123.702 Organic Chemistry

bX

c

HR2

dR

a

bX

c

HR2

dR

aX

R

R2

da b

c

heatX

R2

R3R1

X

R1 R3

R2

[3,3]-Sigmatropic rearrangements

• A class of pericyclic reactions whose stereochemical outcome is governed by the geometric requirements of the cyclic transition state

• Reactions generally proceed via a chair-like transition state in which 1,3-diaxial interactions are minimised

• Many similarities to the aldol reaction Absolute stereochemistry - controlled by existing stereocentre (destroyed in rct)Relative stereochemistry - controlled by alkene / enolate geometry

1

X

R1 R3

R2

X

R2

R

dcb

a

123.702 Organic Chemistry

H

Me

MePh

H Me

PhMe

91%

H

Ph

MeMe

Me H

MePh

9%

Me

Me

Ph

Cope rearrangement

• A very simple example of a substrate controlled [3,3]-sigmatropic rearrangement is the Cope rearrangement

• To minimise 1,3-diaxial interactions phenyl group is pseudo-equatorial • Note: the original stereocentre is destroyed as the new centre is formed• This process is often called ‘chirality transfer’

2

1,3-diaxial interactions disfavoured

123.702 Organic Chemistry

Claisen rearrangements

• One of the most useful sigmatropic rearrangements is the Claisen rearrangement and all it’s variants

3

Claisen rearrangement

Johnson-Claisen rearrangement

Eschenmoser-Claisen rearrangement

OH +OEt Hg+ O O

H

heat

OH +Me OMe

MeO OMe H+ O

OMe

O

OMe

heat

OH +Me NMe2

MeO OMe H+ O

NMe2

O

NMe2

heat

Ireland-Claisen rearrangement

OH +Me O Me

O O Et3N

Me

O

O

O

OSiR3

O

OSiR3

heatR3SiClbase

123.702 Organic Chemistry

Me

Me

OMe

NMe2

Me NMe2

MeO OMe

Me

Me

OH MeH2

Lindlar cat.

MeNMe2

Me

Me O

≡

MeMe

Me

NMe2

O HMe

Me

O

Me

NMe2

Me NMe2

MeO OMeNaNH3 Me

Me

OH

MeMe

Me

Me

OH

Me

Me

Me

OH

‘Enantioconvergent’ synthesis

• Both enantiomers of initial alcohol can be converted into the same enantiomer of product

• This process (Eschenmoser-Claisen) shows the importance of alkene geometry

4

SET reduction gives most stable alkene

heterogeneous hydrogenation leads to syn addition of H2

O

H NMe2

i-Pr

Me

O

H NMe2

i-Pr

Me

HH

Me2N

O

H Me

Hi-PrMe2N

O

H Me

Hi-Pr

same configuration

MeH

Me

NMe2

O Me

≡

123.702 Organic Chemistry

O

H

H

OSiR3MeMe O

H

H

OSiR3MeMe

O

OSiR3Me

Me

1. LDA, THF/HMPA2. R3SiCl

O

MeMe

OSiR3

O

H

Me

OSiR3Me

H

O

OSiR3Me

MeO

H

Me

OSiR3Me

H

1. LDA, THF2. R3SiCl

O

MeOSiR3

Me

O

MeMe

O

Ireland-Claisen reaction

• Enolate geometry controls relative stereochemistry• Therefore, the enolisation step controls the stereochemistry of the final product• As we saw earlier it is relatively easy to control enolate geometry...

5

123.702 Organic Chemistry

Substrate control in Ireland-Claisen rearrangement

• In a similar fashion to the Cope rearrangement we saw earlier, the Ireland-Claisen rearrangement occurs with ‘chirality transfer’

• Initial stereogenic centre governs the conformation of the chair-like transition state• Largest substituent will adopt the pseudo-equatorial position

• Once again, the relative stereochemistry is governed by the geometry of the enolate

6

O

Me Me

OHO

91% ee

1. LHMDS2. TMSCl

H

O

OTMS

H

Me

OTMS

Me

H

O

OTMS

H

Me

OTMS

Me

HO2CMe

OTMS

Me98% syn91% ee

methyl group is pseudo-equatorial

123.702 Organic Chemistry

Auxiliary controlled rearrangement in total synthesis

• (–)-Malyngolide is an antibiotic isolated from the blue-green marine algae Lyngbya majuscula

