondary centre there is little prospect of being able to carry out the transformation to form two adjacent carbon chiral centres of defined absolute configuration.



B

RH

O

OCl

Nu-B

RH

O

OClNu

ZnCl2Nu

B

RH

OO

Secondary α–chloroboronates undergo substitution by nucleophiles with clean inversion of configuration via rearrangement of intermediate boronate anions.

Secondary α–chloroboronates undergo substitution by nucleophiles with clean inversion of configuration via rearrangement of intermediate boronate anions.

Another example of SN2 substitution via intramolecular rearrangement

Another example of SN2 substitution via intramolecular rearrangement



B

iPrH

O

OCl

iPrH

O

MeO

1. THF, -100 oC2. ZnCl2, MeCN

68 %

iPrH

O

MeO

B

iPrH

OO

1. Bu3SnLi2. H2O2,NaOH3. ClCH2OMe4. BuLi

1. H2O2, NaOH

2. H+

iPrH

HO

OH

iPrH

Substitution with tributyltin: inversion;Replacement of boron hydroxyl: retention of configuration.

Substitution with tributyltin: inversion;Replacement of boron hydroxyl: retention of configuration.


56


The scope of this unprecedented synthesis of a molecular containing two adjacent chiral centres is considerable, particularly since the configurations of the centres can be selected by appropriate choice of the enantiomer of the starting materials.

The scope of this unprecedented synthesis of a molecular containing two adjacent chiral centres is considerable, particularly since the configurations of the centres can be selected by appropriate choice of the enantiomer of the starting materials.



increased s-character

increasedp-character

Carbanions which are generated on three-membered rings also have enhanced configuration stability. The hybridisation of their ring atoms provides a greater degree of p-character in the overlapping hybrid orbitals forming the bent banana bonds of the ring; This allows for a narrower angle than the 109o between normal sp3-bybrid orbitals.

Carbanions which are generated on three-membered rings also have enhanced configuration stability. The hybridisation of their ring atoms provides a greater degree of p-character in the overlapping hybrid orbitals forming the bent banana bonds of the ring; This allows for a narrower angle than the 109o between normal sp3-bybrid orbitals.



At the transition state for inversion of the carbanion, the ring bonds at this carbon are the result of overlap of sp2-hybrid orbitals having an increased angle of 120o

between them.The net result is that the energy of the transition state for this carbanion inversion is raised relative to that of a carbanion in an acyclic substrate which can accommodate normal sp2-bond angles without the same increase in strain.

At the transition state for inversion of the carbanion, the ring bonds at this carbon are the result of overlap of sp2-hybrid orbitals having an increased angle of 120o

between them.The net result is that the energy of the transition state for this carbanion inversion is raised relative to that of a carbanion in an acyclic substrate which can accommodate normal sp2-bond angles without the same increase in strain.



X X X

The same rationale accounts for the increased inversion barriersat nitrogen in aziridines by compared with cyclic amines.

The same rationale accounts for the increased inversion barriersat nitrogen in aziridines by compared with cyclic amines.



Ph

Ph

Me

COPhNaNH2

toluene

Ph

Ph98 % e. e.

H2O Ph

Ph H96 % e. e.

OD

H

D

Ph3Si

BuLi

-78 oCH2OO

D

H

Ph3Si

OD

H

H

Ph3Si

1. LDA, -75 oC NH

PhSPh

O

2. BuLi3. D2O

ND

PhSPh

O

Haller Bauer cleavage



Examples of carbanion generation and reaction with an electrophile with retention of configuration in a cyclopropane, an epoxide and an aziridine.

Examples of carbanion generation and reaction with an electrophile with retention of configuration in a cyclopropane, an epoxide and an aziridine.


57


1. LDA, -75 oC NH

PhSPh

O

2. BuLi3. D2O

ND

PhSPh

O

The optical rotation of the deuterated product was almost identical with that of the starting material, showing that carbanion and nitrogen inversion had not occurred.

The optical rotation of the deuterated product was almost identical with that of the starting material, showing that carbanion and nitrogen inversion had not occurred.



Finally, the reaction of many metal-carbon bonds, with transfer of a ligand from the metal to carbon, takes place with retention of configuration.Transmetallation reactions, in which one metal-carbon bond is replaced by another metal-carbon bond, also usually proceed with retention of configuration at carbon.

Finally, the reaction of many metal-carbon bonds, with transfer of a ligand from the metal to carbon, takes place with retention of configuration.Transmetallation reactions, in which one metal-carbon bond is replaced by another metal-carbon bond, also usually proceed with retention of configuration at carbon.


SummarySummary

There are limitations to the use of SN2 reactions in stereoselective synthesis.Tertiary substrates do not react intermolecularly and the reactions of secondary substrates are unsatisfactory withnucleophiles of even modest bulk, including most carbanions. In intramolecular reactions, however, SN2 substitution is practicable, sometimes even at tertiary centres.

There are limitations to the use of SN2 reactions in stereoselective synthesis.Tertiary substrates do not react intermolecularly and the reactions of secondary substrates are unsatisfactory withnucleophiles of even modest bulk, including most carbanions. In intramolecular reactions, however, SN2 substitution is practicable, sometimes even at tertiary centres.

Double inversion ( = retention) of configuration is common in many reactions in which a neighboring group participates.Net retention of configuration can also be accomplished using palladium chemistry.

Double inversion ( = retention) of configuration is common in many reactions in which a neighboring group participates.Net retention of configuration can also be accomplished using palladium chemistry.


SummarySummary

1,2-Migration of C-C bonds to sp3-hybridised centres with loss of a leaving group commonly proceeds with inversion at the migration terminus with the migrating bond behaving as the nucleophile in an SN2-type substitution.

1,2-Migration of C-C bonds to sp3-hybridised centres with loss of a leaving group commonly proceeds with inversion at the migration terminus with the migrating bond behaving as the nucleophile in an SN2-type substitution.

Concerted 1,2-migration with retention of configuration in the migrating sp3 carbon takes place in the Baeyer-Villiger and relatedreactions where migration of a C-C, C-B or C-Si bond takesplace to give a C-O bond. Similar 1,2-migrations from carbonto nitrogen with retention of configuration in the migrating group take place in the Hofmann, Curtius and related reactions.

Concerted 1,2-migration with retention of configuration in the migrating sp3 carbon takes place in the Baeyer-Villiger and relatedreactions where migration of a C-C, C-B or C-Si bond takesplace to give a C-O bond. Similar 1,2-migrations from carbonto nitrogen with retention of configuration in the migrating group take place in the Hofmann, Curtius and related reactions.


SummarySummary

Pyramidal carbanions substituted with oxygen, nitrogen or halogens have retarded rates of inversion and, at sufficiently low temperatures. The carbonion is configurationally stable and can be generated and related with retention of configuration. Carbanions generated on three-membered rings are also configurationally stable at lower temperatures.

Pyramidal carbanions substituted with oxygen, nitrogen or halogens have retarded rates of inversion and, at sufficiently low temperatures. The carbonion is configurationally stable and can be generated and related with retention of configuration. Carbanions generated on three-membered rings are also configurationally stable at lower temperatures.


Simple Chirality Transfer Reactions:

Those in Which a Single Chiral Centre is Transferred with

Concomitant Migration of one or More Double Bonds

Part 2Part 2


58

OutlineOutline

4.10. 1,3-Simple Chirality Transfer via the SE2’ Reaction; 4.11. 1,3-Simple Chirality Transfer via the SN2’ Reaction;4.12. Simple Chirality Transfer via Concerted

Sigmatropic Rearrangement;4.13. 1,3-Simple Chirality Transfer by [2,3]

Sigmatropic Rearrangement;4.14. Simple Chirality Transfer via [3,3]

Sigmatropic Rearrangement;4.15. [1,5] Sigmatropic Rearrangement;4.16. Simple Chirality Transfer in the

Ene (Retroene) Reaction 4.17. Summary

4.10. 1,3-Simple Chirality Transfer via the SE2’ Reaction; 4.11. 1,3-Simple Chirality Transfer via the SN2’ Reaction;4.12. Simple Chirality Transfer via Concerted

Sigmatropic Rearrangement;4.13. 1,3-Simple Chirality Transfer by [2,3]

Sigmatropic Rearrangement;4.14. Simple Chirality Transfer via [3,3]

Sigmatropic Rearrangement;4.15. [1,5] Sigmatropic Rearrangement;4.16. Simple Chirality Transfer in the

Ene (Retroene) Reaction 4.17. Summary


Type 1 reactions discussed in the previous part are those in which either inversion or retention of configuration takes place at a chiral centre.

Type 1 reactions discussed in the previous part are those in which either inversion or retention of configuration takes place at a chiral centre.

In Part 2, all reactions involve simple transfer of chirality or, more precisely, those which take place with the loss of the existing chiral centres, the migration of at least one configur-ation double bond and the creation of a new chiral centre elsewhere in the molecule.

In Part 2, all reactions involve simple transfer of chirality or, more precisely, those which take place with the loss of the existing chiral centres, the migration of at least one configur-ation double bond and the creation of a new chiral centre elsewhere in the molecule.


Type 1 reactionsType 1 reactions

4.10. 1,34.10. 1,3--Simple Chirality TransferSimple Chirality Transfer

via the SE2’ ReactionThe reaction of allylsilanes with electrophiles is an SE2’ reaction:Loss of the silyl group and reaction with electrophiles takes place in an anti fashion with 1,3-transfer of chirality.

via the SE2’ ReactionThe reaction of allylsilanes with electrophiles is an SE2’ reaction:Loss of the silyl group and reaction with electrophiles takes place in an anti fashion with 1,3-transfer of chirality.

d

c

SiMe3

ba

d

c SiMe3

ab

E+

dc

E

a

b

dc

E b

a


4.10. 1,34.10. 1,3--Simple Chirality TransferSimple Chirality Transfer

OMe3Si

O

ClCl

1. PhSCl2. NaF, MeOH 65 %

OO

ClClPhS

Note: reaction takes place from only one of the two conformationsNote: reaction takes place from only one of the two conformations

Me

H H

PhSiMe3

E+ Me

H H

PhE

85 % e. e. E = tBu or CH2OH, 86 % e. e.


A small number of examples are known in which the inherent anti-bias of the SE2’ is overridden by other factors and synattack of the electrophile and loss of trialkylsilyl group is the stereochemical outcome.

A small number of examples are known in which the inherent anti-bias of the SE2’ is overridden by other factors and synattack of the electrophile and loss of trialkylsilyl group is the stereochemical outcome.

Allylstannanes react with electrophiles in an SE2’ reaction with the same anti preference as allysilanes

Allylstannanes react with electrophiles in an SE2’ reaction with the same anti preference as allysilanes


4.10. 1,34.10. 1,3--Simple Chirality TransferSimple Chirality Transfer 4.11. 1,34.11. 1,3--Simple Chirality TransferSimple Chirality Transfer

X

Nu-

Nu

X-

via the SN2’ ReactionAn SN2’ reaction is the nucleophilic attack at the terminal sp2 centre of an ally system with migration of the double bond and expulsion of a leaving group from the allylic position.

via the SN2’ ReactionAn SN2’ reaction is the nucleophilic attack at the terminal sp2 centre of an ally system with migration of the double bond and expulsion of a leaving group from the allylic position.

With appropriate substitution on the allyl system, this reaction also results in 1,3-transfer of chirality.

With appropriate substitution on the allyl system, this reaction also results in 1,3-transfer of chirality.


59

Nu

X

Nu

X

The stereoelectronic requirement for the SN2’ reactions arises from the necessity for the developing p-orbital formed the breaking C-X bond to overlap with the adjacent p-orbital of the existing π-bond to form the new π-bond in the product.

The stereoelectronic requirement for the SN2’ reactions arises from the necessity for the developing p-orbital formed the breaking C-X bond to overlap with the adjacent p-orbital of the existing π-bond to form the new π-bond in the product.

anti syn


The SThe SNN22’’ ReactionReaction

This stereoelectronic requirement can be satisfied by attack of the nucleophile in either of two orientations relative to the leaving group (syn or anti).

This stereoelectronic requirement can be satisfied by attack of the nucleophile in either of two orientations relative to the leaving group (syn or anti).



a cb

d

X

Nu-

ab

Nu

c d

ad

b

c

X ab

Nu dc

anti-derived

In an enantiopure acyclic substrate having a double bond of defined configuration, there are two conformations from which both syn and anti reaction can proceed.

In an enantiopure acyclic substrate having a double bond of defined configuration, there are two conformations from which both syn and anti reaction can proceed.



ad

b

c

X

Nu-

ab

Nu

dc

a cb

d

XNu-

ab

Nuc d

syn-derived

The products from each of these conformations have opposite configurations at both the chiral centre and the double bond.

The products from each of these conformations have opposite configurations at both the chiral centre and the double bond.



In general, the SN2’ reaction is not highly stereoselective; attack of the nucleophile may be preferentially syn or antito some degree depending on the nucleophile, the leaving group and whether the substitution is inter- or intramolecular.

In general, the SN2’ reaction is not highly stereoselective; attack of the nucleophile may be preferentially syn or antito some degree depending on the nucleophile, the leaving group and whether the substitution is inter- or intramolecular.

The application of copper and palladium chemistry to the SN2’reaction has greatly increased the reliability of its stereochemical outcome.

The application of copper and palladium chemistry to the SN2’reaction has greatly increased the reliability of its stereochemical outcome.



H

OHO

HOBn

1. Me2CuLi, THF, Et2O2. H2O

HO

MeH

OBnOH)(

H

OO

HOBn

Li

Me-

H

OH

Me

Me

OH

HOBn

H OH

MeH

OBn

HO

Me

88 %

12 %



60

Although the reaction has high anti stereoselectivity, two diastereoisomers are still obtained (albeit indisparate amounts) because two conformations of the starting material react competitively.

Although the reaction has high anti stereoselectivity, two diastereoisomers are still obtained (albeit indisparate amounts) because two conformations of the starting material react competitively.



H CO2Me

H

OTs

HtBuMe2SiO

H

Me

Me-

H

CO2MeHH

tBuMe2SiOH

Me

Me

Me2Cu(CN)Li2BF3, THF, -78 oC

96 %> 99 : 1

In favorable cases, cuprate-mediated SN2’ reactions on acyclic substrates can be highly stereoselective, but this is more likely when one of the options of anti reaction is removed by conformational restraints, e.g. when the allylic system is incorporated in a ring.

In favorable cases, cuprate-mediated SN2’ reactions on acyclic substrates can be highly stereoselective, but this is more likely when one of the options of anti reaction is removed by conformational restraints, e.g. when the allylic system is incorporated in a ring.



Me

OAcMe

OAc

Me(CN)CuLi

Me

Me

Me

Me1.2 % 98.8 %94 % 5.9 %



CuCN

R

OAc

HH

CuCN

R

H

R

(6) (7)

CuCNR

HH R

HH

R

(8) SN2 product SN2' product



In these reactions, a π-complex of the alkene with copper isbelieved to be converted into a σ-complex with loss of the

leaving group followed by metal-to-carbon transfer of the ligand R (with retention of configuration at carbon).

In these reactions, a π-complex of the alkene with copper isbelieved to be converted into a σ-complex with loss of the

leaving group followed by metal-to-carbon transfer of the ligand R (with retention of configuration at carbon).



Control of the stereochemistry, therefore, is brought about by the π-complex formation which, in an otherwise unbiased five-or six-membered ring system, will be form the side opposite to the acetoxy group and hence lead to the anti mode of substitution.

Control of the stereochemistry, therefore, is brought about by the π-complex formation which, in an otherwise unbiased five-or six-membered ring system, will be form the side opposite to the acetoxy group and hence lead to the anti mode of substitution.

However, when this face is hindered, even the copper-catalysed SN2’ reaction can revert to the syn mode.

However, when this face is hindered, even the copper-catalysed SN2’ reaction can revert to the syn mode.



61

It is noteworthy that the formation of a π-allyl complex is apparently not favored when the other lignand on copper is cyanide, since the product from transfer of R to the carbon which originally bore the acetoxy group– an SN2 reaction – is at best a very minor one.

It is noteworthy that the formation of a π-allyl complex is apparently not favored when the other lignand on copper is cyanide, since the product from transfer of R to the carbon which originally bore the acetoxy group– an SN2 reaction – is at best a very minor one.

However, using a dialkylcuprate, R2CuLi, this is the major pathway and the regiospecificity of substitution of the SN2’reaction is lost.

However, using a dialkylcuprate, R2CuLi, this is the major pathway and the regiospecificity of substitution of the SN2’reaction is lost.



It has been suggested that the tendency for cuprates to bring about SN2’ reactions with anti stereochemistry can be ascribed to the ability of the filled and diffuse d-orbital of the nucleophilic copper atom to interact with both π*- and σ*-orbitals of the substrate in a bidentate fashion.

It has been suggested that the tendency for cuprates to bring about SN2’ reactions with anti stereochemistry can be ascribed to the ability of the filled and diffuse d-orbital of the nucleophilic copper atom to interact with both π*- and σ*-orbitals of the substrate in a bidentate fashion.

Cu

L

R

X

d (Cu)

C C

σ* C-X

π*



H

Me

OPhNH

O

1. MeLi2. CuI3. MeLi

H

Me

ON

OPh

MeCu-

-CO2

H

Me

N

Ph

MeCu- Me

Me

H

Me

Me

Exceptionally, synaddition in these cuprate-mediated SN2’ substitutions can be effected by coordinations of the cuprate to the leaving group, thus directing addition of the copper to the synface of the allyl group.

Exceptionally, synaddition in these cuprate-mediated SN2’ substitutions can be effected by coordinations of the cuprate to the leaving group, thus directing addition of the copper to the synface of the allyl group.



Pd

OHOCOArH

OCOArH

OH

(Ph3P)4PdEt3N, MeCN

OHHH

O H H

OH

HPd)(



By contrast, SN2’ reactions which are brought about by involve-ment of palladium invariably proceed with anti formation of π-allyl complexes followed by anti attack of the nucleophile leading to an overall syn stereochemistry.

By contrast, SN2’ reactions which are brought about by involve-ment of palladium invariably proceed with anti formation of π-allyl complexes followed by anti attack of the nucleophile leading to an overall syn stereochemistry.



Palladium is generally used in only catalytic amounts. Whereas in copper-mediated SN2’ reactions the cuprate is the source of the nucleophile, in palladium-catalysed SN2’ reactions the nucleophile comes from elsewhere.

Palladium is generally used in only catalytic amounts. Whereas in copper-mediated SN2’ reactions the cuprate is the source of the nucleophile, in palladium-catalysed SN2’ reactions the nucleophile comes from elsewhere.

The nucleophile attacks intramolecularly to form a five-membered ring: there can be no attack at other terminus of the system in intermediate because this would require a trans-double bond to contained in a seven-membered ring.

The nucleophile attacks intramolecularly to form a five-membered ring: there can be no attack at other terminus of the system in intermediate because this would require a trans-double bond to contained in a seven-membered ring.

The alternative transition state for five-membered ring formation is disfavoured because of A1,3-strain.

The alternative transition state for five-membered ring formation is disfavoured because of A1,3-strain.



62

OHMe O

HMe

H

(Ph3P)4Pd, THF COO-HMe H

MeH

Pd+

90 %-CH(CO2Me)2

HC(CO2Me)2

HMe

HMe

COO-

OH

HMe

HMe

H

O

)(

In these palladium-catalysed reactions, complete stereo- and regioselectivity using intermolecular attack on acyclic substrates by nucleophiles has also been achieved using the lactone.

In these palladium-catalysed reactions, complete stereo- and regioselectivity using intermolecular attack on acyclic substrates by nucleophiles has also been achieved using the lactone.



OHMe O

HMe

H

(Ph3P)4Pd, THF COO-HMe H

MeH

Pd+

90 %-CH(CO2Me)2

HC(CO2Me)2

HMe

HMe

COO-

OH

HMe

HMe

H

O

)(



The complete stereoselectivity here reflects the lower concentration of the alternative conformer from which ionisation could occur and/or its sluggish reaction withthe bulky complexed palladium.

The complete stereoselectivity here reflects the lower concentration of the alternative conformer from which ionisation could occur and/or its sluggish reaction withthe bulky complexed palladium.

The regioselectivity in this reaction is thought to be the result of charge repulsion between the incoming nucleophile and the carboxylate anion.

The regioselectivity in this reaction is thought to be the result of charge repulsion between the incoming nucleophile and the carboxylate anion.



O

1. (iPrO)3P, Pd(OAc)2

N

N

N

N

NH2

Li

2. , DMSO, THF

3. ClCO2Me, pyr

MeO2CO N

N

NN

NHCO2Me

LiCH(NO2)SO2Ph(dba)3Pd2, PPh3, CHCl3

N

N

NN

NHCO2MeNO2

PhO2S

N

N

NN

NH2HO

HO OH

(+)-aristeromycin



OH

OH

OH

HO

HO2C

O

NH

NCO2Me

(Ph3P)4PdTHF N NCO2Me

HH

HO

The π-allylpalladium species is trapped intramolecularly by anitrogen nucleophile with net intention of configuration at theepoxide carbon atom, i.e. overall this is not equivalent to an SN2’reaction.

The π-allylpalladium species is trapped intramolecularly by anitrogen nucleophile with net intention of configuration at theepoxide carbon atom, i.e. overall this is not equivalent to an SN2’reaction.Stereochemistry, Jian Pei, College of Chemistry, Peking University,


nBu

H

H

AlMe2

+O

O

1. (Ph3P)4Pd, THF

2. H2O, H+

HOOC

tBu

Whereas attack of a nucleophile on the π- allylpalladium intermediate is usually anti, attack involving aryl or vinyl zinc halides or vinylalanes is syn; in these cases the nucleophile is transferred first to the palladium(transmetallation) and thence to the syn face.

Whereas attack of a nucleophile on the π- allylpalladium intermediate is usually anti, attack involving aryl or vinyl zinc halides or vinylalanes is syn; in these cases the nucleophile is transferred first to the palladium(transmetallation) and thence to the syn face.



63

OO

(Ph3P)4Pd, THFPhZnCl

-O2C

Pd+Ph3P PPh3

-O2C

Pd+Ph PPh3

H+

OHO

H

Ph

H

racemic, 94 %

Ph亲核性较弱,易转移到Pd上


The SThe SNN22’’ ReactionReaction 4.12. 4.12. Simple Chirality Transfer via Concerted Simple Chirality Transfer via Concerted SigmatropicSigmatropic RearrangementRearrangement

-Y+X

Y

X

H H

In a sigmatropic rearrangement, the breaking of an existing σ-bond is accompanied by the making of a new σ-bond elsewhere in the same molecule; consequential shifting of one or more double bonds is generally required.

