1

Stereoselective reactions of the carbonyl group

• We have seen many examples of substrate control in nucleophilic addition to the
carbonyl group (Felkin-Ahn & chelation control)
• If molecule does not contain a stereogenic centre then we can use a chiral auxiliary
• The chiral auxiliary can be removed at a later stage

Me L
L Me
O MeMgBr Me Mg O
–78°C O
Me Ph O Me Ph
O Me OH
O O O
Me H H Me H Me
Me 98% de

Me

• Opposite diastereoisomer can be obtained from reduction of the ketone

• Note: there is lower diastereoselectivity in the second addition as the nucleophile,
...‘H–’ is smaller
Me Me
O O
Me Ph KBH(i-OPr)3
Me Ph
O OH
O O
Me Me Me Me H
90% de

Advanced organic
2

Chiral auxiliary in synthesis

Me
Me O Me
O RMgBr Me Ph Me OH
–78°C LiAlH4 HO
Me Ph O OH
O
O Me
Me Me
Me Me

O3
–78°C

O Me

O
Me
(–)-frontalin
100% ee

• The chiral auxiliary, 8-phenylmenthol, has been utilised to form the pheromone,
frontalin

Advanced organic
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Sulfoxides as chiral auxiliaries

hydride directed
lithium can to si face
chelate 2 oxygens
O O
HO H HO H
Tol O Raney Ni
S Li S
R R
LiAlH4 Tol R Me
H AlH3
80% de
O O
S
R
Tol
R i-Bu
DIBAL Tol O O
S Al i-Bu HO H
Raney Ni HO H
O S
H R R Me
H Al Tol
i-Bu i-Bu 70% de

oxygens are not dipoles directed in

directly tethered opposing directions

• Underrated chiral auxiliary - easily introduced, performs many reactions & can be
readily removed
• One auxiliary can give either enantiomer of product
• Selectivity dependent on whether reagent can chelate two groups
Advanced organic
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Chiral reagents
• Clearly, chiral reagents are preferable to chiral auxiliaries in that they function
independent of the substrate’s chirality or on prochiral substrates
• A large number have been developed for the reduction of carbonyls
• Most involve the addition of a chiral element to one of our standard reagents
Me
H O Me H O
B B
+ +
Me RL RS
Me
Me
Me
(+)-α-pinene 9-BBN•THF alpine borane®
proceeds via boat-
like transition state
can be reused

Me
H OH
+ B O
Me RL RS Me H RL
Me
Me Me RS

O H OH
alpine borane®
selectivity governed
(CH2)4Me (CH2)4Me by 1,3-diaxial
interactions
small group as linear 86% ee
Advanced organic
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Chiral reagents II
• Alpine-borane is very good for reactive carbonyls (aldehydes, conjugated ketones
etc)
• It is less efficient with other ketones so a more Lewis acidic variant has been
developed
• Addition of the chloride makes the boron more electrophilic
• Transition state similar to previous slide

Me H
O H OH
BCl
Me Me
+
Me Me Me
Me
2
(+)-Ipc2BCl 98% ee

• And here is another...

O H OH
+ Me Me
Me B Me Me Me
H Me Me
>99% ee

Advanced organic
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Binol derivative of LiAlH4

O 1. (S)-BINAL–H
H OMOM
2. MOM–Cl
Me Me
SnBu3 SnBu3
93% ee

O OEt
Al
O H

Li
(R)-BINAL–H

• Reducing reagent based on BINOL and lithium aluminium hydride

• Selectivity is thought toL arise from a 6-membered transition state (surprise!!)
• Largest substituent
S
(R ) adopts the pseudo-equatorial position and the small
substituent (R ) is axial to minimise 1,3-diaxial interactions

O
RS
Al Li
O O
H O
Et RL

Advanced organic
7

Chiral reagents: allylation

O
Ti Ph Ti Ph H OH
O MgBr O
Cl
OH H Ph OH H Ph Ph H

Ph Ph
O O
Ph Ph
O Me O Me 95% ee
Me Me

• Stereoselective reactions other than reduction can be performed with chiral reagents
• In the above reaction the standard Grignard reagent is reacted with the titanium
complex to give the chiral allylating reagent
• Note: the chirality is derived from tartaric acid (again)

