123.702 Organic Chemistry Stereoselective synthesis: chiral auxiliaries • 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! 1 Chiral auxiliaries substrate (achiral) + chiral auxiliary couple to form new chiral compound product chiral auxiliary substrate (achiral) chiral auxiliary product (chiral) chiral auxiliary + cleave chiral auxiliary product chiral auxiliary resolve other diastereoisomer diastereoselective reaction overall reaction
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123.702 Organic Chemistry
Stereoselective synthesis: chiral auxiliaries
• 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!
1
Chiral auxiliaries
substrate(achiral) +
chiral auxiliary
couple to form new chiral compound
product
chiral auxiliary
substrate(achiral) chiral
auxiliary
product(chiral)
chiral auxiliary
+cleave chiral
auxiliary
product
chiral auxiliary
resolve other diastereoisomer
diastereoselective reaction
overall reaction
123.702 Organic Chemistry
Me
Me Ph
Me
O
OOH
H Me98% deMe
Me
Me
OO
MgO
H
L L
Me
Me Ph
Me
O
OO
H
MeMgBr–78°C
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
2
• 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 Ph
Me
O
OO
Me
KBH(i-OPr)3
Me
Me Ph
Me
O
OOH
Me H90% de
Me
123.702 Organic Chemistry
HO OHMe
MeLiAlH4
Me
Me Ph
Me
O
OO
Me
RMgBr–78°C
Me
Me Ph
Me
O
O
OHMe
Me
Chiral auxiliary in synthesis
• 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
3
O3–78°C
O
O
Me
Me
(–)-frontalin100% ee
123.702 Organic Chemistry
Stereoselective synthesis: chiral reagents
• 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
4
substrate(achiral) +
chiral reagent
product(chiral)
chiral reagent interacts with
achiral substrate
substrate(achiral)
chiral reagent
chiral complex
reaction
dead reagent
+
Chiral reagents
123.702 Organic Chemistry
RL RS
OHH+
Me
Me
Me
B OH
Me
Me
Me RSRL
+RL RS
O
Me
Me
BHMe
alpine borane®
Me
Me
Me
+ BH O
(+)-α-pinene 9-BBN•THF
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
5
(CH2)4Me
Oalpine borane®
small group as linear
(CH2)4Me
OHH
86% ee
proceeds via boat-like transition state
selectivity governed by 1,3-diaxial interactions
can be reused
123.702 Organic Chemistry
Binol derivative of LiAlH4
• Reducing reagent based on BINOL and lithium aluminium hydride• Selectivity is thought to arise from a 6-membered transition state (surprise!!)• Largest substituent (RL) adopts the pseudo-equatorial position and the small
substituent (RS) is axial to minimise 1,3-diaxial interactions
6
MeSnBu3
O 1. (S)-BINAL–H2. MOM–Cl
MeSnBu3
OMOMH
93% ee
OOAlOEt
H
Li(R)-BINAL–H
O
Et
Al
H O
LiORS
O
RL
123.702 Organic Chemistry
NH•HCl
HO
CF3
Me
i. MeNH2, H2O, 130°Cii. HCl
R-(–)-fluoxetineProzac
Cl
HO
CF3
ArOH, PPh3
NN
CO2EtEtO2C
Cl
OHHB OH
Me
Me
Me
Ph
ClIpc
Cl ≥99% e.e.1 recrystallisation
O
Cl Me
Me
Me HBCl
2(+)-Ipc2BCl
Chiral reagent in total synthesis
• (+)-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
7
123.702 Organic Chemistry
OHREH
RZ
H
RR
OH
RERZ
B
OL
RER
RZ
H L
B
OL
REH
RZ
H L
H R
vs
R
OB
RZ RE
L L
OB
RRZ
RE
L L
R
O+ B RE
RZ
L
L
Chiral allyl boron reagents
• 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
8
• Aldehyde will place substituent in pseudo-equatorial position (1,3-diaxail strain)• Therefore alkene geometry controls the relative stereochemistry (like aldol rct)
E-alkene gives anti productZ-alkene gives syn product
disfavoured
H2O2NaOH
R
OH
RZ RE
123.702 Organic Chemistry
OH
Me
H
H
EtB
O
Me
H
H
MeMe
Me
MeMe
MeEt
Me
Me
B
2
Me
Me+
O
Et HEt
Me
OH
92% ee
Chiral allyl boron reagents II
• Reagent is synthesized from pinene in two steps• Gives excellent selectivity but can be hard to handle (make prior to reaction)
crotyl group orientated away from pinene methyl groups
substituent pseudo-equatorial
123.702 Organic Chemistry
Other boron reagents
• 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
10
Me
Me
B
2
Me
RZ
RE
attacks on si face of RCHO
B
RZ
RE
O
O
i-PrO2C
i-PrO2C
attacks on si face of RCHOtartaric acid derivative
B
RZ
RE
N
N
Ph
Ph
attacks on re face of RCHO
Ts
Ts
123.702 Organic Chemistry
Chiral reagent in total synthesis
• 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
11
OBnO2C
Me Me
OBn
H
O
NSi
N
Ar
Ar
Cl
Me
OBnO2C
Me Me
OBn OH
Me
DCM, 0°C
80%95% d.e.