In a sigmatropic rearrangement, the breaking of an existing σ-bond is accompanied by the making of a new σ-bond elsewhere in the same molecule; consequential shifting of one or more double bonds is generally required.

[3,3]

[2,3]

[1,5]


Stereoelectronic control in these sigmatropic rearrangement is a consequence of transition-state geometries (TSG) in which, as always, overlap of the appropriate interacting orbitals(including those form any intervening π-bonds) is maximised.

Stereoelectronic control in these sigmatropic rearrangement is a consequence of transition-state geometries (TSG) in which, as always, overlap of the appropriate interacting orbitals(including those form any intervening π-bonds) is maximised.

Sigmatropic rearrangements are one of the important sub-classes of pericyclic reaction first recognised by Woodward and Hoffman. Pericyclic reactions are single-step reactions which proceed via cyclic transition states in which bonds are being made and broken concertedly.

Sigmatropic rearrangements are one of the important sub-classes of pericyclic reaction first recognised by Woodward and Hoffman. Pericyclic reactions are single-step reactions which proceed via cyclic transition states in which bonds are being made and broken concertedly.


4.12. 4.12. Simple Chirality Transfer via Concerted Simple Chirality Transfer via Concerted SigmatropicSigmatropic RearrangementRearrangement

Concertedness in these pericyclic reactions is allowed only when the orbitals which overlap have the correct symmetry. If the symmetry is not appropriate, the reaction may still proceed but via a non-concerted pathway involving more than a single transition state.

Concertedness in these pericyclic reactions is allowed only when the orbitals which overlap have the correct symmetry. If the symmetry is not appropriate, the reaction may still proceed but via a non-concerted pathway involving more than a single transition state.



Concertedness in these reactions is often accompanied by high stereoselectivity; non-concerted reactions are less likely to be highly stereoselective.

Concertedness in these reactions is often accompanied by high stereoselectivity; non-concerted reactions are less likely to be highly stereoselective.

A feature of pericyclic reactions is that their stereochemical course can usually be predictly when the demands of stereoelectronic control (including correct symmetry of the overlapping orbitals) are considered. Such predictions can be made by using rules devised by Woodward and Hoffman or by using the frontier molecular orbital midification (FMO) of those rules devised by Fukui.

A feature of pericyclic reactions is that their stereochemical course can usually be predictly when the demands of stereoelectronic control (including correct symmetry of the overlapping orbitals) are considered. Such predictions can be made by using rules devised by Woodward and Hoffman or by using the frontier molecular orbital midification (FMO) of those rules devised by Fukui.



4.13. 1,34.13. 1,3--Simple Chirality Transfer by [2,3] Simple Chirality Transfer by [2,3] SigmatropicSigmatropic RearrangementRearrangement

OS

Ar CH2-

O O-O-

+SAr

sulphoxide sulphenate ester [2,3] Wittig rearrangement

S+S

CH2-

sulphonium ylide allyl sulphide

N+N

CH2-

[2,3] Stevens rearrangement

In acyclic system


64

Both the Wittig and Stevens rearrangements are prefaced by [2.3] to distinguish them from their [1,2] (non-concerted) variants.

Both the Wittig and Stevens rearrangements are prefaced by [2.3] to distinguish them from their [1,2] (non-concerted) variants.

Depending on the substitution present, the [2,3] sigmatropic rearrangement may in the net creation of chiral centres in Type 2 or 3 reaction as illustrated for Wittig rearrangement.

Depending on the substitution present, the [2,3] sigmatropic rearrangement may in the net creation of chiral centres in Type 2 or 3 reaction as illustrated for Wittig rearrangement.

O

Me

-O

racemic(b) Type 2

O Me

SiMe3

Me

-O

MeMe

SiMe3(c) Type 3



CH2-

O

H

H HMe O-

(a) simple chirality transfer (Type 3)

We shall consider only those arrangement in which chirality is transferred, i.e. there is not gain in the number of chiral centres. For this to be so the double bond must be configured and both it and the existing chiral centre must be present in the pericyclic array.

We shall consider only those arrangement in which chirality is transferred, i.e. there is not gain in the number of chiral centres. For this to be so the double bond must be configured and both it and the existing chiral centre must be present in the pericyclic array.



Y-

X

ba

cd e

YbX-

c

d

e

a

Y-

X

ba

c e

d

YbX

c

a

e

d

In [2,3]rearrangements involving simple chirality transfer there are only two positions for the chiral centre: either at the allylic or homoallylic position.

In [2,3]rearrangements involving simple chirality transfer there are only two positions for the chiral centre: either at the allylic or homoallylic position.



σ-Bond breaking

σ-Bond forming

Maximised overlap of the orbitals involved in the [2,3] rearrangement can be accommodated.

Maximised overlap of the orbitals involved in the [2,3] rearrangement can be accommodated.



(A) (D)

(B)(C)

HOMOLUMO

same phase

σ-Bond breaking

σ-Bond forming



A formalism by which the symmetry of the orbitals involved in this rearrangement can be deduced:The bond which is breaking is located (A) and the two radical species obtained by a (hypothetical) homolytic cleavage of this bond are identified (B)

A formalism by which the symmetry of the orbitals involved in this rearrangement can be deduced:The bond which is breaking is located (A) and the two radical species obtained by a (hypothetical) homolytic cleavage of this bond are identified (B)



65

Consideration of the highest occupied molecular orbitals (HOMOs) of these two radical species (C) shows that lobesrequired to overlap to form the new σ-bond have the same phase (the lobes of the orbitals produced from the breaking bond must have the same phase) and thus concertedrearrangement is allowed, giving the product (D).

Consideration of the highest occupied molecular orbitals (HOMOs) of these two radical species (C) shows that lobesrequired to overlap to form the new σ-bond have the same phase (the lobes of the orbitals produced from the breaking bond must have the same phase) and thus concertedrearrangement is allowed, giving the product (D).



O O-

The envelope conformation shown for the transition state geometry in previous Scheme is not necessarily that through which all [2,3] sigmatropic rearrangements pass.

The envelope conformation shown for the transition state geometry in previous Scheme is not necessarily that through which all [2,3] sigmatropic rearrangements pass.

The stereochemistry of some [2,3] Wittig rearrangements is better accommodate using an alternative “envelope”.

The stereochemistry of some [2,3] Wittig rearrangements is better accommodate using an alternative “envelope”.



There is a syn relationship between the C-C bond made and the C-O bond broken. Alternatively, one can say that the CH2O unit is transferred across one face of allyl system(superafacial migration)

There is a syn relationship between the C-C bond made and the C-O bond broken. Alternatively, one can say that the CH2O unit is transferred across one face of allyl system(superafacial migration)

Oa

bH

Rc

a

b H

Rc

O-

c

b

aH

R

O

()

cH

R b

aO-



In an acyclic system, there are always two conformation (non-envelope), through which the rearrangement can proceed when a chiral centre is present in the starting material.

In an acyclic system, there are always two conformation (non-envelope), through which the rearrangement can proceed when a chiral centre is present in the starting material.

Oa

bH

Rc

a

b H

Rc

O-

c

b

aH

R

O

()

cH

R b

aO-



O

Me

(R)-Alpine borateOH

Me

1. H2, Lindlar (Type 4)

2. NaH, ICH2SnMe3

OSnMe3

HMe

(R)-Alpine borateB

A particularly valuable experimental by transmetallation.A particularly valuable experimental by transmetallation.



OSnMe3

HMe

BuLi-78 oC

OLi

HMe

Me

HH

OLi

H

Me H

OLi

H

H+OH

Me H

Me

HH

OLi ()

H

Me

HLiO OLi

Me H



66

The preference for rearrangement via (A) rather than (B) is strong when the R group is large and when b is largerThan hydrogen.

The preference for rearrangement via (A) rather than (B) is strong when the R group is large and when b is largerThan hydrogen.

However, this selectivity would be expected to decline when the allylic position bearing R is also sunstituted with a group R1 of a similar bulk. Preferential reaction via (B) can be accomplished if c is a bulky group (methyl or larger) and b is a hydrogen as in next sample.

However, this selectivity would be expected to decline when the allylic position bearing R is also sunstituted with a group R1 of a similar bulk. Preferential reaction via (B) can be accomplished if c is a bulky group (methyl or larger) and b is a hydrogen as in next sample.

A

B

Oa

bH

Rc

a

b H

Rc

O-

c

b

aH

R

O

()

cH

R b

aO-



Bu

OH

Me

1. KH2. Bu3SnCH3I

Bu

O

Me

SnBu3

BuLi

OH

HBu

HMe

Li

H

H Bu

HMe

OLi

Me

H

HBu

H

OLi

()H+

BuMe

OH

The interaction between the butyl and methyl groups indicated in (A) is sufficient to direct all of the rearrange-ment via conformer (B).

The interaction between the butyl and methyl groups indicated in (A) is sufficient to direct all of the rearrange-ment via conformer (B).

B

A

A和B的相对含量取决于R,c的邻交叉作用大,还是R,b(a)的1,3-strain大

A和B的相对含量取决于R,c的邻交叉作用大,还是R,b(a)的1,3-strain大



Allyl Sulphoxide-allyl sulphenate ester interconversion.Allyl Sulphoxide-allyl sulphenate ester interconversion.

The alternative location of the chiral centre in a [2,3] rearrange-ment is at the homoallylic position. This can be the case with sulphoxides since the sulphur is pyramidal and normally configuratioanally stable, i. e. the lone pair of electrons on sulphur does not invert at a measurable rate at r. t..

The alternative location of the chiral centre in a [2,3] rearrange-ment is at the homoallylic position. This can be the case with sulphoxides since the sulphur is pyramidal and normally configuratioanally stable, i. e. the lone pair of electrons on sulphur does not invert at a measurable rate at r. t..



SOAr H

H

S-O

Ar

OH

H

S

Ar

OH

H

SAr

H

H

S-O

Ar

Enantiopure allylic sulphoxides racemise much more rapidly than those lacking an allyl group.

Enantiopure allylic sulphoxides racemise much more rapidly than those lacking an allyl group.



H

H Me

HArSO

SOAr

Me

H

H

H

OSArMe

H

SAr

Me

H

SOAr

H

Me

O-

Me

H

S-O

Ar

[2,3] Sigmatropic rearrangement provides a route for the inversion configuration of the allyl double bond in allyl sulphoxides.

[2,3] Sigmatropic rearrangement provides a route for the inversion configuration of the allyl double bond in allyl sulphoxides.

77 % 23 %

OO

两个构型不一致



+

H O

R

H

ArS

C5H11

HH

R

H

O

C5H11

HArS

H

H

O

C6H11

HArS

R

H

H

C5H11

R

HArS

O-

H

C5H11

H

H

RArS

O-

C5H11

HH

R

HS+

Ar O-

If an allylic sulphoxide contains a configured double bond and a chiral centre at the allylic position, equilibration via sulphenate inverts the configuration of the double bond and the chiral centre,in which the chirality at sulphur is not specified.

If an allylic sulphoxide contains a configured double bond and a chiral centre at the allylic position, equilibration via sulphenate inverts the configuration of the double bond and the chiral centre,in which the chirality at sulphur is not specified. Stereochemistry, Jian Pei, College of Chemistry, Peking University,


67

If a sulphenate esterisprepared from a chiral allylic alcohol Containing a configured double bond, the [2,3] sigmatropic re-arrangement sets up an equilibrium between two sulphenates.

If a sulphenate esterisprepared from a chiral allylic alcohol Containing a configured double bond, the [2,3] sigmatropic re-arrangement sets up an equilibrium between two sulphenates.

R C5H11

HHO 1. ArSCl, Et3N

2. P(OMe)3, MeOH

R C5H11

HArSO

H

C5H11

H

H

H

RS O-

ArC5H11O-S

R

H

Ar H

H

C5H11OS

R

H

Ar H

H

R C5H11OH

H H

Ar: p-MeC6H4

R: O

(CH2)6CO2Me

THPO



MeH

OH

H

1. KH2. ICH2SnMe3

3. BuLi, -78 oC4. MeOH, -78 oC

Me

H

HOHIn Cyclic Systems

Reduction of the conformational freedom of a system undergoing [2,3] rearrangement by its incorporation into a cyclic system will usually lead to increased stereoselectivity.

Reduction of the conformational freedom of a system undergoing [2,3] rearrangement by its incorporation into a cyclic system will usually lead to increased stereoselectivity.



Whereas the sulphoxide-sulphenate ester equilibrium usually lies on the side of the former, the selenoxide-selenate equilibrium favours the latter. The resulting selenate ester is readily hydrolysed to the alcohol.

Whereas the sulphoxide-sulphenate ester equilibrium usually lies on the side of the former, the selenoxide-selenate equilibrium favours the latter. The resulting selenate ester is readily hydrolysed to the alcohol.

OH

HO OMe

OO

ArSeCNBu3P

OArSe

H OMe

OO

H2O2pyr, CH2Cl2

O

OMe

OO

OH

H

Ar: o-NO2C6H4



S

H

1. OTf

2. LDA S

H

SH

[2,3] Rearrangement of an allyl sulphonium ylide is exemplified by the conversion of (A) to (B). Since this rearrangement regenerates an allylic thioether, it may be carried out iteratively to provide larger ring compounds.

[2,3] Rearrangement of an allyl sulphonium ylide is exemplified by the conversion of (A) to (B). Since this rearrangement regenerates an allylic thioether, it may be carried out iteratively to provide larger ring compounds.

A

B



X X X

X X X

4.14. 4.14. Simple Chirality Transfer via [3,3] Simple Chirality Transfer via [3,3] SigmatropicSigmatropic RearrangementRearrangement

The transition-state geometry for [3,3] sigmatropic rearrangement can be either chair- or boat-shaped. The transition-state geometry for [3,3] sigmatropic rearrangement can be either chair- or boat-shaped.

Like the [2,3] rearrangement, the concertedness of the [3,3] rearrangement is allowed since the symmetry of the orbitals of the two allyl radicals produced by (hypothetical) homolytic cleavage of the σ-bond allows for in-phase overlap of the terminal lobes to form a stable new - bond.

Like the [2,3] rearrangement, the concertedness of the [3,3] rearrangement is allowed since the symmetry of the orbitals of the two allyl radicals produced by (hypothetical) homolytic cleavage of the σ-bond allows for in-phase overlap of the terminal lobes to form a stable new - bond.


The all-carbon [3,3] rearrangement – the Cope rearrangement –is useful in stereoselective synthesis but we shall illustrate chirality transfer by particular reference to the Claisen rearrangement since this reaction has been more widely studied and used in stereoselective synthesis.

The all-carbon [3,3] rearrangement – the Cope rearrangement –is useful in stereoselective synthesis but we shall illustrate chirality transfer by particular reference to the Claisen rearrangement since this reaction has been more widely studied and used in stereoselective synthesis.

The Claisen rearrangement is closely related to the [2,3] Wittig rearrangement and, a sin the latter, a C-C bond is made at the expense of the C-O bond which is broken on a single face of the allyl system.

The Claisen rearrangement is closely related to the [2,3] Wittig rearrangement and, a sin the latter, a C-C bond is made at the expense of the C-O bond which is broken on a single face of the allyl system.



68

Acyclic Cases

Oa

H

H

b Oa

H

H

b

O

H

b

H

a

O

H

b

a

H

[1,4]chirality transfer

[1,3]chirality transfer



For chirality transfer using [3,3] sigmatropic rearrangement, there must be at least one chiral centre present in the pericyclic array and one configured double bond, and since in the Claisen rearrangement these is only one sp3-hydridised carbon, this must be the chiral centre. The chirality transfer in Claisen reactions is 1,4 or 1,3 depending on whether the configured double bond is present in the vinyl or allyl ether mioety.

For chirality transfer using [3,3] sigmatropic rearrangement, there must be at least one chiral centre present in the pericyclic array and one configured double bond, and since in the Claisen rearrangement these is only one sp3-hydridised carbon, this must be the chiral centre. The chirality transfer in Claisen reactions is 1,4 or 1,3 depending on whether the configured double bond is present in the vinyl or allyl ether mioety.



Oa

H

Hb Oa

H

H

b

Ob

Ha

H

Oa

H

bH

b

HO

a

H

diastereoisomers

a

H

OH

b

b

H

a

HO

Hb

Oa

H

Oa

H

H

b

b

H

H

O

a

diastereoisomers

enantiomers

enantiomers

There are four possible transition-state geometries through 1,4-chirality transfer can be effected using the single stereo-isomer of the vinyl ether. The product from two chairTSGs are diastereoisomers as are those from the two boat TSGs; the two diastereoisomers formed by the chair TSGs are enantiomers of those formed by the boat TSGs.

There are four possible transition-state geometries through 1,4-chirality transfer can be effected using the single stereo-isomer of the vinyl ether. The product from two chairTSGs are diastereoisomers as are those from the two boat TSGs; the two diastereoisomers formed by the chair TSGs are enantiomers of those formed by the boat TSGs.



Oa

H

Hb

c

Oa

H

b

H

c )(

The great use of the Claisen rearrangement in synthesis derives from a number of factors including: (a) the ease of preparation of substituted allyl vinyl ethers; (b) the equilibrium position which favours the carbonyl

compound;(c) the usefulness of products of the rearrangement for further

manipulation

The great use of the Claisen rearrangement in synthesis derives from a number of factors including: (a) the ease of preparation of substituted allyl vinyl ethers; (b) the equilibrium position which favours the carbonyl

compound;(c) the usefulness of products of the rearrangement for further

manipulation

(A) (B)



OH

R

Me

R

H

MeOO

H

R

Me

O

R

H

Me

R = Et: 9 : 1R = iPr: 13 : 1

Two important consequences of this preferencefor TSG (A).


Its value in stereoselective synthesis is the results not only of a clear preference either for chair transition state (usual for acyclic substrates) or for the boat (common for cyclic substrates), but also that chair TSG in which b is equatorial (A) rather than axial (B).

Its value in stereoselective synthesis is the results not only of a clear preference either for chair transition state (usual for acyclic substrates) or for the boat (common for cyclic substrates), but also that chair TSG in which b is equatorial (A) rather than axial (B).


)(O

H

Et

Me

Me Et

H

MeO

Me

O

H

Et

Me

Me

O

Et

H

Me

Me

> 99 % < 1%

1. There will be increasingly selective formation of an E-double bond as the 1,3-diaxial-type interaction in TSG (B) becomes more serious.

1. There will be increasingly selective formation of an E-double bond as the 1,3-diaxial-type interaction in TSG (B) becomes more serious.



69

R

OH

MeO OMe

Me NMe2

OMe

Me NMeMeO-

R

O

MeO NMe2

R

O

NMe2

O

R

NMe2

Relevant to the nature of c is the reaction by which the vinyl ether in the starting materials is formed. Two valuable modifications of the Claisen rearrangement in situ and in both, the bulk of the c group leads to enhanced diastereoselectivity.

Relevant to the nature of c is the reaction by which the vinyl ether in the starting materials is formed. Two valuable modifications of the Claisen rearrangement in situ and in both, the bulk of the c group leads to enhanced diastereoselectivity.



R

OH

R

O

EtO

R

O

OEt

, 138 oCMeC(OEt)3

EtCO2H

A closely related procedure uses an orthoester as the source of the vinyl ether carbons and the product is an ester, a weak acid is usually present here as a catalyst.

A closely related procedure uses an orthoester as the source of the vinyl ether carbons and the product is an ester, a weak acid is usually present here as a catalyst.



R

O

O

1. LDA2. R'3SiCl

O

OSiR'3 H

R

O

R

H

OSiR'3

O

OSiR'3

R

Not only does the trialkylsilyloxy group improve the stereoselectivity [large diaxial repulsion between R and OSiR1

3 in the alternative chair TSG (down)] but it also facilitates the rearrangement such that it proceeds at or close to ambient temperature.

Not only does the trialkylsilyloxy group improve the stereoselectivity [large diaxial repulsion between R and OSiR1

3 in the alternative chair TSG (down)] but it also facilitates the rearrangement such that it proceeds at or close to ambient temperature.



O

H

Me

Me

Me2N

O Me

NMe2

Me

H

Me Me

HHOC(OMe)2

NMe2

Me

xylene, 17 h

2. Use of an enantiopure allyl vinyl ether will result in a product of predictable configuration at its sp3-chiral centre.

2. Use of an enantiopure allyl vinyl ether will result in a product of predictable configuration at its sp3-chiral centre.

90 % enantioselectivity

Two important consequences of this preference for TSG (A).



Enantiopurified secondary allyl alcohols required for enantioselective Claisen rearrangement are accessible by enantioselective reduction of acetylenic ketones with Alpineborane or by kinetic resolution using the enantioselective Sharpless epoxidation.

Enantiopurified secondary allyl alcohols required for enantioselective Claisen rearrangement are accessible by enantioselective reduction of acetylenic ketones with Alpineborane or by kinetic resolution using the enantioselective Sharpless epoxidation.



Use of sterically hindered Al catalysts.

The bulky Al catalyst, by complexing to the ether oxygen, forces the isobutyl group to occupy the pseudo-axial position, if the the oxygen is more sp2- than sp3-hybridised.

The bulky Al catalyst, by complexing to the ether oxygen, forces the isobutyl group to occupy the pseudo-axial position, if the the oxygen is more sp2- than sp3-hybridised.

OiBu

MeBr

But

But

OAl

Me

O

tBu

tBu

Br

OMe

Bui

Al

OMe

AlBui )(

OMe

BuiH

_

OMe

Bui

H

78 % e. e.

84 : 16



70

O b

OSiR3

aO

H

ba

O-

R3SiClO

H

ba

OSiR3

O

H

ba

O

LDA

O

H

b

O-

a

O b

OSiR3

a

R3SiClO

H

b

OSiR3

a

A difficulty in practice in bringing about 1,4-chirality transfer in Claisen rearrangement is the generation of a configurationally homo-geneous vinyl ether double bond in the vinyl allyl ether undergoing rearrangement.

High selectivity 9 : 1



OBnO

OH

Me

Li

LDA

OBnO

O

Me3SiCl

OBnO

OTMSH

Me1. H2O2. CH2N2

OBnO

OMeH

Me

If the substituent a contains achelating atom (O, S or N), the configurational purity of the silyl ketene acetal is often assured because the chelation in the enolate demands that the double bond be contained in a ring.

