Download Stereoselective reactions of the carbonyl group

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
Me
Me
O
Ph
O
O
L
L
Mg
O
O
Me
MeMgBr
–78°C
Me
H
Me
Me
O
OH
H Me
Me
H
Me
O
Ph
O
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
Me
Me
O
Ph
O
O
Me
KBH(i-OPr)3
O
Me
Me
Ph
O
OH
Me H
90% de
Advanced organic
2
Chiral auxiliary in synthesis
Me
Me
O
Me
Me
Ph
O
O
RMgBr
–78°C
Me
Me
O
Ph
O
Me
OH
LiAlH4
HO
Me
OH
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
3
Sulfoxides as chiral auxiliaries
hydride directed
to si face
lithium can
chelate 2 oxygens
O
Tol
S
LiAlH4
O
R
O
HO H
Li
R
H AlH3
O
Raney Ni
S
R
HO H
R
Tol
Me
80% de
O
S
Tol
R
DIBAL
Tol
S
O
O
i-Bu
Al i-Bu
HO H
H
R
H Al
i-Bu i-Bu
oxygens are not
directly tethered
O
Raney Ni
S
Tol
HO H
R
Me
70% de
dipoles directed in
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
4
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
B
+
Me
O
Me
H
O
B
+
RL
Me
Me
9-BBN•THF
(+)-α-pinene
RS
Me
alpine borane®
proceeds via boatlike transition state
can be reused
Me
H OH
Me
+
RL
B O
RS
Me
Me
H
Me
O
alpine borane®
(CH2)4Me
small group as linear
Me
RS
H OH
(CH2)4Me
86% ee
RL
selectivity governed
by 1,3-diaxial
interactions
Advanced organic
5
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
BCl
Me
+
Me
H OH
Me
Me
Me
Me
2
(+)-Ipc2BCl
98% ee
• And here is another...
O
Me
B
H
Me
+
Me
H OH
Me
Me
Me
Me
Me
>99% ee
Advanced organic
6
Binol derivative of LiAlH4
1. (S)-BINAL–H
2. MOM–Cl
O
Me
H OMOM
Me
SnBu3
O
O
SnBu3
93% ee
OEt
Al
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!!)
(R ) adopts the pseudo-equatorial position and the small
• Largest substituent
S
substituent (R ) is axial to minimise 1,3-diaxial interactions
O
O
Al
O
H
RS
Li
Et RL
O
Advanced organic
7
Chiral reagents: allylation
Ti
Cl
OH
Ph
Ph
O
H
Ph
Ph
O
O
Me
Me
MgBr
Ti
OH
Ph
Ph
O
H
O
Ph
Ph
Ph
H OH
H
O
O
Me
Me
95% ee
• 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
8
Chiral allyl boron reagents
L
RZ
O
+ L
R
O
RE
B
L
B
O
RZ
R
L
L
L
OH
H2O2
NaOH
B
R
R
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
R
RE
H
B
O
RZ
disfavoured
H
L
H
L
vs
RE
R
RZ
B
O
H
OH
H
L
RE
R
RZ
OH
R
RZ
RE
E-alkene gives anti product
Z-alkene gives syn product
• Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain)
• Therefore alkene geometry controls the relative stereochemistry (like aldol rct)
Advanced organic
9
Chiral allyl boron reagents II
Me
OH
O
B
+
Me
Et
Me
Me
H
Et
Me
92% ee
2
crotyl group
orientated away from
pinene methyl groups
Me
Me
Me
H
H
H
Et
Me
H
B
Me
Me
O
Et
Me
OH
Me
substituent pseudoequatorial
• 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
10
Other boron reagents
RZ
Me
RE
B
Me
Me
RZ
O
