Advanced organic

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

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

1

• 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

Advanced organic

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

2

O3–78°C

O

O

Me

Me

(–)-frontalin100% ee

Advanced organic

RSO

Tol

HO H

R Me

HO HRaney Ni

70% de

OS O Al

RTol

H

i-Bui-Bu

AlHi-Bu i-Bu

DIBAL

R Me

HO HRaney NiR

SO

Tol

HO H

80% de

RS O Li

OTol

AlH3HLiAlH4

RS

O O

Tol

Sulfoxides as chiral auxiliaries

• 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

3

lithium can chelate 2 oxygens

hydride directed to si face

oxygens are not directly tethered

dipoles directed in opposing directions

Advanced organic

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

4

(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

Advanced organic

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

• And here is another...

5

Me

Me

Me HBCl

2(+)-Ipc2BCl

+

OMe

Me

Me

Me

H OH

98% ee

MeMe

Me

O

+B MeMe

H

MeMe

Me

H OH

>99% ee

Advanced organic

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

Advanced organic

Ph H

OH OH

95% ee

MgBrTi

OO

MeMe

OO Ph

Ph

PhPh

HH

Ti

OO

MeMe

Cl OO Ph

Ph

PhPh

HH

Chiral reagents: allylation

• 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)

7

Advanced organic

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

Advanced organic

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

Advanced organic

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

Advanced organic

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...

11

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

Advanced organic

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

12

RL RS

H OH

Advanced organic

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

13

MeOHNMe2

MeMe

(–)-DAIB

disfavoured

Advanced organic

Catalytic chiral Lewis acid mediated allylation

• 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...)

14

Ph H

O+ SnBu3

cat. (5%), DCM, rt, 7h

Ph

OHH

88%62% ee

Rh N

OO

N

Bn Bn

Cl

Cl

cat. derived from amino acid (via the alcohol)

Ph H

O+ SnBu3

cat. (10%), DCM, rt, 72h

Ph

OHHMe

Me E : Z95 : 5

2 : 98

anti (ee) : syn (ee)71 (57) : 29 (8)63 (60) : 37 (7) SnBu3

R H

OM

open transition state

Advanced organic

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

15

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

Advanced organic

O

Ph Ph92% ee

85% de (trans)

SEt Et

PhPh

O

Ph H

O

SEt Et

Ph

Ph Br

SEt Et

cat. (10%)NaOH

Organocatalysts

• 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

16

Advanced organic

N

R

O O

Ar

N

H

BocH

NO2R+Ar

N

H

Boc

cat. (10%) ArNO2

HN

R

P(O)Ph2

90% ee90% de

NH HNHH

N NH

OTf

Organocatalysts II

• 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

17

Advanced organic

NMe

Me

N N

S

F3C

CF3

H HO

N

R

HO

Ar

NDpp

H

N N

S

F3C

CF3

H HO O

N

H

H

N MeMe

H

R

NO2R +Ar

N

H

P(O)Ph2

cat. (10%)DCM, rt

ArNO2

HN

R

P(O)Ph2

76% ee

NH

NH

S

F3C

CF3

NMeMe

Bifunctional organocatalysts

• 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

18