If the substituent a contains achelating atom (O, S or N), the configurational purity of the silyl ketene acetal is often assured because the chelation in the enolate demands that the double bond be contained in a ring.



OO

chair

H

MeO

boat

H

MeO

H

[3,3]Sigmatropic Rearrangement Involving Rings.[3,3]Sigmatropic Rearrangement Involving Rings.



If the allyl unit in the Claisen rearrangement is confined to a ring with eight or less members, the four TSGs available in an acyclic case are reduced to two. Only one face of the allyl double bond can enter into the rearrangement and the configuration of the new chiral centre on the ring is predictable irrespectiveof whether a chair or boat TSG is involved.

If the allyl unit in the Claisen rearrangement is confined to a ring with eight or less members, the four TSGs available in an acyclic case are reduced to two. Only one face of the allyl double bond can enter into the rearrangement and the configuration of the new chiral centre on the ring is predictable irrespectiveof whether a chair or boat TSG is involved.



H

R1O

HR2

R4

R3

O

R2

H

R1

R4

R3)( H

R1O

R2

R4

R3

A substituent R2 on the vinyl ether double bond and cissubstituents R3, R4 on the ring are likely to destabilise the chair more than the boat form, and it is in this case that the boat-derived stereostructure is most likely to be found for the product.

A substituent R2 on the vinyl ether double bond and cissubstituents R3, R4 on the ring are likely to destabilise the chair more than the boat form, and it is in this case that the boat-derived stereostructure is most likely to be found for the product.

Boat-derived product



O

H

HOH

O

Me

Me

1. LDA

2. TMSCl O

H

HOTMSH

TMSO

Me

Me

OTMSO

Me

TMSO

Me

PhCH3reflux

TMSOO

OTMS

Me

Me H

H

HO

Me

MeMeO2C

When the vinyl ether moiety is confined to aring of eight or less atoms, the only possibleTSG is the boat form. The Ireland-Claisenrearrangement is capable of bringing about the formation of a quaternary chiral centre.

When the vinyl ether moiety is confined to aring of eight or less atoms, the only possibleTSG is the boat form. The Ireland-Claisenrearrangement is capable of bringing about the formation of a quaternary chiral centre.

A quaternary chiral centre:in this case, directly bonded to two tertiary chiral centres.

A quaternary chiral centre:in this case, directly bonded to two tertiary chiral centres.



71

OH

OH O -

H

H

H +

H

HO



Both the Claisen and Cope rearrangements may lead to products in which one of the double bonds in the first-formed product is part an enolate which is converted into a ketone in the work-up. In the retro-synthetic analysis of the product as a target molecule, vinylcarbinol does not immediately suggest itself as a precursor– the synthetic potential of the [3,3] rearrangement is disguised. This disguised results from need to draw the enolised form of the product in an unfovoured boat conformation for the possibility of the reverse sigmatropic rearrangement to become evident

Both the Claisen and Cope rearrangements may lead to products in which one of the double bonds in the first-formed product is part an enolate which is converted into a ketone in the work-up. In the retro-synthetic analysis of the product as a target molecule, vinylcarbinol does not immediately suggest itself as a precursor– the synthetic potential of the [3,3] rearrangement is disguised. This disguised results from need to draw the enolised form of the product in an unfovoured boat conformation for the possibility of the reverse sigmatropic rearrangement to become evident



Nevertheless, blowing the cover of a disguised reverse [3,3] sigmatropic rearrangement may be rewarding, particularly since the anionic ‘oxy-Cope’ rearrangement can be carried out under very mild conditions. Evans and Golob showed that conversion of alcohol into its alkoxide brought about an increase of up to 1017-fold in the rate of the Cope rearrange-ment. Thus, whereas thermal rearrangement of the starting material was previously carried out at 300 oC, the potassium alkoxide, in the presence of a crown ether, rearrangement below room temperature.

Nevertheless, blowing the cover of a disguised reverse [3,3] sigmatropic rearrangement may be rewarding, particularly since the anionic ‘oxy-Cope’ rearrangement can be carried out under very mild conditions. Evans and Golob showed that conversion of alcohol into its alkoxide brought about an increase of up to 1017-fold in the rate of the Cope rearrange-ment. Thus, whereas thermal rearrangement of the starting material was previously carried out at 300 oC, the potassium alkoxide, in the presence of a crown ether, rearrangement below room temperature.



Much use has been made of the mild conditions required for this anionic oxy-Cope rearrangement, particularly since the anionic oxygen has been found to have a preference for the ‘equatorial’ position which is greater than that of a hydroxygroup.

Much use has been made of the mild conditions required for this anionic oxy-Cope rearrangement, particularly since the anionic oxygen has been found to have a preference for the ‘equatorial’ position which is greater than that of a hydroxygroup.

Me Me

MeOH KH, 18-crown-6

DME, reflux

Me

MeMe

O-

H+

MeMe

HO

Me



R1 R2

OH

1. NaH

2. CF3CN3. H+, H2O

R1 R2

OHN

CF3

xylenereflux

R1 R2

NHCOCF3

Some examples of chirality transfer in [3,3] sigmatropic rearrangements other than the Claisen rearrangement:

Some examples of chirality transfer in [3,3] sigmatropic rearrangements other than the Claisen rearrangement:

S

S

MeCO3H S

S

O-

S

S

O-

S

SO



Me Me

S

Cl3CCOCl

Zn/Cu, Et2O

Cl2C C OS

O-

Cl

Cl

Me

Me

Cl

Cl

Me

Me

S

O

67 %, 81 e. e.



72

4.15. [1,5] 4.15. [1,5] SigmatropicSigmatropic RearrangementRearrangement

ba R

cd

ba

cd

R

ba

cd

R

ba

dc

R

ba

dc

R

ba

R

dc

Thermal [1,5] sigmatropic rearrangement of the C-R bond takes place suprafacially with retention of configuration in the migrating group R. The hypothetical homolytic cleavage of the C-R bond results in a pentadienyl radical whose terminal lobes have correct phase for this suprafacial rearrangement to occur.

Thermal [1,5] sigmatropic rearrangement of the C-R bond takes place suprafacially with retention of configuration in the migrating group R. The hypothetical homolytic cleavage of the C-R bond results in a pentadienyl radical whose terminal lobes have correct phase for this suprafacial rearrangement to occur.Stereochemistry, Jian Pei, College of Chemistry, Peking University,

ba R

cd

ba

cd

R

ba

cd

R

ba

dc

R

ba

dc

R

ba

R

dc

Thus, given the configurations of the terminal double bond and the chiral centre in the starting material, the transition state geometry allows one to predictconfidently the relationship between the configuration of the new chiral centre and that of the double bond in the product, although there remains the question of whether path (above) will be favoured over (down) or vice versa.

Thus, given the configurations of the terminal double bond and the chiral centre in the starting material, the transition state geometry allows one to predictconfidently the relationship between the configuration of the new chiral centre and that of the double bond in the product, although there remains the question of whether path (above) will be favoured over (down) or vice versa.



ba R

cd

ba

cd

R

ba

cd

R

ba

dc

R

ba

dc

R

ba

R

dc



In practice, the majority of [1,5] shifts have been those of hydrogen although other groups (CHO, PhCH3, SiMe3 and CH3CO) have been shown to have higher migratory aptitudes than hydrogen. Because of the difficulty in attainingthe s-cis-diene conformation depicted in an acyclic substrate, [1,5] shifts are most commonly found in dienyl systems which are contained in a ring and especially in cyclopentadienyl, cyclohexadienyl, cycloheptadienyl or cyclohepta-trienyl systems. The ambiguity as to the stereochemical outcome which exists in the acyclic case is also removed since superficial migration is possible only to one face in these cyclic systems.

In practice, the majority of [1,5] shifts have been those of hydrogen although other groups (CHO, PhCH3, SiMe3 and CH3CO) have been shown to have higher migratory aptitudes than hydrogen. Because of the difficulty in attainingthe s-cis-diene conformation depicted in an acyclic substrate, [1,5] shifts are most commonly found in dienyl systems which are contained in a ring and especially in cyclopentadienyl, cyclohexadienyl, cycloheptadienyl or cyclohepta-trienyl systems. The ambiguity as to the stereochemical outcome which exists in the acyclic case is also removed since superficial migration is possible only to one face in these cyclic systems.



R2

HR1

R2

R1

H

H

R2

R1

H

Unfortunately, it is often difficult in practice in these case to limit the [1,5] shift to a single migration and serial [1,5] H rearrangements often result. In cyclopentadienyl systems, facile [1,5] sigmatropic rearrangement usually means that isomeriacally pure mono- or disubstituted derivatives are unobtained. From a synthetic point of view this is most unfortunate because it limits the use of substituted cyclopentadienes as dienes in Diels-Alder cycloadditions: a mixture of interconverting dienes will usually result in an intractable mixture of isomeric adducts.

Unfortunately, it is often difficult in practice in these case to limit the [1,5] shift to a single migration and serial [1,5] H rearrangements often result. In cyclopentadienyl systems, facile [1,5] sigmatropic rearrangement usually means that isomeriacally pure mono- or disubstituted derivatives are unobtained. From a synthetic point of view this is most unfortunate because it limits the use of substituted cyclopentadienes as dienes in Diels-Alder cycloadditions: a mixture of interconverting dienes will usually result in an intractable mixture of isomeric adducts.



hydroquinoneBu3N, 190 oC

moreceasily redu1. H2/Pd2. O3

3. DMSwork-up

HOHC

O

Possibly the most useful [1,5] sigmatropic rearrangements are those used to in tandem reactions: the diene from one or more [1,5] shifts is trapped, often by an intramolecular pericyclic reaction.

Possibly the most useful [1,5] sigmatropic rearrangements are those used to in tandem reactions: the diene from one or more [1,5] shifts is trapped, often by an intramolecular pericyclic reaction.



73

ba H

cd

H H

cd

ba

H

H H

cdb

a H

More amenable to control are homo-[1,5] sigmatropic shifts in which a cyclopropane or other three-membered ring takes the place of one of the double bonds; the product is now non-conjugated and therefore cannot undergo a further [1,5] rearrangement. The migrating group here is again usually a hydrogen and the energetically favorable cleavage of the strainedthree-membered ring ensures that reaction is irreversible.

More amenable to control are homo-[1,5] sigmatropic shifts in which a cyclopropane or other three-membered ring takes the place of one of the double bonds; the product is now non-conjugated and therefore cannot undergo a further [1,5] rearrangement. The migrating group here is again usually a hydrogen and the energetically favorable cleavage of the strainedthree-membered ring ensures that reaction is irreversible.



OMe

MeH

H

H

98 oCCope

OMe

Me

OMe

Me

140 oC(homo-[1,5])

O

Me

Me

OMe

HH

H

cis-cyclopropane via a Cope rearrangementcis-cyclopropane via a Cope rearrangement

trans-cyclopropane via the homo-[1,5] sigmatropic rearrangementtrans-cyclopropane via the homo-[1,5] sigmatropic rearrangement



4.16. 4.16. Simple Chirality Transfer in the Simple Chirality Transfer in the EneEne ((RetroeneRetroene) Reaction) Reaction

The simplest all-carbon ene reaction

This reaction has features in common with both the Diels-Alder reaction and the [1,5] sigmatropic rearrangement of hydrogen, but the transition-state geometry (TSG) which results from overlap or orbitals is more like that of the [2,3] sigmatropic rearrangement.

This reaction has features in common with both the Diels-Alder reaction and the [1,5] sigmatropic rearrangement of hydrogen, but the transition-state geometry (TSG) which results from overlap or orbitals is more like that of the [2,3] sigmatropic rearrangement.

H

ene

H

'retro-ene'

'ene'

enophile


The ene reaction and its reverse, the retroene reaction, are pericyclic reactions: bonds are made and broken concertedly in a cyclic transition state involving six electrons and the symmetry of the orbitals involved is appropriate for this to occur.

The ene reaction and its reverse, the retroene reaction, are pericyclic reactions: bonds are made and broken concertedly in a cyclic transition state involving six electrons and the symmetry of the orbitals involved is appropriate for this to occur.



b

Hd

c

ab

Hdc

a

H

dc

a b

H

dc

a

b

diastereoisomers

Since there is a single sp3-centre available in ene reaction ensemble, simple chirality transfer requires this to be the chiral centre and one of two double bonds to be configured.

Since there is a single sp3-centre available in ene reaction ensemble, simple chirality transfer requires this to be the chiral centre and one of two double bonds to be configured.

Two transition state to diastereosiomeric productsTwo transition state to diastereosiomeric products



CO2MeMeO2C

S

D

HiPr

H

Ph

NN

D

H

iPrH

Ph

NN CO2Me

CO2Me

Both diastereoisomeric products are formed in the reaction in which the S/R ratio at the new chiral centre in the the product is the same as the D/H ratio at the vinyl position.

Both diastereoisomeric products are formed in the reaction in which the S/R ratio at the new chiral centre in the the product is the same as the D/H ratio at the vinyl position.

NN

D

iPrH

H Ph

NN

MeO2C

MeO2C

D

iPrH

H

Ph

CO2MeMeO2C



74

OSiME2But

SEt

Me H+ PhCHO Me2AlCl

CH2Cl2, -78 oC PhOSiMe2But

SEt

Me

OH

Me

HH

H

tBuMe2SiO

O

EtS

Al-

PhH

MeEtS

Ph HOH

tBuMe2SiO



Some of the the most useful stereoselective ene/retroene reactions have one or more carbon atoms in the ene or enophile components replaced by heteroatoms. Thus the role of the enophile is often taken on by N=N, C=O, O=O, etc., in stead of C=C or C≡C. With a carbonyl group as the enophile, the ene reaction can be catalysed by Lewis acids, e.g. SnCl4 or R3Al, which coordinate with the oxygen of the carbonyl group and greatly reduce the temperature at which the reaction will take place.

Some of the the most useful stereoselective ene/retroene reactions have one or more carbon atoms in the ene or enophile components replaced by heteroatoms. Thus the role of the enophile is often taken on by N=N, C=O, O=O, etc., in stead of C=C or C≡C. With a carbonyl group as the enophile, the ene reaction can be catalysed by Lewis acids, e.g. SnCl4 or R3Al, which coordinate with the oxygen of the carbonyl group and greatly reduce the temperature at which the reaction will take place.



SummarySummary

Simple chirality transfer reactions are those in which a chiral centre in the starting material is lost and a new chiral centre is created elsewhere in the molecule; this transformation is mediated by the shift of one or more double bonds, at least one of which is configured, to a new position in the product.Diastereoselectivity in these reactions is more likely when all or part of the system undergoing the chiraltity transfer is in-corporated into a cyclic system, although the substitution present in the starting material can sometimes give rise to high diastereoselectivity even in acyclic cases.

Simple chirality transfer reactions are those in which a chiral centre in the starting material is lost and a new chiral centre is created elsewhere in the molecule; this transformation is mediated by the shift of one or more double bonds, at least one of which is configured, to a new position in the product.Diastereoselectivity in these reactions is more likely when all or part of the system undergoing the chiraltity transfer is in-corporated into a cyclic system, although the substitution present in the starting material can sometimes give rise to high diastereoselectivity even in acyclic cases.


SummarySummary


The reversibility of the allylic sulphoxide-sulphenate ester [2,3]sigmatropic rearrangement allows the interconversion of diastereoisomeric sulphenate esters and hence provides a means of inverting the configuration in an enantiopure allylicalcohol at both the double bond and the chiral centre simultaneously.

The reversibility of the allylic sulphoxide-sulphenate ester [2,3]sigmatropic rearrangement allows the interconversion of diastereoisomeric sulphenate esters and hence provides a means of inverting the configuration in an enantiopure allylicalcohol at both the double bond and the chiral centre simultaneously.

The [3,3] sigmatropic rearrangement is a most valuable simple chirality transfer reaction because of the usual preference in an acyclic system for a chair-shaped transition state with the bulkier substituent located in an equatorial position. Using the Ireland-Claisen rearrangement requires methods for diatereoselective enolate generation. The oxy-Cope [3,3] sigmatropic rearrangement can proceed at even lower temperatures than the Ireland-Claisenrearrangement.

For the [1,5] sigmatropic rearrangement to be useful in synthesis,Ways must be found of circumventing the serial [1,5] sigmatropic rearrangements which otherwise tend to occur in cyclic dienes.

The [3,3] sigmatropic rearrangement is a most valuable simple chirality transfer reaction because of the usual preference in an acyclic system for a chair-shaped transition state with the bulkier substituent located in an equatorial position. Using the Ireland-Claisen rearrangement requires methods for diatereoselective enolate generation. The oxy-Cope [3,3] sigmatropic rearrangement can proceed at even lower temperatures than the Ireland-Claisenrearrangement.

For the [1,5] sigmatropic rearrangement to be useful in synthesis,Ways must be found of circumventing the serial [1,5] sigmatropic rearrangements which otherwise tend to occur in cyclic dienes.


SummarySummary

Type 2 Reactions


Chapter 5Chapter 5

75

Part 1Part 1

Simple Diastereoselectivity in 1,2-Addition to Alkenes,

Diels-Alder and 1,3-Dipolar Cycloadditions and The Ene Reactions


OutlineOutline

1. General;2. Relative Configuration in Type 2 Reactions;3. Epoxidaton, Aziridination and Cyclopropanation;4. Bromination and Similar additions to Alkenes;5. Hydroboration-Oxidation;6. Diels-Alder Reactions;7. Type 2 1,3-dipolar cycloadditions8. The Ene reaction9. Summary

1. General;2. Relative Configuration in Type 2 Reactions;3. Epoxidaton, Aziridination and Cyclopropanation;4. Bromination and Similar additions to Alkenes;5. Hydroboration-Oxidation;6. Diels-Alder Reactions;7. Type 2 1,3-dipolar cycloadditions8. The Ene reaction9. Summary


In Type 2 reactions, two or more chiral centres are formed simultaneously from one or more precursors, at least one of which is prochiral but neither of which is chiral; if a reagent is used, this is achiral.

In Type 2 reactions, two or more chiral centres are formed simultaneously from one or more precursors, at least one of which is prochiral but neither of which is chiral; if a reagent is used, this is achiral.


The largest number of highly diastereoselective Type 2 reactionsare those in which the prochiral precursors are double bonds, usually C=C, C=O, C=N or C=C-C=C. These reactions include:1) Those which result in the addition of X, X-X or X-Y across a

configured double bond;2) Many pericycle reactions including electrocyclic reactions,

cycloadditions, simatropic rearrangements and cheletropic additions.

The largest number of highly diastereoselective Type 2 reactionsare those in which the prochiral precursors are double bonds, usually C=C, C=O, C=N or C=C-C=C. These reactions include:1) Those which result in the addition of X, X-X or X-Y across a

configured double bond;2) Many pericycle reactions including electrocyclic reactions,

cycloadditions, simatropic rearrangements and cheletropic additions.


Type 2 ReactionsType 2 ReactionsType 2 Reactions

Almost all of the products from these Type 2 reactions are either cyclic or are formed via cyclic transition states and thediastereoselectivity which arises is referred to as simplediastereoselectivity.

Almost all of the products from these Type 2 reactions are either cyclic or are formed via cyclic transition states and thediastereoselectivity which arises is referred to as simplediastereoselectivity.

R R

a b+

x

y

'addition' a

bR

R

xy

R R

a b+

- RR' a

bR

R'

xy

R' R'

x y R = R' = Hoxidation

Two chiral centres are formed from addition of a precursor having a prochiral centre to a prochiral double bond.

Two chiral centres are formed from addition of a precursor having a prochiral centre to a prochiral double bond.

from the combination of two precursors each having prochiral centres.

from the combination of two precursors each having prochiral centres.


Relative Configuration in Type 2 ReactionsRelative Configuration in Type 2 Reactions

The absence of chirality in the precursor(s) in Type 2 reactionshas two important consequences:1) The products are always racemic and therefore any

stereoselectivity in Type 2 reactions will be diastereoselectivity;2) There can be no asymmetric introduction.

The absence of chirality in the precursor(s) in Type 2 reactionshas two important consequences:1) The products are always racemic and therefore any

stereoselectivity in Type 2 reactions will be diastereoselectivity;2) There can be no asymmetric introduction.

It is this latter consequence which distinguishes Type 2 from Type 3 reactions:Type 2 reactions become Type 3 (or Type 2/3) when one of the components contains a chiral centres.

It is this latter consequence which distinguishes Type 2 from Type 3 reactions:Type 2 reactions become Type 3 (or Type 2/3) when one of the components contains a chiral centres.

A characteristic of many Type 2 reactions which proceed via cyclic transition states is that they show inherent diastereoselectivity (stereospecificity).

A characteristic of many Type 2 reactions which proceed via cyclic transition states is that they show inherent diastereoselectivity (stereospecificity).


This arises from the single well defined transition state geometries (TSGs) through which the reactions proceed. The relative configuration at the two more chiral centres that are formed derives from the TSG and from the configuration(s) of the prochiral precursor(s).

This arises from the single well defined transition state geometries (TSGs) through which the reactions proceed. The relative configuration at the two more chiral centres that are formed derives from the TSG and from the configuration(s) of the prochiral precursor(s).

Other type 2 reactions (e.g. the aldol reaction) lack this inherent diastereoselectivity. Nevertheless, such reactions can occasionally exhibit high diastereoselectivity because of the particular combination of substituents on their reacting components. The occasional diastereoselectivity which results in Type 2 versions of these reactions will clearly be less reliable than inherent diastereoselectivity.

Other type 2 reactions (e.g. the aldol reaction) lack this inherent diastereoselectivity. Nevertheless, such reactions can occasionally exhibit high diastereoselectivity because of the particular combination of substituents on their reacting components. The occasional diastereoselectivity which results in Type 2 versions of these reactions will clearly be less reliable than inherent diastereoselectivity.


Relative Configuration in Type 2 ReactionsRelative Configuration in Type 2 Reactions

76

For some Type 2 reactions proceeding vi cyclic transition states(e.g. Diels-Alder reactions), the diastereoselectivity may be inherent or occasional or both, depending on the substitution ofthe reacting components.

For some Type 2 reactions proceeding vi cyclic transition states(e.g. Diels-Alder reactions), the diastereoselectivity may be inherent or occasional or both, depending on the substitution ofthe reacting components.


Relative Configuration in Type 2 ReactionsRelative Configuration in Type 2 Reactions EpoxidatonEpoxidaton, , AziridinationAziridination and and CyclopropanationCyclopropanation

In the Bartlett mechanisms for the epoxidation of alkenes using peroxyacids, both bonds to peroxy oxygen are formed from the same face of the configured double bond in a single step.