Advanced organic
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Chiral allyl boron reagents

L L L L
RZ B B H2O2 OH
O O O NaOH
+ L
B RE RZ R
R R R
L RZ RE
RE RZ RE

• Allyl boron reagents have been used extensively in the synthesis of homoallylic
alcohols
• Reaction always proceeds via coordination of Lewis basic carbonyl and Lewis acidic
boron
• This activates carbonyl as it is more electrophilic and weakens B–C bond, making
the reagent more nucleophilic
• Funnily enough, reaction proceeds by a 6-membered transition state
H L H L H
R H H OH
B B
L vs L
RE RE RE R
O O OH
H R R RZ RE
RZ RZ RZ
E-alkene gives anti product
Z-alkene gives syn product
disfavoured

• Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain)

• Therefore alkene geometry controls the relative stereochemistry (like aldol rct)
Advanced organic
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Chiral allyl boron reagents II

Me
OH
B O
+
Me Et
Me Et H
Me
Me
2 92% ee

crotyl group
orientated away from Me Me
pinene methyl groups
Me
H

H H
B OH
Me Et
H Me Me
O
Et
Me Me

substituent pseudo-
equatorial

• Reagent is synthesized from pinene in two steps

• Gives excellent selectivity but can be hard to handle (make prior to reaction)
• Remember pinene controls absolute configuration
Geometry of alkene controls relative stereochemistry
Advanced organic
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Other boron reagents

Me RZ RZ
Ts
B RE O N
B RE B RE
i-PrO2C Ph
Me RZ O N
Ts
Me i-PrO2C Ph
2
attacks on si face of RCHO attacks on si face of RCHO attacks on re face of RCHO
tartaric acid derivative

• A number of alternative boron reagents have been developed for the synthesis of
homoallylic alcohols
• These either give improved enantiomeric excess, diastereoselectivity or ease of
handling / practicality

• Ultimately, chiral reagents are wasteful - they need at least one mole of reagent for
each mole of substrate
• End by looking at chiral catalysts

Advanced organic
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Catalytic enantioselective reduction

OMe O CBS catalyst (10%) MeO H OH
BH3•THF
MeO MeO

93% ee

• An efficient catalyst for the reduction of ketones is Corey-Bakshi-Shibata catalyst

(CBS)
• This catalyst brings a ketone and borane together in a chiral environment
• The reagent is prepared from a proline derivative
• The reaction utilises ~10% heterocycle and a stoichiometric amount of borane and
works most effectively if there is a big difference between each of the substituents
on the ketone
• The mechanism is quite elegant...

H H
Ph Ph
N BH3 N
Ph Ph
B O H3B B O
Me Me
CBS catalyst active catalyst
proline derivative

Advanced organic
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Mechanism of CBS reduction

• interaction of amine & borane activates borane
• it positions the borane
• it increases the Lewis acidity of the endo boron

H H
Ph BH3•THF Ph
catalyst turnover N N
Ph Ph
B O H3B B O
Me Me

H OH O

RL RS RL RS

coordination of
Ph Ph aldehyde activates
aldehyde and places
O Me O Me it close to the borane
N B N B
Ph H Ph H
H B O H B O
RS RS
H H
RL RL

chair-like transition state

largest substituent is pseudo-equatorial

Advanced organic
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Catalytic enantioselective nucleophilic addition

O H OH
O (–)-DAIB (2%) O
+ C5H11 Zn C5H11
H C5H11
Me Me
>95% ee
NMe2
OH
Me (–)-DAIB

Me Me Me Me Me Me
Me Me Me Me Me
N C5H11 N C5H11
N Me
O Zn O Zn
O Zn C H
5 11 O Ar vs. O H
Me Zn Me Zn
Me Zn C H
C5H11
5 11 C5H11 C5H11
C4H9 H C4H9 Ar
disfavoured

