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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)
• Remember pinene controls absolute configurationGeometry of alkene controls relative stereochemistry
9
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
16
PP
PhPh
PhPh
E:Z 95:5 56% 70%de 94%eeE:Z 2:98 72% 70%de 91%eeE:Z 53:47 45% 70%de 94%ee
SnBu3
Me
RE SnBu3
RZ
SnBu3
H Me
Ph H
OAg
P
P
PhMe
OH
disfavoured
SnBu3
Me H
Ph H
OAg
P
P
PhMe
OH
123.702 Organic Chemistry
Catalytic chiral Lewis base mediated allylation
• 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.,
1993, 115, 1593
19
OMe
H
(R)-muscone
H
OH
MeO
N
MeMe Me
ZnOZn
Et
Et
H
Me
(CH2)10
i. HBCy2ii. Et2Zn, (+)-DAIB (1mol%)iii. NH4Cl
75%92%e.e.
H
H
HOH
Et2Zn, ClCH2I
91%
HOH
Hi. (COCl)2, DMSO; then Et3Nii. Li, NH3(l), –78°C
82%
catalytic asymmetric
carbonyl addition
hydroxyl-directed Simmons Smith reaction
(substrate control)
addition to Si-face
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