i-PrO2C
RE
O
i-PrO2C
2
attacks on si face of RCHO
B
RZ
Ts
attacks on si face of RCHO
tartaric acid derivative
N
Ph
RE
B
N
Ts
Ph
attacks on re face of RCHO
• 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
11
Catalytic enantioselective reduction
OMe O
CBS catalyst (10%)
BH3•THF
MeO
H OH
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
N
Ph
Ph
B O
Me
CBS catalyst
proline derivative
H
BH3
Ph
N
Ph
H3B B O
Me
active catalyst
Advanced organic
12
Mechanism of CBS reduction
• interaction of amine & borane activates borane
• it positions the borane
• it increases the Lewis acidity of the endo boron
H
catalyst turnover
H
Ph
N
BH3•THF
Ph
Ph
N
H3B B O
Me
B O
Me
Ph
O
H OH
RL
RS
RL
Ph
coordination of
aldehyde activates
aldehyde and places
it close to the borane
Ph
O
Ph
RS
N
B
Me
H
B
O
H
O
Ph
RS
H
N
B
Me
H
B
O
H
RS
H
RL
RL
chair-like transition state
largest substituent is pseudo-equatorial
Advanced organic
13
Catalytic enantioselective nucleophilic addition
O
O
H
+
C5H11
Zn C5H11
Me
H OH
(–)-DAIB (2%)
O
Me
C5H11
>95% ee
NMe2
OH
Me (–)-DAIB
Me
Me
Me Me
Me
C5H11
N Me
O Zn C H
5 11
Zn C H
5 11
Me
Me Me
Me
Me
N
C5H11
O Zn
Ar vs.
O
Zn
C5H11
C4H9
H
Me Me
Me
C5H11
O Zn
H
O
Zn
N
Me
C5H11
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
14
Catalytic chiral Lewis acid mediated allylation
O
+
Ph
SnBu3
cat. (5%), DCM, rt, 7h
H OH
O
Cl
Ph
H
O
N
88%
62% ee
Rh
N
Cl
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...)
O
+
Ph
Me
SnBu3
H
E:Z
95 : 5
2 : 98
cat. (10%),
DCM, rt, 72h
O
H OH
Ph
Me
anti (ee) : syn (ee)
71 (57) : 29 (8)
63 (60) : 37 (7)
R
M
H
SnBu3
open transition state
Advanced organic
15
Catalytic chiral Lewis base mediated allylation
O
+
R
RE
Lewis base catalyst (LB)
SiCl3
RE
R
H
H
H OH
RZ
RE
R
RZ
LB
Cl
Si LB
O
Cl
Cl
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
H
H
N
O
P
N
N
Me
RE = Me
86% ee
anti/syn 99/1
N
O
5
()
N
P
N
H
Ph
Me
N
Ph
Me
H
Me
RZ = Me
95% ee
syn/anti >19/1
H
RE = Me
98% ee
anti/syn >99/1
O
RZ = Me
98% ee
syn/anti 40/60
Me
RE = Me
86% ee
anti/syn 97/3
N
N
O
O
RZ = Me
84% ee
syn/anti 99/1
Advanced organic
16
Organocatalysts
O
cat. (10%)
NaOH
Ph
Et
Br
Et
S
Et
S
Ph
Et
Ph
H
Et
O
Et
S
Ph
Ph
O
Ph
Ph
92% ee
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
17
Organocatalysts II
H
H
NH
HN
N H N
OTf
N
Ar
HN
Boc
+
R
NO2
Ar
cat. (10%)
H
P(O)Ph2
NO2
R
90% ee
90% de
H
Ar
N
Boc
H
O
N
O
R
• 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
18
Bifunctional organocatalysts
CF3
S
F3C
R
NO2
N
+
Ar
P(O)Ph2
H
N
H
N
H
Me
N
Me
P(O)Ph2
NO2
Ar
cat. (10%)
DCM, rt
R
76% ee
CF3
CF3
S
S
F3C
HN
N
H
O
R
N
H
N H
N Me
H
Me
O
H
F3C
N
N
H
H
Me
O
O N
N
H Me
NDpp
R
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