• This synthesis utilises Enders' RAMP hydrazone as a chiral auxiliary to set up the quarternary centre

• Dieter Enders & Monika Knopp Tetrahedron 1996, 52, 5805

7

NN

OMe

O

O LiTMP NN

OMe

O

OLi LiAlH4 N

N

OMe

OHO

OMe

OHMe

( )7

(–)-malyngolide

123.702 Organic Chemistry

O

OHMe

Me96% ee

warmO

O

Me

R*2B

MeEt3NTol / hexane

–78°C

O

OHMe

Me>97% ee

warmO

OMe

Me

R*2Bi-Pr2NEtCH2Cl2–78°C

O

OMe

Me

+ NBN

Ph Ph

ArO2S SO2Ar

Br

Chiral reagent control in the Ireland-Claisen rearrangement

• Funnily enough, it is possible to carry the reaction out under “reagent” control • Although, it could be argued that this is just a form of temporary auxiliary control!• Enolate formation (enolate geometry) governs relative stereochemistry

8

123.702 Organic Chemistry

The use of a chiral reagent in total synthesis

• Dolabellatrienone is a marine diterpenoid isolated from gorgonian octocorals such as Eunicea calyculata and other marine organisms

• This synthesis of dolabellatrienone relies on boron enolate chemistry to establish the stereochemistry of the final molecule

• E. J. Corey & Robert S. Kania, J. Am. Chem. Soc. 1996, 118, 1229

9

O

Me

MeMe

O

NBN

Ph Ph

Br

SO2O2S

CF3F3C

F3CCF3 Me Me

CO2HH

Me

Me Me

HMe

O

Me

Medolabellatrienone

Ni-Pr

N(i-Pr)2

(i-Pr)2N

86%>98%ee

123.702 Organic Chemistry

Chiral catalyst control in the Ireland-Claisen rearrangement

• It is also possible to perform the reactions under chiral catalyst control• Presumably, the Lewis acid coordinates to the oxygen & influences the reactive

conformation thus controlling enantioselectivity

10

O

Ph

SiMe

MeMe

HO

SiMe3

Ph

O

Ph

SiMe3

MeAl(OR*)2

OO

Al Me

SiMe2t-Bu

SiMe2t-Bu

MeAl(OR*)2 =

123.702 Organic Chemistry

H

Me

O

H H

H H

Me

HO

H H

H

MeMe

≡ HO

Me

98%de98%ee

Me

OBuLi–85°CMe

Me

H

H

HO

H H

Me

H

≡ HO

Me

98%deH

H

O

H H

Me

H

O

MeBuLi–85°C

11

2

2 3

1

12

2 3

O Z H HO ZO Z Base O Z

2,3-Wittig rearrangement

• Useful rearrangement allowing good 'chirality transfer'• Requires method for formation of anion - either acidic proton (Z=electron

withdrawing group) or metal-functional group exchange• Driving force is stability of alkoxide (although other elements can be used...)

• Transition state debatable but useful model is the 'envelope' based on chair

11

• Largest substituents adopt pseudo-equatorial position

123.702 Organic Chemistry

Enantioselectivity in the 2,3-Wittig rearrangement

• Reagent control utilising boron reagent seen in both aldol & Claisen reactions• Chiral catalysis is far less developed in this area• One example is given below:

12

O

Me

CO2Me+

NBN

Ph Ph

PhO2S

Br

SO2Ph

Et3N O

Me

R2BO OMe

MeO

MeO OBN

NSO2

O2S

Ph

Ph

Ph

Ph

≡ HO

Me

CO2Me

66%de96%ee

O

ArR2*RNPh(CH2)2

OO

Ar

cat (20mol%)MeOH, rt, 5d

75%60%ee (dr 2:1)

Ph(CH2)2

O

OH

Ar

NH N

123.702 Organic Chemistry

[2,3]-aza-Wittig reaction in total synthesis

• Aza-Wittig reaction is less common as normally no driving force• Here relief of ring-strain accelerates reaction• Utilised in the synthesis of indolizidine 209B from Dendrobates pumilio or the

strawberry poison dart frog by Jens Åhman & Peter Somfai, Tetrahedron, 1995, 51, 9741

13

C5H11

Me

NCO2t-Bu

LDA

97%

N

C5H11

H

H

MeHLiO

Ot-Bu

NH

C5H11 CO2t-Bu

Me

NC5H11

Me

indolizidine 209B