Chapter 45 — Asymmetric synthesis

- Pure enantiomers from Nature: the chiral pool and chiral induction -  Asymmetric synthesis: chiral auxiliaries

Enolate alkylation Aldol reaction

- Enantiomeric excess (ee) -  Asymmetric synthesis: chiral reagents and catalysts

CBS reagent for chiral reductions Sharpless asymmetric epoxidation

Synthesizing pure enantiomers starting from Nature’s chiral pool

+H3NO–

O

OHOHO

OHOH

OH

OB

HO

HO

O N

AcO

AcO

HOH …

Sulcatol - insect pheremone OOH

HO

HOOH

O

Synthesis from the chiral pool — chiral induction turns one stereocenter into many

O OH

HO

HO

Deoxyribose

40 stepsO

O

O

O

O

OBn

OBnH Me Me H

H H H MeMe

**

Only one chiral reagent

Fragment of Brevetoxin B

Asymmetric synthesis 1.

Producing a new stereogenic centre on an achiral molecule makes two enantiomeric transition states of equal energy… and therefore two enantiomeric products in equal amounts.

N

OPhLi

N

Ph OH

N

PhHO

+

R1 R2

O

R1 R2

O

NuR1 R2

O

Nu

R2R1

OH

Nu R2R1

OH

Nu

E

Asymmetric synthesis 2.

N

OPhLi

N

Ph OH

N

PhHO

N

O

N

O

PhN

OH

Ph

N

O

PhPhLi

N

O

Ph

N

OPh

N

Ph

OH

When there is an existing chiral centre, the two possible TS’s are diastereomeric and can be of different energy. Thus one isomer of the new stereogenic centre can be produced in a larger amount.

R1 R*

O

R1 R*

O

Nu

R1 R*

O

Nu

R*R1

OH

Nu*RR1

OH

Nu

E

A removable chiral centre… synthesis with chiral auxiliaries

R

O

R

O ???

R*

O

R*

O

1) Add a chiral auxiliary

2) Add the new stereocentre via chiral induction

3) Remove the chiral auxiliary

Enantiopure oxazolidinones as chiral auxiliaries 1. Enantioselective enolate alkylation

Cl

O HN O

O

+ N O

OOEt3N

N O

OO

N O

OOLi

LDA N O

OOEtI

94%

N O

OO

6%

+

1) Installation of auxiliary

3) Removal of auxiliary

2) Reaction with chiral induction

N O

OOLiOMe

OMe

O

HN O

O

+

N O

OOLiOH

OH

O

HN O

O

+

or

More on Evans’ chiral oxazolidinones

A) A 3D model helps understand the observed chiral induction.

B) Many related chiral oxazolidinones are easily prepared from naturally occuring amino acids and their readily available unnatural enantiomers.

N O

OOLi

L-Valine L-Valinol

phosgene

ON

O OLi

H

E

E

H2N CO2H H2N OHBH3 Cl Cl

O

HNO

O

Cl

ONH

Ph

O

O

+ N

Ph

O

O OEt3N N

Ph

O

O OBu2BOTfEt3N

BBu Bu

N

Ph

O

O O

H Ph

O

CH(OH)Ph

N

Ph

O

O OCH(OH)Ph

H *

N

Ph

O

O O

Ph

OH

*

HO

O

Ph

OH LiOH,H2O

Enantiopure oxazolidinones as chiral auxiliaries 2. Enantioselective aldol reactions

cis boron enolate

syn aldol

a) Position of added benzaldehyde fragment induced by oxazolidinone

b) Aldol stereochemistry comes from enolate stereochemistry

c) > 85% total yield for three steps

Essentially a single isomer

A quick word on enantiomeric excess (ee)

Enantiomeric excess is the most common way to report the level of enantioselectivity observed for a reaction.