In the Bartlett mechanisms for the epoxidation of alkenes using peroxyacids, both bonds to peroxy oxygen are formed from the same face of the configured double bond in a single step.

a y

b x

OR

OOH

O

a yb x

O

a yb x

a y

b x

OR

OO H

Both faces of the alkene are equally likely to react in this way leading to a racemic product.

Both faces of the alkene are equally likely to react in this way leading to a racemic product.


The syn addition of oxygen to the double bond results in the inherent diastereoselectivity of the reaction and is a feature of all peroxyacid epoxidations of configured double bonds.

The syn addition of oxygen to the double bond results in the inherent diastereoselectivity of the reaction and is a feature of all peroxyacid epoxidations of configured double bonds.

The same syn addition is found in the formation of aziridines from alkenes using the aziridinating agent.The same syn addition is found in the formation of aziridines from alkenes using the aziridinating agent.

N

N

R O

NH2

Pd(OAc)4

N

N

R O

NHOAc

Me

Me

Me H

H Me

OMe

ONH

X

N

Me HH Me

X


EpoxidatonEpoxidaton, , AziridinationAziridination and and CyclopropanationCyclopropanation

The same syn addition is found in the cyclopropanation of alkenes using a carbenoid (the Simmons-Smith reaction).

The same syn addition is found in the cyclopropanation of alkenes using a carbenoid (the Simmons-Smith reaction).

Me MeH HMe Me

H H+ ICH2ZnI

Me Me

H HC

IZn I

H H

Type 2 aziridination and cyclopropanation of alkenes can also be brought about by cheletropic addition of singlet nitrenes and carbenes, respectively.

Type 2 aziridination and cyclopropanation of alkenes can also be brought about by cheletropic addition of singlet nitrenes and carbenes, respectively.


EpoxidatonEpoxidaton, , AziridinationAziridination and and CyclopropanationCyclopropanation

BrominationBromination and Similar additions to Alkenesand Similar additions to Alkenes

Bromination of a configured double bond is similar to epoxidation in that a cyclic bromonium ion is formed by syn addition to each face of the double bond. However, the bromonium ion undergoes spontaneous ring opening by bromide anion in an SN2 fashion leading to overall anti addition of bromide.

Bromination of a configured double bond is similar to epoxidation in that a cyclic bromonium ion is formed by syn addition to each face of the double bond. However, the bromonium ion undergoes spontaneous ring opening by bromide anion in an SN2 fashion leading to overall anti addition of bromide.

Br2 Br-

a y

b x

Br+

a yb x

Br+

a yb x

Bra

y

b

xBr

Bra

y

b

xBr


Ring opening of the bromonium ion is regiospecific with attack of bromide at the a,b-substituted carbon, although in fact the same racemic dibromide would have been obtained had the bromide attacked in the opposite regio-sense, at the x,y-substituted carbon (in the same SN2 fashion).

Ring opening of the bromonium ion is regiospecific with attack of bromide at the a,b-substituted carbon, although in fact the same racemic dibromide would have been obtained had the bromide attacked in the opposite regio-sense, at the x,y-substituted carbon (in the same SN2 fashion).

Br2, M+Nu-

Nu-a y

b xBr+

a yb x

Bra

y

b

xNu

Nua

y

b

xBr+ mirror image



77

Ring opening of the bromonium ion may be brought about by nucleophiles other than bromide if these are present (including the solvent itself) and in these cases there will be the possibility of regioisomer formation.

Ring opening of the bromonium ion may be brought about by nucleophiles other than bromide if these are present (including the solvent itself) and in these cases there will be the possibility of regioisomer formation.



Bromonium ion formation and ring opening in a stereo-defined way, if not always in a regio-defined way, is analogous to a number of other anti additions to alkenes which proceed via ring opening of –onium ions including episulphonium and selenenium as well as other halonium ions of which the iodonium ion is the most important.

Bromonium ion formation and ring opening in a stereo-defined way, if not always in a regio-defined way, is analogous to a number of other anti additions to alkenes which proceed via ring opening of –onium ions including episulphonium and selenenium as well as other halonium ions of which the iodonium ion is the most important.

S

RSe

R

O

R

The oxonium ion formed by reaction of an epoxide with an electrophile usually a proton or Lewis acid like the bromonium ion, then undergoes rapid SN2 ring opening by nucleophiles.These overall anti additions are more valuable because most other highly diastereoselective Type 2 additions to double bondstake place in a syn fashion.

The oxonium ion formed by reaction of an epoxide with an electrophile usually a proton or Lewis acid like the bromonium ion, then undergoes rapid SN2 ring opening by nucleophiles.These overall anti additions are more valuable because most other highly diastereoselective Type 2 additions to double bondstake place in a syn fashion.



HydroborationHydroboration--OxidationOxidation

Although the product from hydrogenation of an alkene is not cyclic, the transition state is regarded as being cyclic in character.

Although the product from hydrogenation of an alkene is not cyclic, the transition state is regarded as being cyclic in character.

R2BH

a y

b x

Type 2

a yb x

H BR2

a yb x

H BR2

H2O2, NaOH

Type 1

a yb x

H OH

The overall addition of water to the double bond is syn since replacement of the boron-carbon bond by oxygen-carbon proceeds with complete retention of configuration at carbon. Complete regioselectivity has been assumed with the boron adding to the x,y-substituted alkene carbon. This regioselectivity is normally determined by the bulk of the substituents a,b or x,y on the alkene, with the boron adding to the less substituted carbon.

The overall addition of water to the double bond is syn since replacement of the boron-carbon bond by oxygen-carbon proceeds with complete retention of configuration at carbon. Complete regioselectivity has been assumed with the boron adding to the x,y-substituted alkene carbon. This regioselectivity is normally determined by the bulk of the substituents a,b or x,y on the alkene, with the boron adding to the less substituted carbon.

区域选择性:B加到位阻小的C上


HydroxylationHydroxylation

Epoxidation of a configured double bond followed by treatment of the epoxide with aqueous acid brings about anti hydroxylation (also referred as dihydroxylation).

Epoxidation of a configured double bond followed by treatment of the epoxide with aqueous acid brings about anti hydroxylation (also referred as dihydroxylation).

O

a yb x

O

a yb x

H

OH H

-H+

OHa

y

b

xHO

+mirror image


A stereochemically complementary method for hydroxylation of alkene giving the product of syn addition uses osmium tetraoxide followed by cleavage of the osmate ester. It is possible that the osmate ester is formed by rearrangement of the four-membered ring species. The same syn-hydroxylation can be accomplished using potassium permanganate; in this case a cyclic manganate ester is an intermediate.

A stereochemically complementary method for hydroxylation of alkene giving the product of syn addition uses osmium tetraoxide followed by cleavage of the osmate ester. It is possible that the osmate ester is formed by rearrangement of the four-membered ring species. The same syn-hydroxylation can be accomplished using potassium permanganate; in this case a cyclic manganate ester is an intermediate.



a y

b x

a yb x

OOs

O

O O

OsO4

a yb x

OsOO O

O

NaHCO3

a yb x

OHHO

a y

b x KMnO4

a yb x

OMn

O

O O- H2O



78

The relative configuration shown for the two chiral centres is a consequence of the conrotatory mode of ring closure. This conrotatory ring closure is dictated by the symmetry of the highest occupied molecular orbital (HOMO), ψ2; only by rotating around the axes shown in the same sense does in-phase overlap of the p-orbitals on C-1 and C-4 (Frontier Molecular Orbital Theory).

The relative configuration shown for the two chiral centres is a consequence of the conrotatory mode of ring closure. This conrotatory ring closure is dictated by the symmetry of the highest occupied molecular orbital (HOMO), ψ2; only by rotating around the axes shown in the same sense does in-phase overlap of the p-orbitals on C-1 and C-4 (Frontier Molecular Orbital Theory).

Ring closure of the same butadiene by photochemical means via the HOMO of first excited single (ψ3) gives a cyclobutene having the alternative relative configuration since the orbital symmetry-directed cyclisation in this case is disrotatory.

Ring closure of the same butadiene by photochemical means via the HOMO of first excited single (ψ3) gives a cyclobutene having the alternative relative configuration since the orbital symmetry-directed cyclisation in this case is disrotatory.


HydroxylationHydroxylation Type 2 Type 2 PericyclicPericyclic ReactionsReactions

Electrocyclic ReactionsIn Type 2 4π→2π thermal electrocyclic ring closure, two configured double bonds are converted into two adjacent chiral centres.

In Type 2 4π→2π thermal electrocyclic ring closure, two configured double bonds are converted into two adjacent chiral centres.

ba x

y

b

a x

y a

b y

x

enantiomers

ba x

y

conrotatory

conrotatory


ba x

y

b

a y

x a

b x

y

enantiomers

ba x

y

disrotatory

disrotatory

hv

hv


Type 2 Type 2 PericyclicPericyclic ReactionsReactions CycloadditionsCycloadditions -- Inherent and Occasional Inherent and Occasional DiastereoselectivityDiastereoselectivity

In the Type 2 reactions, two adjacent chiral centres are formed in the product. In cycloadditions, more than two chiral centres may be formed and, when only two are formed, they are not necessarily on adjacent carbon atoms.

In the Type 2 reactions, two adjacent chiral centres are formed in the product. In cycloadditions, more than two chiral centres may be formed and, when only two are formed, they are not necessarily on adjacent carbon atoms.

ac

a+ y

xH

H y H

a a

xH+ mirror image

The singlet carbene adds in completely syn fashion to the configured alkene, i.e. the trans relationship of x and y in the alkene is retained in the cyclopropane product

The singlet carbene adds in completely syn fashion to the configured alkene, i.e. the trans relationship of x and y in the alkene is retained in the cyclopropane product


ac

a+ H

xH

y H y

a a

xH+ mirror image

Since addition to the corresponding cis-alkene gives only the product in which x and y are cis, this cycopropanation by singlet carbenes is stereospecific. This complete syn diastereoselectivity is inherent in the carbene cycloaddition mechanism and, in fact, is used to determine the spin state of the carbene since triplet carbenes do not normally show such complete diastereoselectivity.

Since addition to the corresponding cis-alkene gives only the product in which x and y are cis, this cycopropanation by singlet carbenes is stereospecific. This complete syn diastereoselectivity is inherent in the carbene cycloaddition mechanism and, in fact, is used to determine the spin state of the carbene since triplet carbenes do not normally show such complete diastereoselectivity.


CycloadditionsCycloadditions -- Inherent and Occasional Inherent and Occasional DiastereoselectivityDiastereoselectivity

y H

b a

xHa

cb

+ Hx

H

y H y

a b

xH

+ mirror image

If, however, the carbene bears two different substituents, then a third chiral centre is formed in the product.

If, however, the carbene bears two different substituents, then a third chiral centre is formed in the product.

Although both cyclopropanes have x and y trans (inherent diastereoselectivity), prediction of the relative configuration of the third (a,b-substituted) chiral centre is far from safe and both diastereoisomers will in general be formed, albeirt in unequal amounts.

Although both cyclopropanes have x and y trans (inherent diastereoselectivity), prediction of the relative configuration of the third (a,b-substituted) chiral centre is far from safe and both diastereoisomers will in general be formed, albeirt in unequal amounts.



79

The inherently diastereoselective part of the carbene addition is the result of concerted addition of the electron-deficient carbene to either enantioface of the alkene, a process analogous to epoxidation and giving rise to racemic cyclopropane.

The inherently diastereoselective part of the carbene addition is the result of concerted addition of the electron-deficient carbene to either enantioface of the alkene, a process analogous to epoxidation and giving rise to racemic cyclopropane.

ac

a+ y

xH

H y H

a a

xH+ mirror image

a y

b x

OR

OOH

O

a yb x

O

a yb xa y

b x

OR

OO H



Using a carbene bearing two different substituents, however, the two enantiofaces of the alkenes become diastereofaces when associated withthe carbene in the transition state. As a result, the two transition states

are diastereoisomeric and give rise to two racemic diastereoisomericproducts; in each case the inherent diastereoselectivity referred to above is still manifested.

Using a carbene bearing two different substituents, however, the two enantiofaces of the alkenes become diastereofaces when associated withthe carbene in the transition state. As a result, the two transition states

are diastereoisomeric and give rise to two racemic diastereoisomericproducts; in each case the inherent diastereoselectivity referred to above is still manifested.

x H

b a

yH

C

x H

a b

yH

C

x H

b a

yH

x H

a b

yHHx

ab

H y

Hx

ba

H y

Hx

ab

H y

Hx

ba

H y



Whether the creation of the third chiral centre at the erstwhile carbenecarbon results in a single diastereoisomers in the cyclopropanation(occasional diastereoselectivity) depends on the relative energies of these two compounds, which in turn will depend on the steric and/or electronic interactions between a and x (or y) and y (or x) in these transition states. These interactions can lead to to a single (relative) configuration at the third chiral centre (most often when metal-coordinated carbenes or carbenoids are used). However, complete diastereoselectivityin this sense is not inherent to the cyclopropanation.

Whether the creation of the third chiral centre at the erstwhile carbenecarbon results in a single diastereoisomers in the cyclopropanation(occasional diastereoselectivity) depends on the relative energies of these two compounds, which in turn will depend on the steric and/or electronic interactions between a and x (or y) and y (or x) in these transition states. These interactions can lead to to a single (relative) configuration at the third chiral centre (most often when metal-coordinated carbenes or carbenoids are used). However, complete diastereoselectivityin this sense is not inherent to the cyclopropanation.

The division of the diastereoselectivity obtaining in cyclo-propanation into inherent and occasional is typical of many of the Type 2 cycloadditions which follow.

The division of the diastereoselectivity obtaining in cyclo-propanation into inherent and occasional is typical of many of the Type 2 cycloadditions which follow.


CycloadditionsCycloadditions -- Inherent and Occasional Inherent and Occasional DiastereoselectivityDiastereoselectivity DielsDiels--Alder ReactionsAlder Reactions

The transition-state geometry for the Diels-Alder reaction is that shown below, where both components add suprafacially. This is the best way in which the frontier molecular orbitals of the diene and dienophile can overlap in-phase.

The transition-state geometry for the Diels-Alder reaction is that shown below, where both components add suprafacially. This is the best way in which the frontier molecular orbitals of the diene and dienophile can overlap in-phase.

HOMO

LUMO HOMO

LUMO


DielsDiels--Alder ReactionsAlder Reactions

In the Type 2 Diels-Alder reactions, both the diene and the dieno-phile are achiral and if a catalyst is used, this is also achiral. Diels-Alder reactions in which chiral centres are present in the sub-stiuents on the diene, or catalyst are Type 3 or Type 2/3 and will be considered later.

In the Type 2 Diels-Alder reactions, both the diene and the dieno-phile are achiral and if a catalyst is used, this is also achiral. Diels-Alder reactions in which chiral centres are present in the sub-stiuents on the diene, or catalyst are Type 3 or Type 2/3 and will be considered later.


HOMO

LUMO HOMO

LUMO

As the transition-state geometry shows above, syn addtion takes place on one face of dienophile by the diene and reciprocally on one face of the diene by the dienophile. This mutual (stereospecific) syn addition of diene and dienophile is an inherent stereochemical characteristic of the Diels-Alder reactions.

As the transition-state geometry shows above, syn addtion takes place on one face of dienophile by the diene and reciprocally on one face of the diene by the dienophile. This mutual (stereospecific) syn addition of diene and dienophile is an inherent stereochemical characteristic of the Diels-Alder reactions.



80

Ha

a HH

yx

H

2 3

Hy

xH

Ha

a H

23

Hy

xH

H

a

a

H23

a

xa y

1

2

5 5'



It is reflected in the stereostructure of the product cyclohexene (5), in which four chiral centres have been created in the reaction of diene (1) and dienophile (2). Thus in (5), the trans disposition of x and y in the dienophile (2), and of the substituents a (relative to the C2-C3 bond) of the diene (1), has been retained.

It is reflected in the stereostructure of the product cyclohexene (5), in which four chiral centres have been created in the reaction of diene (1) and dienophile (2). Thus in (5), the trans disposition of x and y in the dienophile (2), and of the substituents a (relative to the C2-C3 bond) of the diene (1), has been retained.



Ha

a HH

yx

H

2 3

Hy

xH

Ha

a H

23

Hy

xH

Ha

a

H2

3

or Hy

Hx

H

a

a

H23

Hy

xH

H

a

a

H23

a

xa y

1

23 4

5 5'



There is now little doubt that the Diels-Alder reactions can proceed via a continuum of transition states in terms of the degree to which the new –bonds between the diene and dienophileare made. However, complete syn diastereoselectivity in addtionsto the dienophile is a stereochemical ballmark of all Diels-Alder reactions and means, for example, that for the reaction the cycolhexene diastereoisomers (3) and (4) are not obtained.

There is now little doubt that the Diels-Alder reactions can proceed via a continuum of transition states in terms of the degree to which the new –bonds between the diene and dienophileare made. However, complete syn diastereoselectivity in addtionsto the dienophile is a stereochemical ballmark of all Diels-Alder reactions and means, for example, that for the reaction the cycolhexene diastereoisomers (3) and (4) are not obtained.



The enantiomeric product and the transition state which leads to it are drawn as the mirror images of thosshown in the previous scheme. Reacting opposite face of both dieneand dienophile to those used in the previous scheme will also lead to enantiomers. In the remainder of this chapter, the products from Type 2 reactions will usually be drawn as a single enantiomers but will in fact always have been formed as racemates.

The enantiomeric product and the transition state which leads to it are drawn as the mirror images of thosshown in the previous scheme. Reacting opposite face of both dieneand dienophile to those used in the previous scheme will also lead to enantiomers. In the remainder of this chapter, the products from Type 2 reactions will usually be drawn as a single enantiomers but will in fact always have been formed as racemates.

yx

H

H

aHH a

yx

H

H

a

HHa

a

H H

aH

H

y

x

xH

a

Hy

a

H

H

enantiomers



In this transition state, y locates on the same side as the diene (the endo position) and x on the opposite side (the exo position) and the product is therefore (5): in the transition state in anotherscheme, the location of x and y is revised, x being endo and y exo. In this scheme, the inherent syn addition of diene to dienophileand dienophile to diene still obtains.

In this transition state, y locates on the same side as the diene (the endo position) and x on the opposite side (the exo position) and the product is therefore (5): in the transition state in anotherscheme, the location of x and y is revised, x being endo and y exo. In this scheme, the inherent syn addition of diene to dienophileand dienophile to diene still obtains.

y

HH

x

Ha

a H

23

y

HH

x

H

a

a

H23

a

xa y

5 5'

endo

exo exo,endo是针对某个取代基而言的



81

Comparison of the two cyclohexene products reveals that these are indeed diastereoisomers and not enantiomers or regiomers. Where one or other or both of these diastereoisomers is produceddepends on the preference of x (or y) for the endo (or exo) position. This exo/endo diastereoselectivity of the Diels-Alder reaction is occasional, although in ether case the inherent synaddition to the dienophile and diene still prevails.

Comparison of the two cyclohexene products reveals that these are indeed diastereoisomers and not enantiomers or regiomers. Where one or other or both of these diastereoisomers is produceddepends on the preference of x (or y) for the endo (or exo) position. This exo/endo diastereoselectivity of the Diels-Alder reaction is occasional, although in ether case the inherent synaddition to the dienophile and diene still prevails.

yx

H

H

a

HHa

y

HH

x

H

a

a

H23

5



The situation at this point is very similar to that described earlier for addition of an unsymmetrical carbene to a figured alkenes: diastereoselectivity is in part inherent and in part occasional. However, there is an additional complication in the Diels-Alder reaction when both the diene and the dienophile are unsymmetrically substituted. This is the problem not of diastereoselectivity but of regioselectivity.

The situation at this point is very similar to that described earlier for addition of an unsymmetrical carbene to a figured alkenes: diastereoselectivity is in part inherent and in part occasional. However, there is an additional complication in the Diels-Alder reaction when both the diene and the dienophile are unsymmetrically substituted. This is the problem not of diastereoselectivity but of regioselectivity.



Hx

y

H

Hb

a HH

xy

H

H

b

a

Hb

ya x

xH

Hy

Hb

a Hx

HH

y

H

b

a

Hb

ya x

Hy

xH

Hb

a HH

yx

H

H

b

a

Hb

xa y

y

HH

x

Hb

a Hy

HH

x

H

b

a

Hb

xa y

diastereoisomers

diastereoisomers

regioisomers

Thus in the reaction of the unsymmetrical diene and dienophile there are four possible products (each a racemate; only one enantiomers of each is shown).

Thus in the reaction of the unsymmetrical diene and dienophile there are four possible products (each a racemate; only one enantiomers of each is shown).



Consequently, for the formation of a single product, the Type 2 Diels-Alder reactions must be completely diastereoselective in the exo/endo sense and also completely regioselective; syn addition to the diene and the dienophile can be taken for granted.

Consequently, for the formation of a single product, the Type 2 Diels-Alder reactions must be completely diastereoselective in the exo/endo sense and also completely regioselective; syn addition to the diene and the dienophile can be taken for granted.



RegioselectivityRegioselectivity in the Dielsin the Diels--Alder ReactionsAlder Reactions

Frontier molecular orbital theory can be used to predict the regioselectivity of Diels-Alder reactions by

(a) Identifying the HOMO and LUMO of diene and dienophilewhich are closer in energy.

(b) Containing the orbital coefficients on the terminal atoms of the diene and dienophile in this HOMO-LUMO combination.

(c) Matching the larger coefficient at the 1 and 4 positions of the diene with the larger coefficient at the 1 and 2 positions of the dieneophile.

Frontier molecular orbital theory can be used to predict the regioselectivity of Diels-Alder reactions by

(a) Identifying the HOMO and LUMO of diene and dienophilewhich are closer in energy.

(b) Containing the orbital coefficients on the terminal atoms of the diene and dienophile in this HOMO-LUMO combination.

(c) Matching the larger coefficient at the 1 and 4 positions of the diene with the larger coefficient at the 1 and 2 positions of the dieneophile.


ax

HOMO LUMO

preferrred

a

x

a

x

'ortho'

'meta'

a

x1

4

5

6

Where the size of the circle represents the magnitude of the coefficients on the interacting lobes, formation of the ‘ortho” isomer is favored.

Where the size of the circle represents the magnitude of the coefficients on the interacting lobes, formation of the ‘ortho” isomer is favored.



