stereoselective synthesis: chiral auxiliariesgjrowlan/stereo2/lecture4.pdf · stereoselective...

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


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


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


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


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


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


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

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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


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


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


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


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)


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


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


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


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


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


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

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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


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

stereoselective synthesis: chiral auxiliariesgjrowlan/stereo2/lecture4.pdf · stereoselective...

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