The ee is the amount (in %) of one enantiomer present subtracted from the amount of the other, thus…

50:50 0% ee

75:25 50% ee

90:10 80% ee

99:1 98% ee

99.5:0.5 99% ee

Asymmetric synthesis: chiral catalysts and reagents

Chiral reagents can form energetically different TS’s when approaching prochiral faces or groups on a molecule, and thus perform enantioselective reactions DIRECTLY on an achiral starting material.

R1R2

O

R1R2

O

Nu

R2R1

OH

NuR2R1

OH

Nu

E

Ph

O

PhPh

HOH OH H(H– *) (H– *)

∗

R1R2

O

Nu∗

Chiral reductions with Corey-Bakshi-Shibata (CBS) reagent

Borane adduct - top view Borane adduct - side view

NB ON

HCO2HH

L-proline

H

Me

PhPh

p. 1233N

B O

H

Me

PhPh

H3B

BH3

H B HH

S-(–)-CBS reagent Borane adduct

Elias J. Corey

Nobel prize (1990) for retrosynthetic analysis

Predicting the stereochemistry of CBS reductions

Hard way… Easy way…

L

O

S L S

OHS-(–)-CBSBH3

L

O

S L S

OHR-(+)-CBSBH3

CBS/BH3 reduction examples…

Remember that BH3 is usually unable to reduce ketones, but it can reduce amides and carboxylic acids because they activate it by first engaging it’s empty p-orbital.

The CBS reagent’s amine lone pair fills the borane p-orbital, and the resulting borane adduct is activated enough to make the reduction of ketones possible.

Only catalytic amounts of CBS are required!

SmithKline Beecham blood pressure drug

OS-(–)-CBS (0.1 eq.)BH3 (1 eq.) OH

99% yield97% ee

OCl

OHCl

S-(–)-CBS (0.01 eq.)BH3 (0.6 eq.)

97% yield96.5% ee

OPrO

OO

PrO

OO

R-(+)-CBS (0.05 eq.)BH3 (1 eq.)

OH

95% yield94% ee

PrO

OO

OMe

CO2HO OH

Sharpless asymmetric epoxidation (S.A.E.)

K. Barry Sharpless

Nobel prize (2001) for catalytic asymmetric oxidations

HO HOO

Ti(Oi-Pr)4t-BuOOH

(+)-DETHO HO

OTi(Oi-Pr)4t-BuOOH

(–)-DET

EtO2CCO2Et

OH

OH

(+)-Diethyl tartrate (DET)

EtO2CCO2Et

OH

OH

(–)-Diethyl tartrate (DET)

Ti(i-PrO)4, the chiral DET, and t-BuOOH make a chiral aggregate that coordinates the allyl alcohol and delivers the epoxide selectively to one prochiral face of the alkene.

Predicting the stereochemistry of Sharpless asymmetric epoxidations

Hard way… Easy way…

HO

R R

RO

HO

R R

RTi(Oi-Pr)4t-BuOOH

(+)-DET

OH

RE HORERZ RZ

(–)DET

(+)-DET

Alcohol in the top left, (+)-DET delivers from the bottom, (–)-DET delivers from the top.

Sharpless asymmetric epoxidation examples

OH

Ti(Oi-Pr)4t-BuOOH

(+)-DET OHO

85% yield94% ee

BnO O OH

Ti(Oi-Pr)4t-BuOOH

(+)-DET

BnO O OH

O

Ti(Oi-Pr)4 and DET are used catalytically (1–5%), but t-BuOOH, as the source of the epoxide oxygen atom, must be used stoichiometrically

Only allylic alcohols are epoxidized by these reagents

Synthesis of gypsy moth pheromone by S.A.E.

OH Ti(Oi-Pr)4t-BuOOH

(–)-DET C9H19

OH

OC9H19

OO

PDC (like PCC)

H

Ph3P

C9H19O

H2, Pd/CO

80% yield91% ee

(+)-disparlure

Enantiopure (+)-disparlure attracts male gypsy moths to their female mates

A racemic mixture of (±)-disparlure inhibits attraction