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
HO +H O– O N
OH 3N OH
HO OH O H
AcO

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

HO 40 steps Me Me
H O H
O O O OBn
OH
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

R1 R1 Nu
Nu R2 R2

OH OH
R1 O R1
Nu Nu
R2 R2
R1
R2

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

R1
R* Nu When there is an existing
O chiral centre, the two possible
TS’s are diastereomeric and
E
Nu R1
R* can be of different energy.
Thus one isomer of the new
stereogenic centre can be
OH OH
O produced in a larger amount.
R1 R1
Nu Nu
*R R1 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 O Li
O
N O H N
O

B) Many related chiral oxazolidinones are easily prepared from naturally occuring amino
acids and their readily available unnatural enantiomers.
O
O
O
H2N CO2H BH3 H2N Cl Cl HN
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 Et3N H Ph
O NH Et3N O N O N O N
+
Cl
H *
CH(OH)Ph
cis boron
Ph Ph Ph Ph
enolate

O O
a) Position of added benzaldehyde *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
∗
R1 Nu
R2
O
∗
E Nu R1
R2

OH O OH
R1 R1
Nu Nu
R2 R1 R2
R2

(H– *) O (H– *)
H OH 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
N CO2H N Ph Ph
N
H
p. 1233 B O H3B B O
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 BH3 OH

L S L S

R-(+)-CBS
O BH3 OH

L S L S
CBS/BH3 reduction examples…

S-(–)-CBS (0.1 eq.)

Remember that BH3 is usually unable to
O BH3 (1 eq.) OH
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
O
S-(–)-CBS (0.01 eq.)
OH
the borane p-orbital, and the resulting
Cl
BH3 (0.6 eq.)
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

PrO BH3 (1 eq.) PrO PrO O 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
HO O
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
RZ RE
OH RZ

(+)-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
OH (+)-DET OH 94% ee

Ti(Oi-Pr)4
t-BuOOH O
Bn 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 O
(–)-DET C9H19 C9H19
80% yield
91% ee
Ph3P

H2, Pd/C
O O
C9H19

(+)-disparlure