82

In practice, formation of a single regioisomer in the sense is often the case when a is a strongly electron-donating substituents and x a strongly electron-withdrawing substituent. This regioselectivity is that which would result if, in the transition state, formation of the 4,5-bond has run slightly ahead of that of the 1,6-bond leading to stabilisation by a and x of the fractional charges thereby generated.

In practice, formation of a single regioisomer in the sense is often the case when a is a strongly electron-donating substituents and x a strongly electron-withdrawing substituent. This regioselectivity is that which would result if, in the transition state, formation of the 4,5-bond has run slightly ahead of that of the 1,6-bond leading to stabilisation by a and x of the fractional charges thereby generated.

ax

HOMO LUMO

preferrred

a

x

a

x

'ortho'

'meta'

a

x1

4

5

6



The regioselectivity of the Diels-Alder reactions may be affected by a number of factors including catalysis, pressure and solvent, but for the many reactions which are not very regioselective, one reliable solution is to tether the diene and dienophile together in such a way that the reaction -now intramolecular-can form only one regioisomer.

The regioselectivity of the Diels-Alder reactions may be affected by a number of factors including catalysis, pressure and solvent, but for the many reactions which are not very regioselective, one reliable solution is to tether the diene and dienophile together in such a way that the reaction -now intramolecular-can form only one regioisomer.



From our previous discussion, exo/endo diastereoselectivity is determined by the preference of the dienophile substituentsfor exo or endo positions in the cycloaddition transition state.

From our previous discussion, exo/endo diastereoselectivity is determined by the preference of the dienophile substituentsfor exo or endo positions in the cycloaddition transition state.

Exo/endo-Diastereoselectivity (occasional diastereoselectivity) in the Diels-Alder reaction

Exo/endo-Diastereoselectivity (occasional diastereoselectivity) in the Diels-Alder reaction

RO

O+

O

O

R

O

O

RH

H

R : OMe, 72 % CO2Me, 65 %


ExoExo//endoendo--DiastereoselectivityDiastereoselectivity

There are a few Diels-Alder reactions which show complete exo diastereoselectivity, usually as a result of steric repulsion in the endo transition state.

There are a few Diels-Alder reactions which show complete exo diastereoselectivity, usually as a result of steric repulsion in the endo transition state.



H

H

b

a

H

R

O

b

CORa

aH

b

HO

R

HOMO (diene)

LUMO (dienophile)

attractivesecondary interaction

primary interaction

endo Selectivity is found when the dienophile bears single carbonyl group. This is thought to result from an attractive secondary orbital interaction in the endo transition state between orbitals on the carbonyl group and the diene although other explanations have been suggested. In frontier orbital terms, this attractive secondary orbital interaction can be ascribed to overlap of orbitals of matching symmetry on the carbonyl carbon and the diene C-2 in the dominant HOMO-LUMO pair.

endo Selectivity is found when the dienophile bears single carbonyl group. This is thought to result from an attractive secondary orbital interaction in the endo transition state between orbitals on the carbonyl group and the diene although other explanations have been suggested. In frontier orbital terms, this attractive secondary orbital interaction can be ascribed to overlap of orbitals of matching symmetry on the carbonyl carbon and the diene C-2 in the dominant HOMO-LUMO pair.



The dienophile reacts as a 2π system but is, in fact, part of a 4 πsystem. The LUMO of this 4π system is that it has the appropriate symmetry for both primary and secondary orbital overlap with the HOMO of the 4π system of the diene.

The dienophile reacts as a 2π system but is, in fact, part of a 4 πsystem. The LUMO of this 4π system is that it has the appropriate symmetry for both primary and secondary orbital overlap with the HOMO of the 4π system of the diene.

O

O

O

O

OH

HOO

O

OH

Hno



83

Attractive secondary interactions of this type are the bias of the Alder endo rule which is more usually applied to bicyclicsystems, e.g. the formation of the endo isomer from reaction of cyclopentadiene and maleic anhydride.

Attractive secondary interactions of this type are the bias of the Alder endo rule which is more usually applied to bicyclicsystems, e.g. the formation of the endo isomer from reaction of cyclopentadiene and maleic anhydride.



The same endo selectivity is responsible for the stereostructure of the product from reaction of the acyclic diene and maleic anhydride.

The same endo selectivity is responsible for the stereostructure of the product from reaction of the acyclic diene and maleic anhydride.

O

O

O

O

OH

HOO

O

OH

Hno

OOO

OMe

TMSO

O

O

O

HOMe

H H

TMSO

O

OH

HOH

OMe

TMSO H+

O

H

H

O

OO

OMe





Complete endo selectivity in Diels-Alder reaction is the expectationrather that the rule. Thus the reactions of cyclopentadiene with various carbonyl-substituted dienophile show that the endo (carbonyl)-substituted diastereoiomers is not the exclusive product nor even sometimes the major product. It appears that a methyl group has its own attractive secondary interaction withthe diene and can compete with the carbonyl group for the endo position.

Complete endo selectivity in Diels-Alder reaction is the expectationrather that the rule. Thus the reactions of cyclopentadiene with various carbonyl-substituted dienophile show that the endo (carbonyl)-substituted diastereoiomers is not the exclusive product nor even sometimes the major product. It appears that a methyl group has its own attractive secondary interaction withthe diene and can compete with the carbonyl group for the endo position.



Me CO2Me

CO2Me+

CO2Me

CO2Me

Me CO2Me

Me

CO2Me

75 : 2594 : 6 (AlCl3)

CO2Me+

CO2Me

HCO2Me

H

78 : 2295 : 5 (AlCl3)

CO2MeMe+

CO2Me

MeCO2Me

Me

31 : 6960 : 40 (AlCl3)

Me

CO2Me

+

CO2Me

H

Me

CO2Me

H

Me

54 : 4694 : 6 (AlCl3)

endo (carbonyl) Diastereoselectivity is much improved by catalysis with Lewis acid although, in the case of methyl methacrylate, this only changes the endo/exo ratio from 31:69 to 60:40.

endo (carbonyl) Diastereoselectivity is much improved by catalysis with Lewis acid although, in the case of methyl methacrylate, this only changes the endo/exo ratio from 31:69 to 60:40.



NHCOCl3

+

CHO110 oC, 36 h

46 %

NHCOCl3CHO

NHCOCl3CHO

3 : 1

SPh

+

CO2Me 130 oC, 20 h

90 %

CO2Me

SPh

CO2Me

SPh

1 : 1

Incomplete endo selectivity is not restricted to Diels-Alder reactions with cyclopentadiene as the diene, as the example using acyclic dienes, only the cis-subsituted products are endo-derived. Not surprisingly, endo selectivity increases when dienophiles such as maleic anhydride are used in which both alkene carbons are substituted with carbonyl groups, and there are cis.

Incomplete endo selectivity is not restricted to Diels-Alder reactions with cyclopentadiene as the diene, as the example using acyclic dienes, only the cis-subsituted products are endo-derived. Not surprisingly, endo selectivity increases when dienophiles such as maleic anhydride are used in which both alkene carbons are substituted with carbonyl groups, and there are cis.



84

Increased diastereoselectivity may also be accompanied by increased regioselectivity and both can be accounted for in frontier orbital terms by an augmented secondary interaction.

Increased diastereoselectivity may also be accompanied by increased regioselectivity and both can be accounted for in frontier orbital terms by an augmented secondary interaction.

aH

b

HO

R

HOMO (diene)

LUMO (dienophile)

increase in orbital coefficient leading to greatersecondary interaction

without catalysis

aH

b

HOE+

R

with catalysis by E+



endo Diastereoselectivity for many Diels-Alder reactions along with regioselectivity and rate constants can be markedly increased by changes in other experimental conditions and particularly by using water as the solvent, by addition of metalsalts to organic solvents (e.g. LiClO4 in diethyl ether), and by an increase in pressure.

endo Diastereoselectivity for many Diels-Alder reactions along with regioselectivity and rate constants can be markedly increased by changes in other experimental conditions and particularly by using water as the solvent, by addition of metalsalts to organic solvents (e.g. LiClO4 in diethyl ether), and by an increase in pressure.

+

OMe

COMe

COMe+

in cyclopentadiene 3.9 : 1in H2O 21.4 : 1in H2O, LiCl 28 : 1



Thus, endo/exo selectivity in the reaction of cyclopentadieneand methyl vinyl ketone is increased in water and is increased further using water containing dissolved lithium chloride.

Thus, endo/exo selectivity in the reaction of cyclopentadieneand methyl vinyl ketone is increased in water and is increased further using water containing dissolved lithium chloride.



It is thought that, as a result of hydrophobic reactions with water, the reactants are aggregated and subjected to an internal pressure in the solvent cavities that they occupy. Thiseffect is magnified in the presence of lithium chloride.

It is thought that, as a result of hydrophobic reactions with water, the reactants are aggregated and subjected to an internal pressure in the solvent cavities that they occupy. Thiseffect is magnified in the presence of lithium chloride.

LiClO4, Et2O+

OMeO

CO2Me

CO2Me+

8 : 1 4 : 1

RT, 4 h94 %

H2O



Lithium perchlorate dissolves in diethyl ether, in the reaction of cyclopentadiene and methyl acrylate in this solvent, the exo/endo ratio is increased over that obtained using water. The origin of this increased selectivity is thought to be the result of lithium functioning as a Lewis acid.

Lithium perchlorate dissolves in diethyl ether, in the reaction of cyclopentadiene and methyl acrylate in this solvent, the exo/endo ratio is increased over that obtained using water. The origin of this increased selectivity is thought to be the result of lithium functioning as a Lewis acid.



Diels-Alder reactions using furans as dienes are potentially useful because the furans are often readily available and oxygen bridge in the bicyclo[2.2.1] adducts is easily broken. However, the reaction of simple furans in this reation is often reversible and the equilibrium may lie on the side of the furan and dienophile rather than adduct.

Diels-Alder reactions using furans as dienes are potentially useful because the furans are often readily available and oxygen bridge in the bicyclo[2.2.1] adducts is easily broken. However, the reaction of simple furans in this reation is often reversible and the equilibrium may lie on the side of the furan and dienophile rather than adduct.

O

O

O+

O

O

O

H

H

O O

OH

H+

20 kbar

1 bar



85

A further consequence of the reversibility is that, when the equilibrium does favor the adduct, a thermodynmicallyformed mixture of endo and exo products may be obtained. Occasional diastereoselectivity under these conditions is, in general, less likely than in kinetically controlled irreversibleDiels-Alder reactions

A further consequence of the reversibility is that, when the equilibrium does favor the adduct, a thermodynmicallyformed mixture of endo and exo products may be obtained. Occasional diastereoselectivity under these conditions is, in general, less likely than in kinetically controlled irreversibleDiels-Alder reactions



Characteristic of Diels-Alder reactions is a high negative volume of activation (from –25 to –45 cm3 for intermolecular reactions). The application of high pressures to these cycloadditions (8-20 kbar), therefore, increases the rate of reaction. Using simple furans, the application of high pressure often brings about Diels-Alder reactions in greater yields than can be achieved at atmospheric pressure and the products are kinetically formed. Formation of the endo diastereoisomer is usually favored but high diastereoselectivity is in common.

Characteristic of Diels-Alder reactions is a high negative volume of activation (from –25 to –45 cm3 for intermolecular reactions). The application of high pressures to these cycloadditions (8-20 kbar), therefore, increases the rate of reaction. Using simple furans, the application of high pressure often brings about Diels-Alder reactions in greater yields than can be achieved at atmospheric pressure and the products are kinetically formed. Formation of the endo diastereoisomer is usually favored but high diastereoselectivity is in common.



The Diels-Alder adducts, formed at high pressure, may start to dissociate at atmospheric pressure. If these adducts are required for synthetic purposes, therefore, they must be reacted directly in a way which eliminates this possibility of cycloreversion.

The Diels-Alder adducts, formed at high pressure, may start to dissociate at atmospheric pressure. If these adducts are required for synthetic purposes, therefore, they must be reacted directly in a way which eliminates this possibility of cycloreversion.

O

O

O+

O

O

O

H

H

O O

OH

H+

20 kbar

1 bar



The problem of both incomplete regioselectivity and endo/exodiastereoselectivity in the intermolecular Diels-Alder reactions arise because of the ability of diene and dienophile to react via different transition states of comparable energies.

The problem of both incomplete regioselectivity and endo/exodiastereoselectivity in the intermolecular Diels-Alder reactions arise because of the ability of diene and dienophile to react via different transition states of comparable energies.

Type 2 Intramolecular DielsType 2 Intramolecular Diels--Alder (IMDA) ReactionsAlder (IMDA) Reactions

Complete control of the regioselectivity in the Diels-Alder reaction can be exercised by linking the diene and dienophiletogether using a tether of limited length, i.e. comprised of a limited number of atoms. In practice, the tethers most often used contain three or four atoms with the diene linked at C-1 or C-4.

Complete control of the regioselectivity in the Diels-Alder reaction can be exercised by linking the diene and dienophiletogether using a tether of limited length, i.e. comprised of a limited number of atoms. In practice, the tethers most often used contain three or four atoms with the diene linked at C-1 or C-4.


These intramolecular Diels-Alder (IMDA) reactions lead, in the all-carbon cases, to hydroindene or hydronaphthalenesystems.

These intramolecular Diels-Alder (IMDA) reactions lead, in the all-carbon cases, to hydroindene or hydronaphthalenesystems.

(CH2)n (CH2)n

It is important to be able to represent the transition states for these IMDA reactions adequately so that interactions of substituents on the diene, dienophile and tether can be appreciated.

It is important to be able to represent the transition states for these IMDA reactions adequately so that interactions of substituents on the diene, dienophile and tether can be appreciated.



For the hydroindene system, the approach of diene and dienophile can be depicted as in the intermolecular versions.

For the hydroindene system, the approach of diene and dienophile can be depicted as in the intermolecular versions.

H HH

H

H

trans

H H

H

H

H

cis



86

For the hydronaphthalene system it is often more appropriate to draw the corresponding transition states such that the chair-like perspective of the tether becomes apparent.

For the hydronaphthalene system it is often more appropriate to draw the corresponding transition states such that the chair-like perspective of the tether becomes apparent.

H

H

H

H

H

H

trans

H

H

H

H

H

H

cis



A single regioisomer is formed in these IMDA reactions (when n≤4) because the alternative bicyclo[n.3.1] products would be considerably more strained and the transition states leading to them would be correspondingly raised in energy. Although suitable tethering of the diene and dienophile will dictate the regioselectivity of the Diels-Alder reaction, it does not necessarily the exo/endo diastereoselectivity; either cis or trans-fused bicyclic compounds can be formed.

A single regioisomer is formed in these IMDA reactions (when n≤4) because the alternative bicyclo[n.3.1] products would be considerably more strained and the transition states leading to them would be correspondingly raised in energy. Although suitable tethering of the diene and dienophile will dictate the regioselectivity of the Diels-Alder reaction, it does not necessarily the exo/endo diastereoselectivity; either cis or trans-fused bicyclic compounds can be formed.

(CH2)n

H

H

n = 3, 4

(CH2)n

H

H



However, when a cycloaddition such as the Diels-Alder reaction is carried out intramolecularly, particularly with a tether of limited length, new steric and electronic interactions may come into play by comparison with the intermolecular version of the reaction. In general the difference between exo and endotransition-state energies will be augmented by such interactions and higher occasional diastereoselectivity will result.

However, when a cycloaddition such as the Diels-Alder reaction is carried out intramolecularly, particularly with a tether of limited length, new steric and electronic interactions may come into play by comparison with the intermolecular version of the reaction. In general the difference between exo and endotransition-state energies will be augmented by such interactions and higher occasional diastereoselectivity will result.

An addition benefit of intramolecularity is entropy derived: the probability of the diene and dienophile coming together is increased if they are appropriately linked. This will manifest itself in reaction at a lower temperature than is needed for analogous intermolecular reactions and, consequently, by and large, to greater exo/endo selectivity.

An addition benefit of intramolecularity is entropy derived: the probability of the diene and dienophile coming together is increased if they are appropriately linked. This will manifest itself in reaction at a lower temperature than is needed for analogous intermolecular reactions and, consequently, by and large, to greater exo/endo selectivity.



Secondary orbital interactions can favour endo diastereoselectivitywith a carbonyl-bonded substituent on a dienophile and that this often feeble interaction can be augmented by complexation of the carbonyl group with a Lewis acid. This same increase in endodiastereoselectivity can be brought about in an acid-catalysedIMDA reaction.

Secondary orbital interactions can favour endo diastereoselectivitywith a carbonyl-bonded substituent on a dienophile and that this often feeble interaction can be augmented by complexation of the carbonyl group with a Lewis acid. This same increase in endodiastereoselectivity can be brought about in an acid-catalysedIMDA reaction.

aH

b

HO

R

HOMO (diene)

LUMO (dienophile)

increase in orbital coefficient leading to greatersecondary interaction

without catalysis

aH

b

HOE+

R

with catalysis by E+

H

H

b

a

H

R

O

aH

b

HO

R

HOMO (diene)

LUMO (dienophile)

attractivesecondary interaction

primary interaction



The triene is cyclised thermally to cis- and trans- hydroindenes (A) and (B) in a 28:72 ratio, whereas in the presence of ethylaluminium dichloride as a catalyst, only the trans-fused product is obtained, in 80 % yield.

The triene is cyclised thermally to cis- and trans- hydroindenes (A) and (B) in a 28:72 ratio, whereas in the presence of ethylaluminium dichloride as a catalyst, only the trans-fused product is obtained, in 80 % yield.

80 %

CO2Me

EtAlCl223 oC, 48 h

O

MeO

Al-

H

H

H

O

MeO

H

H

HH

O

MeO

H

H

H

150 oC, 40 h72 %72 parts28 parts

HH

H

CO2Me

HH

H

CO2Me

H

五元环的张力决定选择性



The effect of a catalyst cannot, however, always be relied upon;the corresponding triene containing the cis-α,β-unsaturated ester likewise gives a mixture of diastereoisomers but their ratio is almost unaffected by carrying out the reaction in the presence of Lewis acids such as EtAlCl2.

The effect of a catalyst cannot, however, always be relied upon;the corresponding triene containing the cis-α,β-unsaturated ester likewise gives a mixture of diastereoisomers but their ratio is almost unaffected by carrying out the reaction in the presence of Lewis acids such as EtAlCl2.

MeO2C

HCO2Me

H

HCO2Me

H

+

180 oC, 5 h 67 : 33

63 : 37Et2AlCl, 23 oC, 40 h



87

Higher endo diastereoselectivity appears to be more common in the formation of cis-hydronaphthalenes than cis-hydroindenes; possibly the four atom tether gives rise to a marginally looser transition states which allows more efficient secondary orbital interaction (a). The Lewis acid-catalysed reaction in (b) also gives the endo (carbonyl) adduct.

Higher endo diastereoselectivity appears to be more common in the formation of cis-hydronaphthalenes than cis-hydroindenes; possibly the four atom tether gives rise to a marginally looser transition states which allows more efficient secondary orbital interaction (a). The Lewis acid-catalysed reaction in (b) also gives the endo (carbonyl) adduct.

OSiEt3

H

HO

H

H

O

KF, MeOH, 0 oC

H

HO

(a)

六元环的柔性相对较大,endo选择性Stereochemistry, Jian Pei, College of Chemistry, Peking University,


O

O

O

H

HO

KF, MeOH, 0 oC(b)

H

O

H

HOAl 67 %

H

O

H

HO

E-diene



RHH

R

H

H

+

)(

H

H

R

H

H

R H)(R = H, 220 oC, 48 : 52R = Me, 160 oC, 94 : 6

trans cis

B

A



The exo/endo ratio in these IMDA reactions can be influenced by steric interactions between substituents in the diene and the tether (including ‘axial’ hydrogens). The steric interaction between an alkyl group R and the axial hydrogen shown in (A) is greater than that between R and the axial hydrogen shown in (B), so exo becomes the preferred mode of addition.

The exo/endo ratio in these IMDA reactions can be influenced by steric interactions between substituents in the diene and the tether (including ‘axial’ hydrogens). The steric interaction between an alkyl group R and the axial hydrogen shown in (A) is greater than that between R and the axial hydrogen shown in (B), so exo becomes the preferred mode of addition.



The presence of a heteroatom in the tether can also affect the exo/endo ratio. Complete diastereoselectivity arises from the preference for endo transition state (A) in which overlap of the urethane and diene systems is largely conserved and the A1,3-strain present in (A) is absent.

The presence of a heteroatom in the tether can also affect the exo/endo ratio. Complete diastereoselectivity arises from the preference for endo transition state (A) in which overlap of the urethane and diene systems is largely conserved and the A1,3-strain present in (A) is absent.

N

CO2Me

190 oC, 16 h N

MeO OH

H N

CO2MeH

H

endo

N

MeO OH)(

A

B



Heating the triene, whose diene component is linked to the dienophile via a non-terminal carbon atom, gave the oxabicyclo[4.3.1], which contains a bridgehead double bond. The tightness of the transition state here ensures that the reaction is completely diastereoselective (exo-ethoxycarbonyl) and, of course, completely regioselective.

Heating the triene, whose diene component is linked to the dienophile via a non-terminal carbon atom, gave the oxabicyclo[4.3.1], which contains a bridgehead double bond. The tightness of the transition state here ensures that the reaction is completely diastereoselective (exo-ethoxycarbonyl) and, of course, completely regioselective.

MeO O

HH

EtO2C

180 oC78 %

MeO O

HH

EtO2C 1. Pt/H22. NaOEt, EtOH

MeO

HH

EtO2C

CO2Et

?

MeOR

EtO2C

HH

EtO2C

(A)

(B)



88

Reduction of the double bond in (A) takes place exclusively fromthe exo face and ring opening give (B). To appreciate the selectivity inherent in this synthesis of (B) one need only consider the problems that would arise in its attempted synthesis starting with the intermolecular Diels-Alder reactions.

Reduction of the double bond in (A) takes place exclusively fromthe exo face and ring opening give (B). To appreciate the selectivity inherent in this synthesis of (B) one need only consider the problems that would arise in its attempted synthesis starting with the intermolecular Diels-Alder reactions.

Linking together the two partners in acycloaddition reaction by a tether designed to be easily broken is valuable for the stereo-selective synthesis of both cyclic and acyclic target molecules.

Linking together the two partners in acycloaddition reaction by a tether designed to be easily broken is valuable for the stereo-selective synthesis of both cyclic and acyclic target molecules.



Replacement of one or more atoms in the all-carbon Diels-Alder reaction by heteroatoms gives rise to six-membered-ring hetereocycles. The double bonds of hetereoatom-containing dienophiles include C=S, C=N, C=O, N=O, O=O, N=S=O and N=N and hetereoatom-containing dienes.