• There are now many different methods for catalytic enantioselective reactions
• Here are just a few examples...
• Many simple amino alcohols are known to catalyse the addition of dialkylzinc
reagents to aldehydes
• Mechanism is thought to be bifunctional - one zinc becomes the Lewis acidic
centre and activates the aldehyde
• The second equivalent of the zinc reagent actually attacks the aldehyde
• Once again a 6-membered ring is involved and 1,3-diaxial interactions govern
selectivity Advanced organic
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Catalytic chiral Lewis acid mediated allylation

O cat. (5%), DCM, rt, 7h H OH
SnBu3 O O
+ Cl
Ph H Ph N Rh N
88% Cl
62% ee Bn Bn
cat. derived from amino
acid (via the alcohol)

• A variety of chiral Lewis acids can be used to activate the carbonyl group
• These can result in fairly spectacular allylation reactions (higher ee than this example)
• A problem frequently arises with crotylation
• Often the reactions proceed with poor diastereoselectivity favouring either the syn
or anti diastereoisomer regardless of geometry of the starting crotyl reagent
• This is because the reactions proceed via an open transition state
• (just to confuse you most actually favour syn! I use this example as the comparisons
were easy to find...)
M
cat. (10%), H OH O
O DCM, rt, 72h
+ Me SnBu3
Ph
Ph H R H
Me
E:Z anti (ee) : syn (ee)
95 : 5 71 (57) : 29 (8)
2 : 98 63 (60) : 37 (7) SnBu3
open transition state

Advanced organic
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Catalytic chiral Lewis base mediated allylation

LB Cl
H OH H
O
RE SiCl3 Lewis base catalyst (LB) Si LB
+ RE Cl Cl
R H R O
RZ RE RZ R
RZ

• An alternative strategy is the use of Lewis bases to activate the crotyl reagent
• Reaction proceeds via the activation of the nucleophile to generate a hypervalent
silicon species
• This species coordinates with the aldehyde, thus activating the aldehyde and
allowing the reaction to proceed by a highly ordered closed transition state
• As a result good diastereoselectivities are observed and the geometry of
nucleophile controls the relative stereochemistry
Me Me
N O O N
H H
P 5
() P Ph N Ph N
H N N H Me O
N N
Me Me H O Me O
N

RE = Me RZ = Me RE = Me RZ = Me
86% ee 95% ee 98% ee 98% ee
RE = Me RZ = Me
anti/syn 99/1 syn/anti >19/1 anti/syn >99/1 syn/anti 40/60
86% ee 84% ee
anti/syn 97/3 syn/anti 99/1
Advanced organic
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Organocatalysts

O
cat. (10%)
NaOH Ph H Et S Et O
Et S Et
Ph Br Ph
Ph Ph Ph
Ph 92% ee
Et S Et O 85% de (trans)

• As we have seen with many stereoselective reactions, small organic molecules are
now finding considerable use as enantioselective catalysts
• Above is a simple example of epoxide formation
• The reaction proceeds by SN2 displacement of the bromide by the sulfide and
subsequent deprotonation to give the reactive ylide
• Nucleophilic attack & cyclisation give the epoxide and regenerate the sulfide catalyst

Advanced organic
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Organocatalysts II

H H
NH HN

N H N
OTf
P(O)Ph2
Boc HN
N
+ R NO2 NO2
cat. (10%) Ar
Ar H
R
90% ee
90% de

O O
H Boc N
N
R
Ar H

• Acts as a ‘chiral proton’

• Protonation of the imine forms a highly electrophilic species
• Aza-Henry reaction can then proceed to give the new amine

Advanced organic
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Bifunctional organocatalysts
CF3

F3C N N
H H P(O)Ph2
P(O)Ph2 N HN
N Me Me
R NO2 + NO2
cat. (10%) Ar
Ar H DCM, rt
R
76% ee

CF3
CF3
S
S
H
F3C N N
F3C N N H
N Me H H
H H Me
Me O O N
O O N H Me
N
NDpp
R
R H
H Ar

• Thio(urea) acts as a Lewis acid to activate & position the nitro substrate
• Pendent amine functionality deprotonates the nitro α-C–H and presumably an
electrostatic interaction shields the bottom face of the nitro enolate
Advanced organic