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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
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