Replacement of one or more atoms in the all-carbon Diels-Alder reaction by heteroatoms gives rise to six-membered-ring hetereocycles. The double bonds of hetereoatom-containing dienophiles include C=S, C=N, C=O, N=O, O=O, N=S=O and N=N and hetereoatom-containing dienes.

HetereocyclesHetereocycles via Dielsvia Diels--Alder reactionsAlder reactions

O NRN

S

Of particular interest in stereoselective synthesis are the reactions of electron-rich dienes with carbonyl groups (usually aldehydes) as the dienophile. These reactions are catalysed by Lewis acids, e.g. zinc chloride or europium salts, and are highly endo diastereoselective.

Of particular interest in stereoselective synthesis are the reactions of electron-rich dienes with carbonyl groups (usually aldehydes) as the dienophile. These reactions are catalysed by Lewis acids, e.g. zinc chloride or europium salts, and are highly endo diastereoselective.


66 %TMSO

Me

OMe

H

OMeHMe H

Eu(fod)3

TMSOMe

OMe

H

Me

OMeH

H

Et3N, MeOH

O

Me

MeMe

OMeO

TFA, Et2O

O

Me

MeMe

O

Eu(fod)3, 0.5-5mol%

TMSOMe

OMe

MeCH3CHO

CHCl3

O

OCF3

tBu

fod

Eu试剂促使Me占endo

Me占e键,孤对电子占a键



The occasional diastereoselectivity is dominated by the large bulk of the europium with its associated ligands; its coordination to the carbonyl group anti to the methyl and its exo placement in the transition state to minimise steric effects lead to an endoplacement of the aldehyde methyl group.

The occasional diastereoselectivity is dominated by the large bulk of the europium with its associated ligands; its coordination to the carbonyl group anti to the methyl and its exo placement in the transition state to minimise steric effects lead to an endoplacement of the aldehyde methyl group.



The 2-methoxy substituent in the adduct can be retained or eliminated, depending on the work-up, and the products are related to natural sugars.

The 2-methoxy substituent in the adduct can be retained or eliminated, depending on the work-up, and the products are related to natural sugars.

The ability of other metal ions (Ti4+, Mg2+) to chelate α- and β-alkoxyaldehydes allows diastereoselective cycloaddtion of aldehydes with chiral centres α to the carbonyl group.

The ability of other metal ions (Ti4+, Mg2+) to chelate α- and β-alkoxyaldehydes allows diastereoselective cycloaddtion of aldehydes with chiral centres α to the carbonyl group.


HetereocyclesHetereocycles via Dielsvia Diels--Alder reactionsAlder reactions Type 2 1,3Type 2 1,3--dipolar dipolar cycloadditionscycloadditions

Like Diels-Alder reactions, 1,3-dipolar cycloadditions involve 4π + 2π concerted reaction of a 1,3-dipolar species (the 4πcomponent) and a dipolarophile (the 2π component).

Like Diels-Alder reactions, 1,3-dipolar cycloadditions involve 4π + 2π concerted reaction of a 1,3-dipolar species (the 4πcomponent) and a dipolarophile (the 2π component).

1,3-Dipoles can be divided into two classes:

1. Those in which three atoms comprising the 1,3-dipole are

linear;

2. Those in which they are not;

1,3-Dipoles can be divided into two classes:

1. Those in which three atoms comprising the 1,3-dipole are

linear;

2. Those in which they are not;


89

azomethine ylide

diazoalkane

nitroneazide

carbonyl ylide

nitrile ylide

ozonenitrile oxideBentlinear

C N O-+

C N C+ _

N N N+ _

N N C+ _

Table 1. Example of 1,3-dipolesTable 1. Example of 1,3-dipoles

O OO

- -

C CO

-+

C ON

-+

C CN

-+


Type 2 1,3Type 2 1,3--dipolar dipolar cycloadditionscycloadditions

Since the products of these cycloadditions are five-membered rings in which the 1,3-dipolar residue must be bent, one might expect the linear type to be less reactive than those which are already bent. This, however, does not seem to be important; the energy required to bend a linear dipole in the transition state is apparently relatively small.

Since the products of these cycloadditions are five-membered rings in which the 1,3-dipolar residue must be bent, one might expect the linear type to be less reactive than those which are already bent. This, however, does not seem to be important; the energy required to bend a linear dipole in the transition state is apparently relatively small.

a cb

-+ + x y cb

ax y

cb

ay x

+



As shown in this scheme, with an unsymmetrical 1,3-dipole and dipolarophile, the possibility of regioisomers arises. The major regioisomer formed in this case can be predicted using the same procedure applied to the Diels-Alder reaction-the HOMO/ LUMO pair closer in energy is identified and, within this pair, those terminal atoms on the dipole and dipolarophile bearing the largest orbital coefficients became bonded.

As shown in this scheme, with an unsymmetrical 1,3-dipole and dipolarophile, the possibility of regioisomers arises. The major regioisomer formed in this case can be predicted using the same procedure applied to the Diels-Alder reaction-the HOMO/ LUMO pair closer in energy is identified and, within this pair, those terminal atoms on the dipole and dipolarophile bearing the largest orbital coefficients became bonded.



Steric effects may control the sense of regioselectivity; nitrile oxides give adducts in which the oxygen atom becomes bonded to the more hindered end of the dipolarophile in the major regioisomer.

Steric effects may control the sense of regioselectivity; nitrile oxides give adducts in which the oxygen atom becomes bonded to the more hindered end of the dipolarophile in the major regioisomer.

+ NOtBu

Me Ph

tBu

Me

N+

Ph

O-

N

Ph

ClHO

Et3N

Some linear 1,3-dipoles, e.g. nitrile oxides, are not prochiral in these cycloadditions and so the only chiral centres in the product are those derived from syn addition to the dipolarophile.

Some linear 1,3-dipoles, e.g. nitrile oxides, are not prochiral in these cycloadditions and so the only chiral centres in the product are those derived from syn addition to the dipolarophile.

Steric effect大基团和O相邻



Nitrile oxides are unstable and must be generated in situ. In the reaction in next scheme, this carried out by thermolysis of the dimer (A), which is in equilibrium with a small concentration of the monomer (B). The relatively high temperature allows cycloaddition of (B) not only to 1,2-disubstituted alkenes but also to trisubstituted alkenes, which are normally less reactive.

Nitrile oxides are unstable and must be generated in situ. In the reaction in next scheme, this carried out by thermolysis of the dimer (A), which is in equilibrium with a small concentration of the monomer (B). The relatively high temperature allows cycloaddition of (B) not only to 1,2-disubstituted alkenes but also to trisubstituted alkenes, which are normally less reactive.

SetereochemistrySetereochemistry of 1,3of 1,3--Dipolar Dipolar CycloadditionsCycloadditions



ON

N

O-

OTMS

OTMS+135-165 oC

OTMSN

O-OTMS

O2N

PhN C OC6H6

Me

H

Me

MeO2C

A

2.2 equiv.

OTMSN

O-

Me

H

Me

MeO2C

NO OTMS

HMeO2CMe Me

B

脱水试剂, PhNH2 CO2


90

For prochiral 1,3-dipole, there can be prochiral syn addition to 1,3-dipole and dipolarophile, as in the Diels-Alder reaction (stereospecificity, inherent diastereoselectivity). However, unlike the Diels-Alder reaction in which the diene is invariably configurationally stable, the barrier to configurational inter-conversion (stereomutation) in bent 1,3-dipoles may be low as in, for example, azomethine ylides.

For prochiral 1,3-dipole, there can be prochiral syn addition to 1,3-dipole and dipolarophile, as in the Diels-Alder reaction (stereospecificity, inherent diastereoselectivity). However, unlike the Diels-Alder reaction in which the diene is invariably configurationally stable, the barrier to configurational inter-conversion (stereomutation) in bent 1,3-dipoles may be low as in, for example, azomethine ylides.



Na

b y

x

R

-+ -a

b

N

y

x

R

+ -a

b

N

x

y

R

+

N

R

xab y N

R

yab x

Na

b x

y

R

-+



Na

b y

x

R

-+ -a

b

N

y

x

R

+ -a

b

N

x

y

R

+

N

R

xab y N

R

yab x

Na

b x

y

R

-+

A B



Consequently, a mixture of diastereoisomeric cycloadductsmay be obtained (with each of the stereoisomeric 1,3-dipolar species A and B reacting with complete syn selectivity). Using unreactive dipolarophiles, this may be the result even if the 1,3-dipolar species was initially generated as a single diastereoisomer.

Consequently, a mixture of diastereoisomeric cycloadductsmay be obtained (with each of the stereoisomeric 1,3-dipolar species A and B reacting with complete syn selectivity). Using unreactive dipolarophiles, this may be the result even if the 1,3-dipolar species was initially generated as a single diastereoisomer.



However, for cycloaddition of prochiral 1,3-dipoles which react via a single configuration with a prochiral dipolarophile the consequence are analogous to those in the Diels-Alder reaction; four (racemic) products may be formed when regioisomers are also considered.

However, for cycloaddition of prochiral 1,3-dipoles which react via a single configuration with a prochiral dipolarophile the consequence are analogous to those in the Diels-Alder reaction; four (racemic) products may be formed when regioisomers are also considered.

endo/exo (occasional) Diastereoselectivity in 1,3-dipolar cycloaddition is, as in the Diels-Alder reaction, determined by the preference of the dipolarophile substituents for the endo or exo position. However, it appears that secondary orbital interactions which usually favour placement of, e.g. carbonyl substituents in the endo position in the Diels-Alder reactions, are much weaker in the corresponding 1,3-dipolar cycloaddition, if they are present at all.

endo/exo (occasional) Diastereoselectivity in 1,3-dipolar cycloaddition is, as in the Diels-Alder reaction, determined by the preference of the dipolarophile substituents for the endo or exo position. However, it appears that secondary orbital interactions which usually favour placement of, e.g. carbonyl substituents in the endo position in the Diels-Alder reactions, are much weaker in the corresponding 1,3-dipolar cycloaddition, if they are present at all.



Like nitrile oxides, azomethine ylides must be also be generated in situ and some of the different ways in which this can be done are shown.

Like nitrile oxides, azomethine ylides must be also be generated in situ and some of the different ways in which this can be done are shown.

(a) aziridine ring opening(a) aziridine ring opening

ArNH

MeO2C

ArNH

MeO2C

+

_

OO

O ArN

OO

O

H

MeO2CHH



91

(b) α-amino acid decarboxylation(b) α-amino acid decarboxylation

N CO2HH

+

O

O

OMeOH

OO

OH2+

N-O2C

OO

N+_

CO2MeHN

O N CO2Me_

+HN

O NCO2Me



(c) 1,2-prototropy

PhCHN

CO2Me

CHPh 105 oCC C

NPh

H Ph

CO2Me

H

-+ NPh

OO

NPhO

OHN

H

H

HPh

MeO2C Ph

(d) fluorosesilylation

N

Me

CH2SiMe3

AgF

N

Me

CH2-

Ag

+

MeO2C CO2Me

N

Me

CO2Me

CO2Me



Examples of diastereoselective nitrone and carbonyl ylide 1,3-dipolar cycloadditions.

Examples of diastereoselective nitrone and carbonyl ylide 1,3-dipolar cycloadditions.

N

O-

+ + Phtoluenereflux

+

H

Ph

NH

O-

NO

HCH2CH2Ph

H



CHO

O

N2

Rh2(OAc)2CHO

O

+ _CHO

O+

_

O OO

O

OO

O

OH

H

CH3 O

O

CH3

O

O

OH

H

+_



Intramolecular 1,3Intramolecular 1,3--Dipolar Dipolar CycloadditionsCycloadditions

The weakened endo-directing secondary orbital interaction in the transition state for 1,3-dipolar cycloaddition means that selectivity in the endo sense is reduced and may easily be overridden by other effects leading to exo diastereoselectivity. High regioselectivity also cannot be relied upon and in any case, where it obtains, the alternative regioisomer may be the one that is actually desired.

The weakened endo-directing secondary orbital interaction in the transition state for 1,3-dipolar cycloaddition means that selectivity in the endo sense is reduced and may easily be overridden by other effects leading to exo diastereoselectivity. High regioselectivity also cannot be relied upon and in any case, where it obtains, the alternative regioisomer may be the one that is actually desired.


Intramolecularity in 1,3-dipolar cycloadditions is an especially valuable device for directing the regiochemical course of the reaction, and often results in enhanced occasional (exo/endo) selectivity also. The latter is usually the result of the limited length of the tether, coupled with non-bonded interactions of substituents on the tether and the 1,3-dipole or dipolarophile. Electronic effects resulting from enforced orientations of substituents may also be introduced or magnified in these intramolecular 1,3-dipolar cycloadditions.

Intramolecularity in 1,3-dipolar cycloadditions is an especially valuable device for directing the regiochemical course of the reaction, and often results in enhanced occasional (exo/endo) selectivity also. The latter is usually the result of the limited length of the tether, coupled with non-bonded interactions of substituents on the tether and the 1,3-dipole or dipolarophile. Electronic effects resulting from enforced orientations of substituents may also be introduced or magnified in these intramolecular 1,3-dipolar cycloadditions.



92

Some examples of completely diastereoselective and regiospecificintramolecular 1,3-dipolar cycloadditions:

Some examples of completely diastereoselective and regiospecificintramolecular 1,3-dipolar cycloadditions:

MeO

OMe

CHOMeNHCH2CO2Et

toluene MeO

OMe

H

NCO2Et

HHMe

_+

NMeO

MeO

H

H

CO2Et

H

Me

89 %



OS

ArNHOH

S

H

ArNO-

H+

S

H

ArNO

H

R-Ni

74 %

Me

H

H

MeArNH

OH



H H

diene

dienophile

H H

enophile

The The EneEne ReactionsReactions

The ene and the Diels-Alder reactions are related pericyclicreactions which frequently co-occur in the reaction of a dienebearing an allylic C-H bond (an enecomponent) with dienophile.

The ene and the Diels-Alder reactions are related pericyclicreactions which frequently co-occur in the reaction of a dienebearing an allylic C-H bond (an enecomponent) with dienophile.

A



The inherent diastereoselectivity (stereospecificity) in the enereaction is evident from inspection of (A): both bonds are made syn to the enophile (the configuration of the enophile is retained in the product) and the bond made to the double bond of the enecomponent is syn to the hydrogen which is transferred.

The inherent diastereoselectivity (stereospecificity) in the enereaction is evident from inspection of (A): both bonds are made syn to the enophile (the configuration of the enophile is retained in the product) and the bond made to the double bond of the enecomponent is syn to the hydrogen which is transferred.


The role of the enophile can be assumed by the same double bonds that can function as dienophiles in the Diels-Alder reaction, e.g. C=O, C=N, C=S, N=N, N=O as well as C=C. Preparatively, aldehydes are particularly useful as enophilesbecause their reactivity is greatly increased by complexationwith Lewis acids, allowing them to be used at low temperatures. The products using aldehydes as enophiles are homoallylic alcohols, i.e. the ene reaction brings about the same transformation as is accomplished by using allylmetaladdition to the aldehyde.

The role of the enophile can be assumed by the same double bonds that can function as dienophiles in the Diels-Alder reaction, e.g. C=O, C=N, C=S, N=N, N=O as well as C=C. Preparatively, aldehydes are particularly useful as enophilesbecause their reactivity is greatly increased by complexationwith Lewis acids, allowing them to be used at low temperatures. The products using aldehydes as enophiles are homoallylic alcohols, i.e. the ene reaction brings about the same transformation as is accomplished by using allylmetaladdition to the aldehyde.



H

OH

R

H

O

HR

ene using aldehyde

M

OH

R

M

O

HR

ene using aldehyde

H+

H

O

HR



93

O

HH

HH

H H

HH

H

H

HH

HH

H

HO

43 o

39 o

The transition-state geometries of the lowest energy for the enereactions of propene with ethylene and of propene with formaldehyde have been calculated by Loncharich and Houkand found to be very similar. For the carbonyl-ene reaction, the substituents on carbons 1 and 1’ are staggered, as illustrated in the Newman projection along with the (forming) 1-1’ carbon-carbon formation.

The transition-state geometries of the lowest energy for the enereactions of propene with ethylene and of propene with formaldehyde have been calculated by Loncharich and Houkand found to be very similar. For the carbonyl-ene reaction, the substituents on carbons 1 and 1’ are staggered, as illustrated in the Newman projection along with the (forming) 1-1’ carbon-carbon formation.



The most important stereochemical features of the Type 2 enereaction by reference to the Lewis acid-catalysed reactions of aldehydes with allyl systems shall be illustrated. With some combinations of substituted ene/enophile the mechanism of the catalysed reaction may involve ion-pair intermediates, but this does not appear to be important for the reactions discussed below.

The most important stereochemical features of the Type 2 enereaction by reference to the Lewis acid-catalysed reactions of aldehydes with allyl systems shall be illustrated. With some combinations of substituted ene/enophile the mechanism of the catalysed reaction may involve ion-pair intermediates, but this does not appear to be important for the reactions discussed below.



O

HR

H

H H

Ha

b

ALn R

ba

HOH

Ra

HO

b

H

O

RH

H

H H

H

ab

ALn H

ba

ROH

Ra

H

b

OH

A endo

B exo



In the reaction of a 1,1-disubstituted propene with an aldehyde, two transition states, exo and endo, are possible. In these transition states, the carbonyl oxygen is assumed to be sp2-hybridised with the Lewis acid ALn, complexed to the lone pair syn to the aldehyde hydrogen to minimise steric effects.

In the reaction of a 1,1-disubstituted propene with an aldehyde, two transition states, exo and endo, are possible. In these transition states, the carbonyl oxygen is assumed to be sp2-hybridised with the Lewis acid ALn, complexed to the lone pair syn to the aldehyde hydrogen to minimise steric effects.



The major factors which control the occasional (exo/endo) diastereoselectivity in these ene reactions are (i) stericinteractions between R and a in (A) and between R and b in (B) and (ii) steric interactions between the Lewis acid ALn and substituents on the ene component.

The major factors which control the occasional (exo/endo) diastereoselectivity in these ene reactions are (i) stericinteractions between R and a in (A) and between R and b in (B) and (ii) steric interactions between the Lewis acid ALn and substituents on the ene component.



O

HMeO2C

H

H H

H

HMe

AlMe2OTf

CO2MeH

HO

Me

H

O

CO2MeH

H

H H

H

HMe

TfOMe2lAH

MeH

CO2MeOH

CO2MeH

H

Me

OH

-78 oC

CH2Cl2

-78 oCCH2Cl2

MeO2C

MeH

HOH

+

9 : 91

65 %

(A)(B)



94

Methyl glyoxylate reacts with an excess of (Z)-but-2-ene in the presence of AlMe2OTf to give a 9:91 ratio of diastereoisomers resulting from endo and exo addition, respectively. This is rationalised on the basis of greater steric interaction between substituents on the coordinated aluminium and the ene methyl group in (A) than between the methoxycarbonyl group and the same methyl group in (B).

Methyl glyoxylate reacts with an excess of (Z)-but-2-ene in the presence of AlMe2OTf to give a 9:91 ratio of diastereoisomers resulting from endo and exo addition, respectively. This is rationalised on the basis of greater steric interaction between substituents on the coordinated aluminium and the ene methyl group in (A) than between the methoxycarbonyl group and the same methyl group in (B).



Catalysis of the ene reaction of alkyl glyoxylates by tin(IV) chloride is different because the tin atom is able to complex with the oxygens of both carbonyl groups. Reaction with (E)-but-2-ene gives mainly trans-diastereoisomers (A) because of greater repulsion between the Lewis acid and the methyl group in (B). Cis and trans refer to the relative positions of the substituents(Me, OH) with the lonest chain drawn in the zig-zagconformation; the hydrogens at these chiral centres are omitted for clarity.

Catalysis of the ene reaction of alkyl glyoxylates by tin(IV) chloride is different because the tin atom is able to complex with the oxygens of both carbonyl groups. Reaction with (E)-but-2-ene gives mainly trans-diastereoisomers (A) because of greater repulsion between the Lewis acid and the methyl group in (B). Cis and trans refer to the relative positions of the substituents(Me, OH) with the lonest chain drawn in the zig-zagconformation; the hydrogens at these chiral centres are omitted for clarity.



OH

H

H H

H

MeH

SnCl4O

MeO

CO2MeMe

HO

H

H

H

HMe

CO2MeOH

CO2MeMe

H

H

OH

-78 oC

CH2Cl2

-78 oCCH2Cl2

MeO2C

MeH

HOH

A

O

H

H H

H

MeH

H

O

MeO

Cl4Sn

C B A : B = 92 : 8

构型相反



The same trans isomer is the major diastereoisomer obtained when (Z)-but-2-ene is used, although in this case the diastereoselectively is not high; probably there is some interaction between the olefinic proton and the substituents on the tin.

The same trans isomer is the major diastereoisomer obtained when (Z)-but-2-ene is used, although in this case the diastereoselectively is not high; probably there is some interaction between the olefinic proton and the substituents on the tin.



CO2MeH

HO

Me

H

-78 oCCH2Cl2

MeO2C

MeH

HOH

O

H

H H

H

HMe

H

O

MeO

Cl4Sn

trans : cis = 72 : 28

On the other hand, this 2-trimethylsilyl substituent brings about a reversal of the sense of diastereoselectivity using the 1,2-cis-dimethyl isomer.

On the other hand, this 2-trimethylsilyl substituent brings about a reversal of the sense of diastereoselectivity using the 1,2-cis-dimethyl isomer.



TMS

trans:cis = 98:2

OH

TMS

H H

H

MeH

SnCl4O

MeO

H

HMe

CO2MeOH

TMS

CO2MeMe

H

H

OH

-78 oC

CH2Cl2

A

The presence of an additional substituent on the enecomponent can further increase the diastereoselectivity.

The presence of an additional substituent on the enecomponent can further increase the diastereoselectivity.



95

TMS

trans:cis = 7:93

OH

TMS

H H

H

HMe

SnCl4O

MeO

H

MeH

CO2MeOH

TMS

CO2MeH

H

Me

OH

-78 oC

CH2Cl2

A


The The EneEne ReactionsReactions RegioselectivityRegioselectivity in The in The EneEne ReactionsReactions

Two major drawbacks to the use of the intermolecular ene reaction in synthesis have been the high temperatures previously needed for reaction and the lack of regioselectivity generally exhibited in such cases. The discovery that Lewis acid catalysis enables the intermolecular carbonyl ene reaction to be accomplished at temperatures as low as –78 oC with beneficial effects on the diastereoselectivity has stimulated efforts to bring about regioselectivity in the reaction.

