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

AcO OH HO B O O HO – O O HO + O N OH H3N OH HO OH O H … AcO

HO OH O OH Sulcatol - insect pheremone HO Synthesis from the chiral pool — chiral induction turns one stereocenter into many

40 steps Me HO H Me H O O OH O O OBn O * * Only one H O HO chiral reagent H H Me OBn Me Deoxyribose 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. O O

1 1 Nu R R2 R R2 Nu

E

OH OH 1 O 1 Nu R R Nu R2 R2 1 R R2

O Ph OH HO Ph PhLi + N N N Asymmetric synthesis 2.

O

1 R R* Nu When there is an existing O chiral centre, the two possible TS’s are diastereomeric and E 1 Nu R R* can be of different energy. Thus one isomer of the new stereogenic centre can be OH O OH produced in a larger amount. 1 1 R Nu Nu R *R 1 R* R R*

HO Ph O O O Ph OH PhLi PhLi Ph Ph N N N N N

Ph N N N N N OH Ph O O O Ph OH Ph A removable chiral centre… synthesis with chiral auxiliaries

O ??? O R R

1) Add a chiral 3) Remove the auxiliary chiral auxiliary

O O

R* R*

2) Add the new stereocentre via chiral induction Enantiopure oxazolidinones as chiral auxiliaries 1. Enantioselective enolate alkylation

O O O

O O Et3N O + HN N 1) Installation of auxiliary Cl

Li O O O O O O O O

N O LDA N O EtI N O N O 2) Reaction with + chiral induction

94% 6%

O O O O LiOMe N O OMe + HN O 3) Removal of auxiliary

or O O O O LiOH N O OH + HN O More on Evans’ chiral oxazolidinones

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

Li O O Li O O N O H N O

E B) Many related chiral oxazolidinones are easily prepared from naturally occuring amino acids and their readily available unnatural enantiomers. O O O H N CO H BH3 H N Cl Cl HN 2 2 2 OH phosgene

L-Valine L-Valinol Enantiopure oxazolidinones as chiral auxiliaries 2. Enantioselective aldol reactions

Bu Bu B O O O O O O O O Bu2BOTf O Et N O NH Et3N O N 3 O N H Ph O N + H Cl C*H(OH)Ph cis boron Ph Ph Ph enolate Ph

O a) Position of added benzaldehyde O *CH(OH)Ph fragment induced by oxazolidinone O N b) Aldol stereochemistry comes from enolate stereochemistry Ph c) > 85% total yield for three steps syn aldol O OH LiOH, O O OH H2O HO Ph O N Ph

Essentially a single isomer Ph 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

O ∗ 1 R R2 Nu O ∗ E Nu 1 R R2

OH O OH R1 R1 2 Nu Nu 2 R 1 R R R2

(H– *) (H– *) H OH O HO H Ph Ph Ph

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

H H Ph H Ph BH3 CO H N 2 N Ph N Ph H O O p. 1233 B H3B B L-proline Me H B H Me H S-(–)-CBS reagent Borane adduct

Elias J. Corey Nobel prize (1990) for retrosynthetic analysis

Borane adduct - side view Borane adduct - top view Predicting the stereochemistry of CBS reductions

Hard way… Easy way…

S-(–)-CBS O OH BH3 L S L S

R-(+)-CBS O OH BH3 L S L S CBS/BH3 reduction examples…

S-(–)-CBS (0.1 eq.) Remember that BH is usually unable to O BH (1 eq.) OH 3 3 reduce ketones, but it can reduce amides and carboxylic acids because 99% yield 97% ee they activate it by first engaging it’s empty p-orbital. The CBS reagent’s amine lone pair fills S-(–)-CBS (0.01 eq.) the borane p-orbital, and the resulting O OH BH3 (0.6 eq.) Cl Cl borane adduct is activated enough to make the reduction of ketones possible. 97% yield 96.5% ee Only catalytic amounts of CBS are required! OMe

O R-(+)-CBS (0.05 eq.) OH O PrO BH3 (1 eq.) PrO PrO OH CO2H SmithKline 95% yield Beecham blood O 94% ee O O pressure drug O O O Sharpless asymmetric epoxidation (S.A.E.)

Ti(Oi-Pr)4 Ti(Oi-Pr)4 t-BuOOH O t-BuOOH O HO HO HO HO (+)-DET (–)-DET

(+)-Diethyl tartrate (DET) (–)-Diethyl tartrate (DET)

OH OH

CO2Et CO2Et EtO2C EtO2C OH OH

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.

K. Barry Sharpless Nobel prize (2001) for catalytic asymmetric oxidations Predicting the stereochemistry of Sharpless asymmetric epoxidations

Hard way… Easy way…

Ti(Oi-Pr)4 t-BuOOH HO R

(+)-DET R R (–)DET

RE HO E Z R OH RZ R

(+)-DET

Alcohol in the top left, (+)-DET delivers from the bottom, (–)-DET delivers from the top. HO R R RO Sharpless asymmetric epoxidation examples

Ti(Oi-Pr)4 t-BuOOH 85% yield O 94% ee OH (+)-DET OH

Ti(Oi-Pr) 4 O Bn t-BuOOH Bn O O OH O O OH (+)-DET

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.

Enantiopure (+)-disparlure attracts male gypsy moths to their female mates A racemic mixture of (±)-disparlure inhibits attraction

OH Ti(Oi-Pr)4 OH PDC H t-BuOOH (like PCC) O O (–)-DET O C9H19 C9H19 80% yield 91% ee Ph3P

H2, Pd/C O O C9H19

(+)-disparlure