Advanced organic

O

Me SiPhMe2

N3

MeO O

Me SiPhMe2

N3

MeO

N N N

O

Me SiPhMe2

OMs

MeO

NaN3

O

Me SiPhMe2

N3

MeO

NaN3

Stereospecificity in organic synthesis• Stereospecific reactions - a reaction where the mechanism means the

stereochemistry of the starting material determines the stereochemistry of the product; there is no choice. Occasionally, the term may be used with chiral reagents or catalysts if the configuration of the product depends uniquely on the configuration of the catalyst or reagent.

• If the reaction starts with a chiral material the reaction will be enantiospecific• If the reaction forms only one diastereoisomer (control of relative stereochemistry

not absolute stereochemistry) it is diastereospecific• A typical example is substitution by a SN2 reaction• The reaction must proceed with inversion

1

Ms = SO

OMe

Enantiospecific

Diastereospecific

Me

CH2OH

OsO4HO

HMe H

CH2OH

HO

MeH CH2OH

H

OH OH+

syn diastereoisomer

syn diastereoisomer

racemic mixture

X

Advanced organic

Me

H OH

Me

H OH

95.5% (S) 4.5% (R)

+

MeMe

HPh

HO PhMe

MeHPh

HO Ph

91.5% 8.5%

+MeMe

O

HPh

PhMgBr

Stereoselectivity in organic synthesis• Stereoselective reactions - a reaction where one stereoisomer of a product is

formed preferentially over another. The mechanism does not prevent the formation of two or more stereoisomers but one does predominate.

• If a stereogenic centre is introduced into a molecule in such a way that diastereoisomers are produced in unequal amounts the reaction is diastereoselective

• If a chemical reaction produces the two enantiomers of a chiral product in unequal amounts it is as an enantioselective reaction

2

Diastereoselective

Enantioselective H

O Me2Zn(–)-DAIB (2%)

MeOHNMe2

MeMe

(–)-DAIB

91% ee

Advanced organic

Me

O

O

OMe

Me Me

Li•H2N(CH2)2NH2O OMe

Me Me

Me

OHR

R

S

R

+>90%

Stereospecific reactions• Initially, we will look at the general principles of stereo-specific and -selective

reactions• This is intended to familiarize the terminology we have just covered and to instill a

number of the basic principles we will be utilising in the rest of the course• In future lectures we will look at ‘asymmetric’ synthesis or various strategies for

enantioselective synthesis

3

Enantiospecific reactions

Me Me

TsO OTs KOHH2S

Me Me

HS OTs

SMe Me

Me Me

S S R SR R

MeMeMeMe

• SN2 reaction occurs with complete inversion - retain stereochemical information• Very useful if we already have incorporated stereochemistry

• Epoxides are excellent candidates for enantiospecific reactions• Highlights area of potential confusion: (R,S) nomenclature is independent of the...chemical process occurring (stereochemistry at Me (R) inverted yet still (R)

no change in stereochemistry;

only name

inversion

Advanced organic

PhHBR2

O OH

PhHOH

HOO

retention of stereochemistry

PhHBR2

syn addition

Ph HBR2

PhH

PhH

Om-CPBA

syn

PhH

HPh

Om-CPBA

anti

Ph

HH

Ph(Z)

Ph

PhH

H(E)

Ph HPhH

OOOH

Ar

Stereospecific reactions II

• Epoxidation with peracids occurs via a concerted process• Results in conservation of alkene geometry

Hydroboration• Again occurs via a concerted reaction (bonds made & broken at same time)• Observe syn addition of hydrogen and boron• Further stereospecific transformations possible

4

A number of very useful reactions of alkenes are diastereospecific

Electrophilic epoxidation

Note: only controlling relative

stereocheimstry NOT absolute

stereochemistry

Note: only controlling relative

stereocheimstry NOT absolute

stereochemistry

Advanced organic

I

Me O Osyn

OOH

Me I2

(Z)

I

Me O O H

I

Me O OantiI

MeMe

Br

Brsyn

rotate central bond

Br2H

Me Me

HBrBr

Me

Br

MeBr

H

Me Me

H

(Z)

MeMe

Br

Branti

Br2Me

H Me

HBr

Br

Me

H Me

H

(E)

Stereospecific reactions IIIBromination

• Bromination of alkenes proceeds with the anti addition of Br2 across the double bond• This is the result of the formation of a bromonium cation followed by SN2 attack• The geometry of the starting material controls the stereochemistry of the product

5

Iodolactonisation• Proceeds in an analogous fashion via an iodonium species• Geometry of alkene controls relative stereochemistry