Two major drawbacks to the use of the intermolecular ene reaction in synthesis have been the high temperatures previously needed for reaction and the lack of regioselectivity generally exhibited in such cases. The discovery that Lewis acid catalysis enables the intermolecular carbonyl ene reaction to be accomplished at temperatures as low as –78 oC with beneficial effects on the diastereoselectivity has stimulated efforts to bring about regioselectivity in the reaction.


Me

RO+

O

H CO2Me

SnCl4 -78 oC

CH2Cl2RO

OH

CO2Me

R = Si(CH3)(t-Bu), CH2Ph, Ph

As usual, this can be accomplished by carrying out the reaction intramolecularly, but work by Nakaihas shown that, in an intermolecular reaction, an allylic oxygen or even a homoallylic oxygen can retard hydrogen transfer from this allyllic position, thereby favouring transfer from alternative allylic position.

As usual, this can be accomplished by carrying out the reaction intramolecularly, but work by Nakaihas shown that, in an intermolecular reaction, an allylic oxygen or even a homoallylic oxygen can retard hydrogen transfer from this allyllic position, thereby favouring transfer from alternative allylic position.


RegioselectivityRegioselectivity in The in The EneEne ReactionsReactions

CH2

RO Se+

H

R

O-RO

Hnot

H

OR

The effect seems to be partly steric and partly electronic on origin and is reminiscent of the complete regioselectivitywhich obtains in the syn elimination reactions of β-alkoxyalkylselenoxides.

The effect seems to be partly steric and partly electronic on origin and is reminiscent of the complete regioselectivitywhich obtains in the syn elimination reactions of β-alkoxyalkylselenoxides.



trans 99%

OH

H

Me H

HH

SnCl4O

MeO

SiO

H

H

CO2MeOH

Me

SiO CO2Me

H OHMe

SiO

-78 oC

CH2Cl2

A

Thus a Type 2 ene reaction using the silyloxy-substituted (E)-but-2-ene with methyl glyoxylate and tin(IV) chloride is both highly regio- and diastereoselective.

Thus a Type 2 ene reaction using the silyloxy-substituted (E)-but-2-ene with methyl glyoxylate and tin(IV) chloride is both highly regio- and diastereoselective.



This scheme also shows that when the hydrogen which is transferred in the ene reaction is derived from a secondary centre (as opposed to a methyl group in the schemes above), a configured double bond is formed, which, in the absence of a substituent at the 2-position on the ene component, is the parent ene compenent.

This scheme also shows that when the hydrogen which is transferred in the ene reaction is derived from a secondary centre (as opposed to a methyl group in the schemes above), a configured double bond is formed, which, in the absence of a substituent at the 2-position on the ene component, is the parent ene compenent.



96

SummarySummary

The Type 2 reactions considered in this chapter are those which are in part stereospecific (inherently diasteroselectivite). Thus, syn additions of a chiral regents XY to configured double bonds give single daistereoisomers as a result of the mechanism of the reaction in which both chiral centres are created more or less simultaneously: overall anti additions result from Type 1 reactions on these syn addition products.

The Type 2 reactions considered in this chapter are those which are in part stereospecific (inherently diasteroselectivite). Thus, syn additions of a chiral regents XY to configured double bonds give single daistereoisomers as a result of the mechanism of the reaction in which both chiral centres are created more or less simultaneously: overall anti additions result from Type 1 reactions on these syn addition products.


Likewise, cycloaddition reactions, e.g. the Diels-Alder reaction, also contain an inherently dastereoselective element arising from the reciprocal syn (suprafacial) addition of the components. However, these cycloaddition reactions may also be diastereoselective in another sense (exo/endo for the Diels-Alder reaction) which is occasional, I.e. depends on the substitution of the interacting components and, unlike the inherent diastereoselectivity, will not be complete in most cases.

Likewise, cycloaddition reactions, e.g. the Diels-Alder reaction, also contain an inherently dastereoselective element arising from the reciprocal syn (suprafacial) addition of the components. However, these cycloaddition reactions may also be diastereoselective in another sense (exo/endo for the Diels-Alder reaction) which is occasional, I.e. depends on the substitution of the interacting components and, unlike the inherent diastereoselectivity, will not be complete in most cases.


SummarySummary

Part 2Part 2

Type 2 Reactions:

Occasional Diastereoselectivity


OutlineOutline

1. Type 2 2π + 2π cycloadditions;2. Type 2 photochemical 1,3-cycloaddition of arenes;3. Photochemistry in crystals;4. Other 2π + 2π cycloadditions;5. Other cycloadditions;6. 1,4-Cheletropic additions to 1,3-dienes;7. Other 1,4-additions to 1,3-dienes;8. [3,3] Sigmatropic rearrangements;9. [2,3] Sigmatropic rearrangements10. Summary

1. Type 2 2π + 2π cycloadditions;2. Type 2 photochemical 1,3-cycloaddition of arenes;3. Photochemistry in crystals;4. Other 2π + 2π cycloadditions;5. Other cycloadditions;6. 1,4-Cheletropic additions to 1,3-dienes;7. Other 1,4-additions to 1,3-dienes;8. [3,3] Sigmatropic rearrangements;9. [2,3] Sigmatropic rearrangements10. Summary


In this part, Type 2 reactions will be considered whose diastereoselectivity is in the main brought about by the particular substitution on the interacting components, i.e. it is occasional rather than inherent in the mechanism of the reaction.

In this part, Type 2 reactions will be considered whose diastereoselectivity is in the main brought about by the particular substitution on the interacting components, i.e. it is occasional rather than inherent in the mechanism of the reaction.



From orbital symmetry consideration, concerted cycloaddition of two alkenes to give a cyclobutane is allowed suprafacially-suprafacially, i.e. syn with respect to both alkenes, provided that one reacts via its singlet excited state. Unfortunately, in practice there are number of factors which conspire to reduce the theoretical diastereoselective promise of this reaction, at least with acyclic alkenes.

1) the tendency for alkenes to undergo photochemical trans/cis (E/Z) diastereoisomerism.

2) in many intermolecular reactions, the photoexcited state involved is a triplet, from which concerted cycloaddition is precluded because of the necessity for spin inversion.

From orbital symmetry consideration, concerted cycloaddition of two alkenes to give a cyclobutane is allowed suprafacially-suprafacially, i.e. syn with respect to both alkenes, provided that one reacts via its singlet excited state. Unfortunately, in practice there are number of factors which conspire to reduce the theoretical diastereoselective promise of this reaction, at least with acyclic alkenes.

1) the tendency for alkenes to undergo photochemical trans/cis (E/Z) diastereoisomerism.

2) in many intermolecular reactions, the photoexcited state involved is a triplet, from which concerted cycloaddition is precluded because of the necessity for spin inversion.

Type 2 2Type 2 2ππ + 2+ 2ππ CycloadditionsCycloadditions


97

In general, therefore, photochemical 2π + 2π cycloadditionsdo not have an inherent diastereoselectivity of the kind that is present in, e.g., Diels-Alder additions. However, if appropriate constraints are applied, this cycloaddition can display high occasional diastereoselectivity. Thus, photochemical E/Z diastereoisomerism can be eliminated by incorporation of the alkene into a ring of sufficiently small size (five-membered or less). By carrying out the reaction intramolecularly, there is a greater chance of reaction occurring via a singlet state and regioselectivity is more likely to be obtained using a tether of an appropriate length.

In general, therefore, photochemical 2π + 2π cycloadditionsdo not have an inherent diastereoselectivity of the kind that is present in, e.g., Diels-Alder additions. However, if appropriate constraints are applied, this cycloaddition can display high occasional diastereoselectivity. Thus, photochemical E/Z diastereoisomerism can be eliminated by incorporation of the alkene into a ring of sufficiently small size (five-membered or less). By carrying out the reaction intramolecularly, there is a greater chance of reaction occurring via a singlet state and regioselectivity is more likely to be obtained using a tether of an appropriate length.



When both alkenes are contained in rings (n ≤ 5) the cycloadditionis invariably syn on both of them although exo and endo products may still be formed as in the photochemical dimerisation of maleicanhydride. With unsymmetrical cyclic alkenes, head-to-head or head-to-tail dimerisation (regioisomerism) is also possible (in addition to exo/endo addition).

When both alkenes are contained in rings (n ≤ 5) the cycloadditionis invariably syn on both of them although exo and endo products may still be formed as in the photochemical dimerisation of maleicanhydride. With unsymmetrical cyclic alkenes, head-to-head or head-to-tail dimerisation (regioisomerism) is also possible (in addition to exo/endo addition).

O

O

O

hv

O

O

O

O

O

O

H

H

HO

O

O

O

O

O

H

HH

+

endo exo

O

hv+

O

OOO



Most stereoselective synthesis which make use of photochemical 2π + 2πreactions take advantage of the E/Z configurational stability of cyclic alkenes. The use of α,β-unsaturated carbonyl compounds with their longer wavelength absorption allows their selective excitation in the presence of the alkenes.

Most stereoselective synthesis which make use of photochemical 2π + 2πreactions take advantage of the E/Z configurational stability of cyclic alkenes. The use of α,β-unsaturated carbonyl compounds with their longer wavelength absorption allows their selective excitation in the presence of the alkenes.

CN OEt

+hv

95 %

CN

H

OEt

OOSiMe2

tBuMe hv, Pyrex, hexane68 %

OOSiMe2

tBu

Me H+HO

O

Me

Retro-aldol reactionand a aldol reaction



Ring opening of the strained cyclobutane intermediate or product is also a pervasive feature of syntheses involving these 2π + 2πreactions photochemical cycloadditions as in the de Mayo reaction.

Ring opening of the strained cyclobutane intermediate or product is also a pervasive feature of syntheses involving these 2π + 2πreactions photochemical cycloadditions as in the de Mayo reaction.

Me

Me

+O

OH

Me

hv, pentaneMe

Me

OH

Me

O

CHO

Me

MeMe

O

Me

MeO

Retro-aldol



The direct creation of two adjacent quaternary chiral centres diastereoselectivity, by syn addition to the alkene C=C bond with the formation of two C-C bonds, is a conversion for which there are few other methods available. Any lack of diastereoselectivityin addition to the enol ether moiety is immaterial since retroaldolisation destroys the chirality at these two centres

The direct creation of two adjacent quaternary chiral centres diastereoselectivity, by syn addition to the alkene C=C bond with the formation of two C-C bonds, is a conversion for which there are few other methods available. Any lack of diastereoselectivityin addition to the enol ether moiety is immaterial since retroaldolisation destroys the chirality at these two centres



Although photostimulated 2π + 2π reactions involving cyclohexenes are not always reliably syn, the strain present in the trans-fused diastereoisomer (1) allows its easy conversion into the cis-fused form (2) by base-catalyzed equilibration.

Although photostimulated 2π + 2π reactions involving cyclohexenes are not always reliably syn, the strain present in the trans-fused diastereoisomer (1) allows its easy conversion into the cis-fused form (2) by base-catalyzed equilibration.

O

+ hv

O

H

H

(1) 4 parts

O

H

H

(2) 1 parts

+

dil. base



98

CO2Me+

O

Me Me

Mehv

85 %

isophorone

OH

Me

CO2Me

K Selectride76 %

H

Me

O

O

1. Li/NH3, tBuOH

2. Oxidation92%

H

H

H

OO

K-Selectride = K(C2H5CH)3B

CH3

Uses a reductive cleavage of the photochemically-derived cyclobutane (3) as a model for a synthesis of (±)-10-epijuneol.

Uses a reductive cleavage of the photochemically-derived cyclobutane (3) as a model for a synthesis of (±)-10-epijuneol.(3)



Lineatin (8) is an aggregation pheromone of the female ambrosia beetle Trypodendron lineatum, a pest causing damage to sawn timber. The obvious disconnection of the target molecule is to the retroacetalisation product (9). However, White used the less obvious retrosynthetic step to give (7) as the target.

Lineatin (8) is an aggregation pheromone of the female ambrosia beetle Trypodendron lineatum, a pest causing damage to sawn timber. The obvious disconnection of the target molecule is to the retroacetalisation product (9). However, White used the less obvious retrosynthetic step to give (7) as the target.

O

O

(8)

CHOOH

OH

(9)

NaH/Et2O67 %

O

OH

HMeTsO

(7)



Synthesis of (7) uses 2π + 2π photoaddition of ethyne to (4) in a key step and also makes good use of the shape of unsaturated [4.2.0] skeleton in directing the hydroboration of (5) and in DIBAL reduction of (6) (after tosylation). Intramolecular SN2 displacement by the hemiacetal hydroxyl group gives (±) lineatin.

Synthesis of (7) uses 2π + 2π photoaddition of ethyne to (4) in a key step and also makes good use of the shape of unsaturated [4.2.0] skeleton in directing the hydroboration of (5) and in DIBAL reduction of (6) (after tosylation). Intramolecular SN2 displacement by the hemiacetal hydroxyl group gives (±) lineatin.

O

OH

HMeTsO

(7)

O

O

Me

hv, HC CH, MeCN O

OH

(4)

1. MeLi2. PCC (via hemiacetal)

OMe

O

O

OH

HMeHO

(5)

1. B2H6

2. H2O2, OH-1. TsCl, pyr2. DIBAL

(6)Me的空阻使双键的加成具选择性



Photochemical 2π + 2π photoaddition of cyclic alkenes with carbonyl groups (the Paterno-Büchi reaction) have been widely studied. Using aliphatic aldehydes, singlet excited states are involved and higher diastereoselectivity results than with, for example, aromatic ketones.

Photochemical 2π + 2π photoaddition of cyclic alkenes with carbonyl groups (the Paterno-Büchi reaction) have been widely studied. Using aliphatic aldehydes, singlet excited states are involved and higher diastereoselectivity results than with, for example, aromatic ketones.

O+ n-C8H17CHO hv

O C8H17

O

HH

OO

H

H

C8H17

O

O



The strain in four-membered (oxetane) ring of the the product is used to advantage. (Type 0) Hydrolysis of the oxetane-acetal unit in (10) leads to a single aldol diastereoisomers (11). The shape of the bicyclo[3.2.0] system allows completely diastereoselective hydrogenation of (10) (Type 3) from the more accessible face; after hydrolysis, the product is (12).

The strain in four-membered (oxetane) ring of the the product is used to advantage. (Type 0) Hydrolysis of the oxetane-acetal unit in (10) leads to a single aldol diastereoisomers (11). The shape of the bicyclo[3.2.0] system allows completely diastereoselective hydrogenation of (10) (Type 3) from the more accessible face; after hydrolysis, the product is (12).

OMe Me+ EtCHO hv

O Et

O

HMe

MeHCl

0.01 NMe

Et

O

OH

MeO(10) (11)

H2, Rh/Al2O3

O Et

O

HMeH

Me

H2O

H+Me

Et

OH

OH

MeO(12)


Type 2 2Type 2 2ππ + 2+ 2ππ CycloadditionsCycloadditions Type 2 Photochemical 1,3Type 2 Photochemical 1,3--CycloadditionCycloaddition of of ArenesArenes

1,3-Cycloaddition of benzene and substituted benzenes to alkenes under the influence of light can be a reaction of high diastereoselectivity. syn Addition to the alkene is accompanied by complete endo diastereoselectivity (methyl groups cis to the double bond).

1,3-Cycloaddition of benzene and substituted benzenes to alkenes under the influence of light can be a reaction of high diastereoselectivity. syn Addition to the alkene is accompanied by complete endo diastereoselectivity (methyl groups cis to the double bond).

Me

Me

Me

Me

MeMe

hv

H

H

H H

MeMe


99

The reaction with substituted benzenes is also often highly regioselective.

The reaction with substituted benzenes is also often highly regioselective.

OMe OMeOMe

hv

OMe

H

H H

H

H


Type 2 Photochemical 1,3Type 2 Photochemical 1,3--CycloadditionCycloaddition of of ArenesArenes

HMe

Me

hv

HMe

Me

HMe

COOH

H

H

(-)-retigeranic acid

This photochemical 1,3-cycloaddition, and particularly the intramolecular version of it, has been brilliantly in syntheses of a number of natural products, which is part of a synthesis of (-)-retigeranic acid.

This photochemical 1,3-cycloaddition, and particularly the intramolecular version of it, has been brilliantly in syntheses of a number of natural products, which is part of a synthesis of (-)-retigeranic acid.


Type 2 Photochemical 1,3Type 2 Photochemical 1,3--CycloadditionCycloaddition of of ArenesArenes

Photochemistry in CrystalsPhotochemistry in Crystals

One of the advantages of photochemistry is that it can be carried out on compounds in the crystalline state as well as in solution.

One of the advantages of photochemistry is that it can be carried out on compounds in the crystalline state as well as in solution.

In a crystal, molecules are stacked in a highly ordered way, usually in the same conformation, and there is little variation in the atomic distances separating nearest neighbors. For intermolecular reactions to occur, therefore, the separation between two molecules and the relative orientation of the reacting functional groups must be appropriate. When this is the case, completely diastereoselective reaction may ensue as in the photochemical dimerisation of hexadienoic acid and its derivatives.

In a crystal, molecules are stacked in a highly ordered way, usually in the same conformation, and there is little variation in the atomic distances separating nearest neighbors. For intermolecular reactions to occur, therefore, the separation between two molecules and the relative orientation of the reacting functional groups must be appropriate. When this is the case, completely diastereoselective reaction may ensue as in the photochemical dimerisation of hexadienoic acid and its derivatives.


Photochemical reaction (sensitized) of these compounds in solution gives mixtures of diastereoisomers.

Photochemical reaction (sensitized) of these compounds in solution gives mixtures of diastereoisomers.

R1

R2

H H

R1

R2

H H

R1

R2

H H

R1

R2

H H

.> 290 nm, hv (solid)Pyrex R1

R2

H H

R1

R2

H H

H


Photochemistry in CrystalsPhotochemistry in Crystals

O

O

O

hv

O

O

O

O

O

O

H

H

HO

O

O

O

O

O

H

HH

+

endo exo

Likewise, the photolysis of maleic anhydride when carried out in the crystalline, gives only the endo diastereoisomers.

Likewise, the photolysis of maleic anhydride when carried out in the crystalline, gives only the endo diastereoisomers.


Photochemistry in CrystalsPhotochemistry in Crystals Other 2Other 2ππ + 2+ 2ππ CycloadditionsCycloadditions

Orbital symmetry considerations not only predict concerted suprafacial-suprafacial cycloaddition of two alkenes when one is in its excited state (2πs + 2πs) but also concerted cycloaddition of two ground state alkenes with one alkene acting antarafacially.

Orbital symmetry considerations not only predict concerted suprafacial-suprafacial cycloaddition of two alkenes when one is in its excited state (2πs + 2πs) but also concerted cycloaddition of two ground state alkenes with one alkene acting antarafacially.

In practice, alkenes fail to undergo concerted 2πs + 2πa cycloadditions, presumably because steric interactions between substituents on the alkene sp2-carbons and other strain factors are too severe.

In practice, alkenes fail to undergo concerted 2πs + 2πa cycloadditions, presumably because steric interactions between substituents on the alkene sp2-carbons and other strain factors are too severe.

HOMOLUMO


100

Reduction of this steric interaction would be expected if the substituents at one terminus of the alkene were absent which would be the case using a ketene. Ketenes do react with alkenes to give cyclobutanones but it is not clear that this cycloadditionis a simple 2πs + 2πa with the ketene acting antarafacially. This is because the orthogonal π*-orbital of the carbonyl group in the ketene may be involved, making the reaction a 2π + 2π + 2π type.

Reduction of this steric interaction would be expected if the substituents at one terminus of the alkene were absent which would be the case using a ketene. Ketenes do react with alkenes to give cyclobutanones but it is not clear that this cycloadditionis a simple 2πs + 2πa with the ketene acting antarafacially. This is because the orthogonal π*-orbital of the carbonyl group in the ketene may be involved, making the reaction a 2π + 2π + 2π type.

HR3

R2H R1

HOMOLUMO

O

R2

H

R1H

R3


Other 2Other 2ππ + 2+ 2ππ CycloadditionsCycloadditions

Although ketene-alkene cycloadditions are inherently syndiastereoselective (syn stereospecific) in addition to the alkenethere is evidence to suggest that in the transition state, formation of the bond to the electron-deficient ketene carbonyl has run ahead of that between the other two carbons, i.e. the reaction has dipolar character.

Although ketene-alkene cycloadditions are inherently syndiastereoselective (syn stereospecific) in addition to the alkenethere is evidence to suggest that in the transition state, formation of the bond to the electron-deficient ketene carbonyl has run ahead of that between the other two carbons, i.e. the reaction has dipolar character.

O D

HPh

Ph Ph

H

C OPh

Ph

H

Ph H

D

H

Ph D

HO H

DPh

Ph Ph

H



δ+

The transition state of lowest energy in the cycloaddition of ethene and ketene is that shown in next Figure, which illustrates that whilst the C1-C3 bond is almost fully the C2-C4 bond is far less developed.

The transition state of lowest energy in the cycloaddition of ethene and ketene is that shown in next Figure, which illustrates that whilst the C1-C3 bond is almost fully the C2-C4 bond is far less developed.

H HC

O

H

H

H H1

2

43

δ-δ-

Asynchronous bonding in the transition state helps to explain the regiochemistry of this reaction; the alkene carbon less able to sustain the partial positive charge becomes bonded to the ketene carbonyl carbon.

Asynchronous bonding in the transition state helps to explain the regiochemistry of this reaction; the alkene carbon less able to sustain the partial positive charge becomes bonded to the ketene carbonyl carbon.



H RC

O

H

H

H H

+

-O

R

C CH

PhO+ 16 h, CHCl3, 20 oC C

O

C

HPh

C

O

C

HPh

(13)(14)

(15)H H

HPh O

26 %



Antarafacial addition of the ketene as show in the figure also explains a subtle stereochemical feature of these 2πs + 2πacycloaddition which leads to the larger ketene substituentsbeing located in the more sterically crowed environment in the product. Thus, addition of phenylketene to cyclopentadienegives as excess of the bicyclo[3.2.0]heptenone diastereoisomer (15) in which the phenyl group is endo.

Antarafacial addition of the ketene as show in the figure also explains a subtle stereochemical feature of these 2πs + 2πacycloaddition which leads to the larger ketene substituentsbeing located in the more sterically crowed environment in the product. Thus, addition of phenylketene to cyclopentadienegives as excess of the bicyclo[3.2.0]heptenone diastereoisomer (15) in which the phenyl group is endo.



