Download Stereoselective synthesis: chiral auxiliaries

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Stereoselective synthesis: chiral auxiliaries
Chiral auxiliaries
substrate
(achiral)
+
couple to form new
chiral compound
chiral
auxiliary
overall
reaction
product
(chiral)
+
substrate
(achiral)
chiral
auxiliary
product
diastereoselective
reaction
cleave chiral
auxiliary
chiral
auxiliary
chiral
auxiliary
resolve other
diastereoisomer
product
chiral
auxiliary
• Chiral auxiliary - allows enantioselective synthesis via diastereoselective reaction
• Add chiral unit to substrate to control stereoselective reaction
• Can act as a built in resolving agent (if reaction not diastereoselective)
• Problems - need point of attachment
....................adds additional steps
....................cleavage conditions must not damage product!
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Chiral auxiliary and addition to 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
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Chiral auxiliary in synthesis
Me
Me
O
Me
Me
Ph
O
O
RMgBr
–78°C
Me
O
Ph
O
Me
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
• Aggregation pheromone of the Southern Pine Beetle - the most destructive beetle to
pine forests in southeastern united states
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Stereoselective synthesis: chiral reagents
Chiral reagents
substrate
(achiral)
+
chiral reagent
interacts with
achiral substrate
chiral
reagent
substrate
(achiral)
reaction
product
(chiral)
chiral
reagent
+
dead
reagent
chiral
complex
• Chiral reagent - stereochemistry initially resides on the reagent
• Advantages - No coupling / cleavage steps required
•
........................Often override substrate control
........................Can be far milder than chiral auxiliaries
Disadvantages - Need a stoichiometric quantity (not atom economic)
.............................Frequently expensive
.............................Problematic work-ups
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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
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
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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
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Chiral reagent in total synthesis
Cl
Me H
O
B
BCl
Cl
Me
Me
Me
H
Me
2
Ipc
O
Ph
H OH
Cl
Me
Cl
(+)-Ipc2BCl
≥99% e.e.
1 recrystallisation
ArOH, PPh3
EtO2C
N
N
CO2Et
CF3
CF3
i. MeNH2,
H2O, 130°C
ii. HCl
O H
O H
Me
N
H•HCl
Cl
R-(–)-fluoxetine
Prozac
• (+)-Ipc2BCl is a more reactive, Lewis acidic version of Alpine-borane
• Might want to revise the Mitsunobu reaction (step 2)
• M. Srebnik, P.V. Ramachandran & H.C. Brown, J. Org. Chem., 1988, 53, 2916
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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)
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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
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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
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Chiral reagent in total synthesis
Ar
OBn O
BnO2C
O
Me
N
+
H
OBn OH
DCM, 0°C
BnO2C
Si
Me Me
80%
95% d.e.
Cl
N
O
Me Me
Ar
Cl
H
Me
H
Si
N
O
R
Ar H
Ar
Me
H
N
Me
H
R
OH
H
• Silicon reagent developed by J. Leighton
• Used in the synthesis of (+)-SCH 351448, a reagent for the activation of low-density
•
lipoprotein receptor (LDLR) promoter (no I don't know what it means either!)
Sergei Bolshakov & James L. Leighton, Org. Lett., 2005, 7, 3809
OH
O
O
O
Me
O
Me Me
NaO2C
OH
CO2H
Me Me
O
Me
OH
O
O
O
HO
(+)-SCH 351448
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Stereoselective synthesis: chiral catalysis
substrate
(achiral)
substrate
(achiral)
chiral
catalyst
chiral
catalyst
product
(chiral)
chiral
catalyst
product
(chiral)
• Chiral catalysis - ideally a reagent that accelerates a reaction (without being
destroyed) in a chiral environment thus permitting one chiral molecule to generate
millions of new chiral molecules...
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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
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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
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
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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
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Lewis acid catalysed allylation / crotylation
O
+
Ph
RE
SnBu
SnBu33
SnBu3
Me
Ph
Me
RZ
H
Ph
P Ph
OH
(R)-BINAP, AgOTf
THF, —20°C
P Ph
Ph
Me
E:Z 95:5
E:Z 2:98
E:Z 53:47
56% 70%de 94%ee
72% 70%de 91%ee
45% 70%de 94%ee
• Chiral Lewis acids can be used to activate carbonyl group with impressive results
• Allylation works very well with high e.e.
• Problem with crotylation - often hard to control d.e.
• Reason is that the reaction proceeds via an open transition state
P
O
P
disfavoured
Ag
H
Ph
P
Me
H
OH
Ph
O
Ag
Me
Ph
Me
SnBu3
P
OH
H
H
Ph
Me
SnBu3
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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
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Lewis acid organocatalysis
OTBS
Me
Me
N
Me
H
cat (10mol%),
toluene, –78°C
O
+
Ph
O
Me
H
OH
N
O
Ph
Me
Me
88%
87% d.e.
98% e.e.
R
O
R
O
• Intermolecular hydrogen bond acts as a
•
•
•
OH
O
H
Lewis acid and activates carbonyl
Intramolecular hydrogen bond organises
catalyst
Catalyst derived from simple nature product,
tartaric acid
Clean, green and effective
OH
O
H
H
O
H
O
Me
intramolecular
H-bond
bulk blocks attack
from one face
H
H
Ph
O
NMe2
t-BuMe2Si
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Catalysis in total synthesis
H
O
H
i. HBCy2
ii. Et2Zn, (+)DAIB (1mol%)
iii. NH4Cl
75%
92%e.e.
Me
Me Me
Me
Me
N
Et
O Zn
O
Zn
Et
addition to
Si-face
H
H
H
H
(CH2)10
hydroxyl-directed
Simmons Smith reaction
(substrate control)
Et2Zn, ClCH2I
HO
i. (COCl)2, DMSO; then Et3N
ii. Li, NH3(l), –78°C
catalytic
asymmetric
carbonyl
addition
91%
O
Me
H
HO
H
H
82%
(R)-muscone
• (R)-Muscone is the primary contributor to the odour of musk, a
glandular secretion of the musk deer.
• A racemic, synthetic version is used in perfumes.
• Wolfgang Oppolzer and Rumen N. Radinov, J. Am. Chem. Soc.,
1993, 115, 1593
123.702 Organic Chemistry