Note: only controlling relative stereocheimstry NOT

absolute stereochemistry

OOHMe

I2

(E) OOHMe

I

Advanced organic

view from this face HPh

O

2 3

1

anti-clockwiseSi faceH Ph

O

23

1

H Ph

O

23

1

Stereoselective reactionsNucleophilic addition to C=O

• Reaction of a nucleophile with a chiral substrate gives two possible diastereoisomers• Reaction is stereoselective if one diastereoisomer predominates

6

MeR

O

H Ph

LiAlH4H3O+

MeR

H Ph

H OHMe

RH Ph

H OH+

R = MeR = t-Bu

75% (50% de)98% (96% de)

25%2%

::

O

PhH

view from this face

clockwiseRe face

Prochiral Nomenclature• Trigonal carbons that are not stereogenic centres but can be made into them are prochiral• Each face can be assigned a label based on the CIP rules• If the molecule is chiral (as above) the faces are said to be diastereotopic• If the molecule is achiral (as below) the faces are enantiotopic

% de = diastereisomeric excess = [major] – [minor]

[major] + [minor]

= %major – %minor

Advanced organic

Ph

Me

H H

O

Ph

Me

H H

O

Ph

H

MeH

O

Ph

H

MeH

O

PhH

O

Me H

PhH

O

Me H

Ph

HMe H

O≡ two substituents (C=O & Ph) are eclipsed - unfavoured

Felkin-Ahn model

• The diastereoselectivity can be explained and predicted via the Felkin-Ahn model• It is all to do with the conformation of the molecule...• Easiest to understand if we look at the Newman projection of the starting material

7

PhH

O

Me H

EtMgBr PhEt

Me H

PhEt

Me H

H OH HO H

25% 75% (50% de)

+

• Rotate around central bond so that substituents are staggered

• Two favoured as largest substituent (Ph) furthest from O & H• Continue to rotate around central bond and find 6 possible conformations

Me

Ph

HH

O

Me

H

Ph H

O

H

Me

PhH

O

H

Ph

Me H

O

largest substituent (Ph) furthest from O & H

largest substituent (Ph) furthest from O & H

Advanced organic

C ORR

C ORR

Nu

C ORR

C ORR

Nu

Felkin-Ahn model II

• As a result of the Bürghi-Dunitz (107°) angle there are four possible trajectories for the nucleophile to approach the most stable conformations

• Three are disfavoured due to steric hindrance of Ph or Me• Therefore, only one diastereoisomer is favoured

8

• Nucleophiles attack the carbonyl group along the Bürghi-Dunitz angle of ~107°

maximum overlap with π* - nucleophile attacks at

90° to C=O

C ORR

Nu

C ORR

repulsion from full π orbital - nucleophile

attacks from obtuse angle

compromise, nucleophile attacks π* orbital at angle

of 107°

Ph

H

MeH

O

Ph

Me

H H

O

Nu NuNu Nu

Bürghi-Dunitz angle: 107°

Ph

H

MeH

O

Ph

Me

H H

O

Nu NuNu Nu

close to Ph

close to Ph

close to Me

unhindered approach

X X X

• Favoured approach passed smallest substituent (H) when molecule in most stable...conformation

Advanced organic

Ph

Me

H

OH

Et

H

Ph

Me

H

OH

Et

H

PhEt

Me H

HO HPh

EtMe H

HO HPh

EtMe H

HO H

PhEt

Me H

HO HPh

Me

H H

O

PhH

O

Me H

EtMgBr

Felkin-Ahn model III

• Apply the Felkin-Ahn model to our example• Most problems seem to occur when swapping between different representations...

9

PhEt

Me H

HO HPh

H

O

Me H

EtMgBr 1. So, assuming we have used the Felkin-Ahn model and Newman projections to predict the product, how do we draw the correct ‘zig-zag’ representation?

PhEt

Me H

HO HPh

H

O

Me H

EtMgBr2. First, remember which parts of the molecule have not been effected by the reaction and draw them3. As the original stereogenic centre has not changed, we will compare the relative orientation of the substituents on the new centre to these

Ph

Me

H

H

HO

Et

PhEt

Me H

HO HPh

H

O

Me H

EtMgBr 4. Remember, we prefer to draw the main carbon chain in the plane of page, therefore, align Ph and Et in Newman projection as well

Ph

Me

H

OH

Et

H

5. Me and OH on same side, therefore, as Me not effected by reaction & is ‘up,’ OH must be ‘up.’ This leaves both H down.