This stereochemical outcome is a consequence of the preferred approach of the ketene in (13), in which the hydrogen of the ketene is directed towards the diene, coupled with the required direction of twisting around the ketene C=C bond as shown in (14). Like the Diels-Alder reaction, therefore, the diastereoselectivity of the 2πs + 2πaaddition of an alkene and a ketene can have an inherent component (syn addition to the alkene) and an occasional component (endo/exo addition)

This stereochemical outcome is a consequence of the preferred approach of the ketene in (13), in which the hydrogen of the ketene is directed towards the diene, coupled with the required direction of twisting around the ketene C=C bond as shown in (14). Like the Diels-Alder reaction, therefore, the diastereoselectivity of the 2πs + 2πaaddition of an alkene and a ketene can have an inherent component (syn addition to the alkene) and an occasional component (endo/exo addition)



101

The endo diastereoselectivity which is found in this scheme cannot be expected in all cases, particularly where the ketene is disubstituted with groups of a similar bulk.

The endo diastereoselectivity which is found in this scheme cannot be expected in all cases, particularly where the ketene is disubstituted with groups of a similar bulk.

C CH

PhO+ 16 h, CHCl3, 20 oC C

O

C

HPh

C

O

C

HPh

(13)(14)

(15)H H

HPh O

26 %



Intramolecular ketene-alkene cycloadditionshave been used to synthesis four-membered ring-containing products, e.g. β-trans-bergotamene (16)

Intramolecular ketene-alkene cycloadditionshave been used to synthesis four-membered ring-containing products, e.g. β-trans-bergotamene (16)

CO2H

O

1. Ph3=CH2

2. H2O(40 %)

CO2H

CH2

(COCl)2

COCl

CH2

NHiPr2

tolueneH

CO

O

1. NH2NH2

2. KOtBu, DMSO



Keteniminium salts can also play the role of the antarafacialcomponent in 2πs + 2πa cycloadditions.

Keteniminium salts can also play the role of the antarafacialcomponent in 2πs + 2πa cycloadditions.

O

N(CF3SO2)2O

collidine, ClCH2CH2Cl H

C N+

H

C N+

H

N+H2OCCl4

H

O


Other 2Other 2ππ + 2+ 2ππ CycloadditionsCycloadditions Other Other CycloadditionsCycloadditions

In recent years, considerable effort has been directed towards developing cycloaddition reactions which would give carbocyclicfive-membered rings with the facility and stereoselectivity with which the Diels-Alder reaction gives six membered rings. This effort has been necessary because of the dearth of available all-carbon 1,3-dipoles and their generally inefficient reactions with alkenes to give five-membered rings. An all-carbon 1,3-dipole which might be expected to have enhanced stability would be one in which a methyl group was present at C-2.

In recent years, considerable effort has been directed towards developing cycloaddition reactions which would give carbocyclicfive-membered rings with the facility and stereoselectivity with which the Diels-Alder reaction gives six membered rings. This effort has been necessary because of the dearth of available all-carbon 1,3-dipoles and their generally inefficient reactions with alkenes to give five-membered rings. An all-carbon 1,3-dipole which might be expected to have enhanced stability would be one in which a methyl group was present at C-2.

+ -N N

hv

or


N

N

H

MeO2C

H

H

MeCNreflux

H

MeO2C

H

H

MeO2C

H

H

H

H H

H

CO2MeH H

HO

( + )-hirsutene-

The part is biradicaloid in its behaviour rather than dipolar and whilst addition to alkenes to give five membered rings occurs, diastero-and regioselectivityare high only when the reaction is intramolecular, the tricyclic skeleton of hirsutene is formed.

The part is biradicaloid in its behaviour rather than dipolar and whilst addition to alkenes to give five membered rings occurs, diastero-and regioselectivityare high only when the reaction is intramolecular, the tricyclic skeleton of hirsutene is formed.


Other Other CycloadditionsCycloadditions

Trost has successfully used palladium complexes of the 1,3-dipole in cycloaddition reactions. These are generated in situ, e.g. by palladium-induced decomposition of 2-(trimethylsilyl-methyl)allyl acetate.

Trost has successfully used palladium complexes of the 1,3-dipole in cycloaddition reactions. These are generated in situ, e.g. by palladium-induced decomposition of 2-(trimethylsilyl-methyl)allyl acetate.

SiMe3

OAc+ PdL4

SiMe3

PdL4+

-OAc

PdL4+

-



102

These trimethylenemethane intermediates cycloadd efficiently to double bonds which are conjugated with at least one electron-withdrawing group.

These trimethylenemethane intermediates cycloadd efficiently to double bonds which are conjugated with at least one electron-withdrawing group.

SiMe3

OAc+

R EWG(Ph3P)4Pd

3-9 mol %

EWG

R

Pd(PPh3)2+

-

R

EWGEWG = CN, SO2Ph, CO2R'



Although high diastereoselectivity is obtained to trans-alkenes, the configuration of cis-alkenes is incompletely retained in the product. It appears, therefore, that the cycloaddition is not concerted and that formation of one bond is complete before any formation of the second bond has taken place allowing intervention of some C-C bond rotation around the original double bond of the cis-alkene.

Although high diastereoselectivity is obtained to trans-alkenes, the configuration of cis-alkenes is incompletely retained in the product. It appears, therefore, that the cycloaddition is not concerted and that formation of one bond is complete before any formation of the second bond has taken place allowing intervention of some C-C bond rotation around the original double bond of the cis-alkene.

The diastereoselectivity of this cycloaddition, therefore, is occasional. Of course, configurational stability of cis-alkenes is assured by containing them in an eight-membered or smaller ring. In these cases, addition of the complexed 1,3-dipole is highly syn selective.

The diastereoselectivity of this cycloaddition, therefore, is occasional. Of course, configurational stability of cis-alkenes is assured by containing them in an eight-membered or smaller ring. In these cases, addition of the complexed 1,3-dipole is highly syn selective.



Ar SiMe3

OCO2Me+

Ph

CO2Me

CO2Me

Pd(OAc)2, 5 %

(iPrO)3P, toluene

Ar

Ph CO2MeCO2Me

O3

O

Ar

Ph CO2MeCO2Me

Ar = p-MeOC6H4

A substituted version of the palladium-complexed 1,3-dipole is generated, the cycloaddition is highly diastereoselective when R is electron-withdrawing (CN, COEt), giving a trans relationship between R and Ph; the diastereoselectivityis less when R is electron donating. However, if the exocyclic methylene group in the product is removed by ozonolysis, thermodynamic equilibration then generates the trans diastereoisomer (21), the first steps in a synthesis of rocaglamide.

A substituted version of the palladium-complexed 1,3-dipole is generated, the cycloaddition is highly diastereoselective when R is electron-withdrawing (CN, COEt), giving a trans relationship between R and Ph; the diastereoselectivityis less when R is electron donating. However, if the exocyclic methylene group in the product is removed by ozonolysis, thermodynamic equilibration then generates the trans diastereoisomer (21), the first steps in a synthesis of rocaglamide.


Other Other CycloadditionsCycloadditions 1,41,4--CheletropicCheletropic Additions to 1,3Additions to 1,3--DienesDienes

Addition of sulphur dioxide across a 1,3-diene is a cheletropicaddition in which two new bonds to sulphur are made concertedly and the diene reacts suprafacially.

Addition of sulphur dioxide across a 1,3-diene is a cheletropicaddition in which two new bonds to sulphur are made concertedly and the diene reacts suprafacially.

In this reaction, therefore, using a diene having two prochiraldouble bonds, two chiral centres are created of defined relative configuration (inherent diastereoselectivity). Unfortunately, there is a dearth of molecules containing an atom (S in SO2) having the filled and empty orbitals necessary for cheletropic addition (siglet carbenes do not, in general react with dienes by 1,4-addition: they add 1,2 to one of the double bonds).

In this reaction, therefore, using a diene having two prochiraldouble bonds, two chiral centres are created of defined relative configuration (inherent diastereoselectivity). Unfortunately, there is a dearth of molecules containing an atom (S in SO2) having the filled and empty orbitals necessary for cheletropic addition (siglet carbenes do not, in general react with dienes by 1,4-addition: they add 1,2 to one of the double bonds).


The reaction is , in practice, more often encountered in the reverse elimination mode, i.e. as a route to configurationally defined dienes from the corresponding dihydrothiophenedioxides (22) and (23), prepared by other means.

The reaction is , in practice, more often encountered in the reverse elimination mode, i.e. as a route to configurationally defined dienes from the corresponding dihydrothiophenedioxides (22) and (23), prepared by other means.

a b+ SO2

Sa bHH

O2(22)

ab

+ SO2Sa H

bH

O2(23)


1,41,4--CheletropicCheletropic Additions to 1,3Additions to 1,3--DienesDienes Other 1,4Other 1,4--Additions to 1,3Additions to 1,3--DienesDienes

Cyclic and acyclic dienes can be converted completely diastereo-selectively into 1,4-addition products using palladium chemistry. Thus cyclohexa-1,3-dienes is converted into cis-1-acetoxy-4-chlorocyclohex-2-ene (24), cis-1,4-diacetoxycyclohex-2-ene (25) or trans-1,4-diacetoxycyclohex-2-ene (26), depending on the conditions.

Cyclic and acyclic dienes can be converted completely diastereo-selectively into 1,4-addition products using palladium chemistry. Thus cyclohexa-1,3-dienes is converted into cis-1-acetoxy-4-chlorocyclohex-2-ene (24), cis-1,4-diacetoxycyclohex-2-ene (25) or trans-1,4-diacetoxycyclohex-2-ene (26), depending on the conditions.

Cl OAc

89 %, > 98 % cis(24)

benzoquinonePd(OAc)2 (5 mol%)

HOAcLiClLiOAc MnO2, benzoquinone,

Pd(OAc)2 (5 mol%)LiOAc, HOAc

AcO OAc

93 %, > 91 % cis(26)

AcO OAc

93 %, > 91 % cis(25)

MnO2, benzoquinone,Pd(OAc)2 (5 mol%)LiOAc, HOAc

LiCl


103

The mechanism suggested for cis-1,4-acetoxychlorinationinvolves coordination of the diene to palladium followed by anti addition of acetate to give a π-allyl complex (27). Coordination by benzoquinoneis followed by external anti attack of chloride to give overall syn addition. Similar mechanisms account for the formation of (25) and (26) with the acetoxy group being intramolecularly delivered from palladium in the latter case.

The mechanism suggested for cis-1,4-acetoxychlorinationinvolves coordination of the diene to palladium followed by anti addition of acetate to give a π-allyl complex (27). Coordination by benzoquinoneis followed by external anti attack of chloride to give overall syn addition. Similar mechanisms account for the formation of (25) and (26) with the acetoxy group being intramolecularly delivered from palladium in the latter case.

(24)

Cl OAc

PdCl42-

Pd2+

Cl Cl

OAc-

OAc

PdCl/2

OO

OAc

PdCl

O

O

Cl-

HOAc, LiCl


Other 1,4Other 1,4--Additions to 1,3Additions to 1,3--DienesDienes

These products of 1,4-addition to conjugated dienes are versatile starting materials for nucleophilic substitution reactions with retention or inversion of configuration.

These products of 1,4-addition to conjugated dienes are versatile starting materials for nucleophilic substitution reactions with retention or inversion of configuration.

Cl OAcOAc

(MeO2C)2CH

NaCH(CO2Me)2

Pd(0)NaCH(CO2Me)2

> 98 % trans

(MeO2C)2CH OAc

> 98 % cis


Other 1,4Other 1,4--Additions to 1,3Additions to 1,3--DienesDienes

An application of this tandem 1,4-addition-nucleophilicsubstitution in a synthesis of (28), a sex pheromone of the carpenter bee.

An application of this tandem 1,4-addition-nucleophilicsubstitution in a synthesis of (28), a sex pheromone of the carpenter bee.

benzoquinone

HOAc, Pd(OAc)2LiCl, LiOAc

Cl

H OAc

H

1. PhSO2CHNO2Na+

Pd(PPh3)42. NaOH

H OH

H

NO2PhSO2

1. Rh(PPh3)3Cl, H2

2. dihydropyran, H+H

NO2PhSO2

OTHP

H

1. KMnO4, NaOH2. H+/H2O

CO2H

H OTHP

Hspontaneous O

O

(28)


Other 1,4Other 1,4--Additions to 1,3Additions to 1,3--DienesDienes [3,3] [3,3] SigmatropicSigmatropic rearrangementsrearrangements

Simple diastereoselectivity in [3,3] sigmatropic rearrangements results in the transformation of two configured double bonds, separated by two saturated atoms, into two adjacent chiral centres.

Simple diastereoselectivity in [3,3] sigmatropic rearrangements results in the transformation of two configured double bonds, separated by two saturated atoms, into two adjacent chiral centres.


[3,3] [3,3] SigmatropicSigmatropic rearrangementsrearrangements

Oa

b

x

yOa

H

x

y

Oa

b

x

yO

a

b

x

y

diastereoisomers

Oa

b x

y

enantiomers

enantiomers

Ob

x

a

y

Oa

y

b

x

Oa

b x

yO

b

y

a

x

Oy

x b

a Oy

x b

aO

a

x

b

y

(29)

(30)


The chair transition state is usually sufficiently lower in energy than the boat for formation of (29) to be favored over formationof (30) by a factor of 20:1 or more.

A change in configuration at one double bond would lead, after rearrangement via a chair transition state, to (30). Accordingly, the use made of Type 2 [3,3] rearrangements to prepare two adjacent chiral centres will depend on the availability of 1,5-dienes, configurationally defined at both double bonds.

The chair transition state is usually sufficiently lower in energy than the boat for formation of (29) to be favored over formationof (30) by a factor of 20:1 or more.

A change in configuration at one double bond would lead, after rearrangement via a chair transition state, to (30). Accordingly, the use made of Type 2 [3,3] rearrangements to prepare two adjacent chiral centres will depend on the availability of 1,5-dienes, configurationally defined at both double bonds.

For the much-used Claisen rearrangement of allyl vinyl ethers, the more difficult bond to obtain configurationally defined is, in general, that of the vinyl ether because of the dearth of methods for their diastereoselective synthesis.

For the much-used Claisen rearrangement of allyl vinyl ethers, the more difficult bond to obtain configurationally defined is, in general, that of the vinyl ether because of the dearth of methods for their diastereoselective synthesis.



104

The Ireland modification of the Claisen rearrangement is a valuable variant, not least because of the much lower temperature required. Diastereoselectivity in this variant requires the generation and silylation of configurationally, defined enolate in a molecule already containing a configurationally pure allyl double bond.

The Ireland modification of the Claisen rearrangement is a valuable variant, not least because of the much lower temperature required. Diastereoselectivity in this variant requires the generation and silylation of configurationally, defined enolate in a molecule already containing a configurationally pure allyl double bond.

O

O

Me

Me1. LDA, THF2. tBuMe2SiCl

OSiMe2tBu

OH

Me

H

MeH+

H

Me

OH

OH

Me

H

Me

OH

OMe

H

87

:

13(31)



The (E)-enolates are generated under kinetically controlled conditions and the major diastereoisomer of the product is formed via the conformations (31) and (32), respectively. The less than complete diastereoselectivityseems more likely to result from incomplete configurational homogeneity of the silyl ketene acetal double bonds in (31) and (32) than from their rearrangements proceeding in part via boat transition states.

The (E)-enolates are generated under kinetically controlled conditions and the major diastereoisomer of the product is formed via the conformations (31) and (32), respectively. The less than complete diastereoselectivityseems more likely to result from incomplete configurational homogeneity of the silyl ketene acetal double bonds in (31) and (32) than from their rearrangements proceeding in part via boat transition states.

O

O

MeMe 1. LDA, THF

2. tBuMe2SiCl

OSiMe2tBu

OH

Me

Me

HH+

H

Me

OH

OH

Me

H

Me

OH

OMe

H

11

:

89(32)



The use of dipolar aprotic cosolvents (HMPA or DMPU) favors the formation of enolates having the alternative configuration to those shown and thus products with the opposite sense of diastereoselectivity.

The use of dipolar aprotic cosolvents (HMPA or DMPU) favors the formation of enolates having the alternative configuration to those shown and thus products with the opposite sense of diastereoselectivity.



R1

H

H

OR2

H

R1

H

H

O

R2

H

H+

R2

R1

OH

R1

H

H

O

H

R2

R1

H

H

OR2

H

H+

R2

R1

OH

(33)

(33')

2


Simple diastereoselectivity (Type 2) in [2,3] rearrangements has been investigated in some detail by Nakai and Mikami. It is suggested that in the Wittig rearrangement the diastereoselectivity is controlled by the balance between two factors. Thus, using the envelope conformation (33), there is an eclipsing interaction between R2 and the hydrogen at C-2, whereas in conformation (33’), there is a gauche interaction between R1 and R2.

Simple diastereoselectivity (Type 2) in [2,3] rearrangements has been investigated in some detail by Nakai and Mikami. It is suggested that in the Wittig rearrangement the diastereoselectivity is controlled by the balance between two factors. Thus, using the envelope conformation (33), there is an eclipsing interaction between R2 and the hydrogen at C-2, whereas in conformation (33’), there is a gauche interaction between R1 and R2.


Using an E-configured alkene, these two interactions appear to be comparable and diastereoselectivity is not high, although the balance can be tipped by, for example, introducing a bulky substituent at C-2. In this case, reaction from conformation (34) is favored.

Using an E-configured alkene, these two interactions appear to be comparable and diastereoselectivity is not high, although the balance can be tipped by, for example, introducing a bulky substituent at C-2. In this case, reaction from conformation (34) is favored.

Me

H

TMS

O

H

Me

H+

(34)

MeH

TMS

OH

Me

MeH

TMS

O

H

Me

Me

TMS OH

Me



For Z-configured alkenes, the stereoselectivity is higher and favors the formation of the cis diastereoisomer with, for example, a preference for reaction from conformation (35).

For Z-configured alkenes, the stereoselectivity is higher and favors the formation of the cis diastereoisomer with, for example, a preference for reaction from conformation (35).

H

Me

H

OPh

H

H+

(35)

HMe

H

O

Ph

HH

Me

H

O

H

Ph

Ph

OH

Me



105

Remarkably high diastereoselectivity with both (E)- and (Z)-alkenes is found using ethynyl groups as substituents on the oxymethylene group in the Wittig rearrangement.

Remarkably high diastereoselectivity with both (E)- and (Z)-alkenes is found using ethynyl groups as substituents on the oxymethylene group in the Wittig rearrangement.

O

Rexo

Rendo

Li

(36)

2



Calculations by Houk suggest that the preferred transition state geometry for the Wittig rearrangement is the alternative envelope shown in (36), but this was only located when the lithium ion was included in the calculation. The preference of an ethylnyl group form the exo position in this envelope does not arise, according to Houk’s calculations, from avoidance of an eclipsing interaction between the endo-ethylnyl group and the C2-H.

Calculations by Houk suggest that the preferred transition state geometry for the Wittig rearrangement is the alternative envelope shown in (36), but this was only located when the lithium ion was included in the calculation. The preference of an ethylnyl group form the exo position in this envelope does not arise, according to Houk’s calculations, from avoidance of an eclipsing interaction between the endo-ethylnyl group and the C2-H.



Whether the envelope conformation suggested by Nakai and Mikami or that in (36) is preferred for the transition state of the [2,3] sigmatropic rearrangement remains an open question.

Whether the envelope conformation suggested by Nakai and Mikami or that in (36) is preferred for the transition state of the [2,3] sigmatropic rearrangement remains an open question.

OH

Me

R

BuLi, THF, -85 oC

Me

H

OH

H

H

R

H+

MeH

H

O

H

R

R = H, TMS : 99 % d.e.



OMe

H

R

BuLi, THF, -85 oC

H

H

OH

H

R

Me

H+

HMe

H

O

H

R

R = H, TMS : 100 % d.e.



SummarySummary

Type 2 photochemical 2π + 2π cycloadditions involving alkenes are normally reliably diastereoselective only when the photo-stimulated alkene contain in a ring of less than six members.

Type 2 photochemical 2π + 2π cycloadditions involving alkenes are normally reliably diastereoselective only when the photo-stimulated alkene contain in a ring of less than six members.

Cyclobutanes and oxetanes resulting from such 2π + 2πcycloadditions are useful because of the ease with which their ring opening can be accomplished.

Cyclobutanes and oxetanes resulting from such 2π + 2πcycloadditions are useful because of the ease with which their ring opening can be accomplished.

Type 2 thermal cycloaddition of ketenes and alkenes can be highly diastereoselective since the ketene can apparently function as the 2πa component in a 2πa + 2πs cycloaddition.

Type 2 thermal cycloaddition of ketenes and alkenes can be highly diastereoselective since the ketene can apparently function as the 2πa component in a 2πa + 2πs cycloaddition.


SummarySummary

Cycloaddition of (substituted) trimethylenemethanepalladiumcomplexes with alkenes gives five-membered rings, but the two carbon-carbon bonds are not formed simultaneously and the reaction is not inherently diastereoselective.

Cycloaddition of (substituted) trimethylenemethanepalladiumcomplexes with alkenes gives five-membered rings, but the two carbon-carbon bonds are not formed simultaneously and the reaction is not inherently diastereoselective.

Some highly diastereoselective 1,4-additions to 1,3-dienes can be accomplished using palladium chemistry.

Some highly diastereoselective 1,4-additions to 1,3-dienes can be accomplished using palladium chemistry.


106

SummarySummary

Type 2 [3,3] sigmatropic rearrangements are usually highly diastereoselective and proceed via chair transition states, but depend on the availability of 1,5-dienes with defined configurations for two double bonds.

Type 2 [3,3] sigmatropic rearrangements are usually highly diastereoselective and proceed via chair transition states, but depend on the availability of 1,5-dienes with defined configurations for two double bonds.

Some Type 2 [2,3] Wittig rearrangements are highly diastereoselective, particularly those with an ethynyl substituent on the oxymethylene group and an E- or Z-substituted double bond.

Some Type 2 [2,3] Wittig rearrangements are highly diastereoselective, particularly those with an ethynyl substituent on the oxymethylene group and an E- or Z-substituted double bond.


Thanks for Thanks for Your Attention!!!Your Attention!!!

Documents

stereochemistry - PKU · Stereochemistry, Jian Pei, College of Chemistry, Peking University, Chirality is a fundamental properties of many three-dimensional objects. An object is