+
NNOSi
Cl
H
H
Me
HR
H
Ar
Ar
OHMe
HR
H
ONaO2C
Me Me
OH O O
HO
Me
O
OCO2H
MeMe
OHOO
OH
Me
O
(+)-SCH 351448
123.702 Organic Chemistry
product(chiral)
chiral catalyst
chiral catalyst
substrate(achiral) chiral
catalyst
Stereoselective synthesis: chiral catalysis
• 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...
12
substrate(achiral)
product(chiral)
123.702 Organic Chemistry
Catalytic enantioselective reduction
• 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...
13
OOMe
MeO
CBS catalyst (10%)BH3•THF
MeO
MeO
OHH
93% ee
NB O
HPhPh
MeCBS catalyst
proline derivative
BH3 NB O
HPhPh
MeH3B
active catalyst
123.702 Organic Chemistry
Ph
Ph
OBNB
HO
MeH
H
RL
RS
RL RS
O
Ph
Ph
OBNB
HO
MeH
H
RL
RS
NB O
HPhPh
MeH3B
BH3•THFNB O
HPhPh
Me
• interaction of amine & borane activates borane• it positions the borane
• it increases the Lewis acidity of the endo boron
coordination of aldehyde activates
aldehyde and places it close to the borane
chair-like transition statelargest substituent is pseudo-equatorial
catalyst turnover
Mechanism of CBS reduction
14
RL RS
H OH
123.702 Organic Chemistry
MeON
MeMe Me
ZnOZn
C5H11
C5H11
Ar
H
Me
C4H9
MeON
MeMe Me
ZnOZn
C5H11
C5H11
H
Ar
Me
C4H9
vs.Me
ON
MeMe Me
MeZn
ZnC5H11
C5H11C5H11
OH
O+ C5H11 Zn C5H11
(–)-DAIB (2%) OC5H11
H OH
>95% ee
Catalytic enantioselective nucleophilic addition
• 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
15
MeOHNMe2
MeMe
(–)-DAIB
disfavoured
123.702 Organic Chemistry
Me SnBu3 PhMe
OH
Ph H
O+
(R)-BINAP, AgOTfTHF, —20°C
Lewis acid catalysed allylation / crotylation
• 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
• 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
17
R H
O+ SiCl3RE
RZ
Lewis base catalyst (LB)R
OHH
RE RZ
Si
OREH
RZR
LBClLB
Cl Cl
NP
NHH N
MeNMe
PN
NOO HH
( )5
RE = Me86% ee
anti/syn 99/1
RZ = Me95% ee
syn/anti >19/1
Ph N Ph
OH
Me Me
RE = Me98% ee
anti/syn >99/1
RZ = Me98% ee
syn/anti 40/60
NMe O
NMe O
RE = Me86% ee
anti/syn 97/3
RZ = Me84% ee
syn/anti 99/1
123.702 Organic Chemistry
Lewis acid organocatalysis
• Intermolecular hydrogen bond acts as a Lewis acid and activates carbonyl
• Intramolecular hydrogen bond organises catalyst
• Catalyst derived from simple nature product, tartaric acid
• Clean, green and effective
18
O
H
H
HO H
O
O
R
R
O
Me H
H Ph
O
NMe2t-BuMe2Si
intramolecular H-bond
bulk blocks attack from one face
MeN
Me
H
OTBS
Me
+Ph H
Ocat (10mol%), toluene, –78°C Me
NMe
O
MePh
OH
88%87% d.e.98% e.e.
OHOHO
O
123.702 Organic Chemistry
Catalysis in total synthesis
• (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.,