Et

Ph

Me

H

OH

Et HPh

Me

H

OH

Et

H

rotate

Advanced organic

Felkin-Ahn model IV

• To explain or predict the stereoselectivity of nuclophilic addition to a carbonyl group with an adjacent stereogenic centre, use the Felkin-Ahn model

• Draw Newman projection with the largest substituent (L) perpendicular to the C=O• Nucleophile (Nu) will attack along the Bürghi-Dunitz trajectory passed the least

sterically demanding (smallest, S) substituent• Draw the Newman projection of the product• Redraw the molecule in the normal representation

• Whilst the Felkin-Ahn model predicts the orientation of attack, it does not give any information about the degree of selectivity

• Many factors can effect this...

10

LR

O

M S

L

M

S R

O

Nu

L

M

S

OH

Nu

R

LR

M S

Nu OH

L = large group, M = medium group, S = small group

Advanced organic

Diastereoselective addition to carbonyl group

• The size of the nucleophile greatly effects the diastereoselectivity of addition• Larger nucleophiles generally give rise to greater diastereoselectivities• Choice of metal effects the selectivity as well, although this may just be a steric effect

• The size of substituents on the substrate will also effect the diastereoselectivity• Again, larger groups result in greater selectivity

• Should be noted that larger substituents normally result in a slower rate of reaction

11

PhR

Me H

HO HPh

H

O

Me H

RMgBr

R = MeR = EtR = Ph

40% de50% de60% de

PhMe

Me H

HO HPh

H

O

Me H

Me(metal)

Me(metal) = MeMgIMe(metal) = MeTi(OPh)3

33% de86% de

MeR

O

H Ph

MeR

H Ph

H OH

R = MeR = EtR = i-PrR = t-Bu

50% de50% de66% de96% de

LiAlH4

Advanced organic

Effect of electronegative atoms

• It is hard to justify the excellent selectivity observed above using simple sterics • The Bn2N group must be perpendicular to C=O but a second factor must explain why

the selectivity is so high (& the reaction much faster than previous examples)• There is an electronic effect

12

Me

EtNBn2

O

H

OLi

OMeMe

EtNBn2

OH

OMe

O

>92% de

Bn2N

HH

OMe

EtOLi

OMeBn2N

H

HO

H

MeEt

CO2Me

• Overlap results in a new, lower energy orbital, more susceptible to nucleophilic attack• Thus if electronegative group perpendicular, C=O is more reactive

ZY

X

O

RNu

Z = electro-negative group

• When an electronegative group is perpendicular to the C=O it is possible to get an...overlap of the π* orbital and the σ* orbital

Z

Y

X

O

RNu

C=O π*

C–Z σ*

nucleophile interacts with π* orbital

C=O π*

C–Z σ*

new π*+σ* LUMO

Z

Y

X

O

RNu

new π*+σ* LUMO

new low energy orbital formed from C=O & C-Z anti-bonding orbitals favours nucleophilic attack at carbonyl

Advanced organic

Et

MeS

H Ph

OZn

rotate to allow

chelationMeS

Et

HPh

O

PhEt

O

SMe

ZnPh

Et

SMe

H OHBH4

PhEt

O

SMe

Li R3BHPh

Et

SMe

HO H

Effect of electronegative atoms II

• A good example of this effect is shown• But as always, chemistry not that simple...

13

MeS

Et

HPh

O

H BR3

MeS

Et

H

HO

H

Ph

Felkin-Ahn attack

Cram-chelation control

Et

MeS

H

OH

H

PhHH3B

• If heteroatom (Z) is capable of coordination and......a metal capable of chelating 2 heteroatoms is present we observe chelation control• Metal chelates carbonyl and heteroatom together• This fixes conformation• Such reactions invariably occur with greater selectivity• Reactions are considerably faster• The chelating metal acts as a Lewis acid and activates the carbonyl group to attack• As shown, chelation can reverse selectivity!

Advanced organic

Chelation control

• Chelation controlled additions are easy to predict• Normally do not need to draw Newman projection (yippee!)• Simple example shown below

14

LR

Nu OH

Z S

MR

OZ

M

S L

LR

O

Z S

Z = heteroatom capable of coordination; M = metal capable of coordinating to more than one heteroatom

NuNucleophile attacks

from least hindered face

O

H

O

Me PhMgI

O

HMe

HO Ph96% de

Advanced organic

Me

Me

Ph2PO

H OH

NaBH4, CeCl3EtOH, –78°C

Me

OMe

Ph2POMe

Me

Ph2PO

H OH

NaBH4MeOH, 20°C

Chelation control II

• Example shows normal Felkin-Ahn selectivity gives one diastereoisomer• Electronegative and bulky phosphorus group in perpendicular position

15

• Chelation control gives opposite diastereoisomer• Chelation can occur through 6-membered ring• Lower temperature typical of activated, chelated carbonyl

P

Me

H

O

Me

O

PhPh

H BH3 Me

P

H

O

HH3BMe

O

PhPh

Ce