Stereoselective reactions of enolatesgjrowlan/stereo2/lecture7.pdf · Addition of an electrophile...

123.702 Organic Chemistry

C-α re faceC-α si face

Stereoselective reactions of enolates

• The stereoselectivity of reactions of enolates is dependent on:• Presence of stereogenic centres on R1, R2 or E (obviously!)• Frequently on the geometry of the enolate (but not always)

1

R1

OR2

H HR1

OR2

H

M

R1

OR2

H E

E

• Use terms cis and trans with relation to O–M to avoid confusion

R1

OH

R2

M

(E)-enolate(trans)

R2

HMO

R1

αα

C-α si face

R1

OR2

H

M

(Z)-enolate(cis)

H

R2MO

R1

αα

C-α re face


R1 O

H

H R2≡

H

R2O

R1

H

R1

R2O

H

H

Enolate formation and geometry• Enolate normally formed by deprotonation • This is favoured when the C–H bond is perpendicular to C=O bond as this allows σ

orbital to overlap π orbital• σ C–H orbital ultimately becomes p orbital at C-α of the enolate p bond

2

C=O π orbital

C–H σ orbital

enolate π orbital

R1

R2O

H

base + H base

• Two possible conformations which allow this• First is given below and results in the formation of cis enolate • Initial conformation (Newman projection) similar to transition state• Little steric interaction between R1 and R2

transition state

base base

H

R2O

R1

Hbase

H

R2O

R1

baseH

(Z)-enolate(cis)


Enolate formation and geometry II

• Second conformation that places C–H perpendicular to C=O gives trans-enolate• Only differs by relative position of R1 and R2

• The steric interaction of R1 and R2 results in the cis-enolate normally predominating• As results below demonstrate stereoselectivity is influenced by the size of R

3

R1 O

H

R2 H≡

R2

HO

R1

H

base base

R2

HO

R1

Hbase

R2

HO

R1

baseH

(E)-enolate(trans)

RMe

OLDATHF

–78°C R

OLi

MeR

OLi

Me+

R = Eti-Prt-BuOMeNEt2

3060

>985

>97

cis:::::

7040<295<3

trans


if R is small, 1,3-diaxial interaction is important as it

destabilises this TS‡ and trans predominates

MeO

OLi

Metrans

MeOMe

OLi

cis

MeOMe

O

O

H

NLiH

Me

i-Pr

i-Pr

OMe

O

H

NLiMe

H

i-Pr

i-Pr

OMe

LDA

R

OLi

Metrans

O

H

NLiH

Me

i-Pr

i-Pr

R

RMe

O

O

H

NLiH

Me

i-Pr

i-Pr

R

O

H

NLiMe

H

i-Pr

i-Pr

R

LDA

Enolate formation and geometry III• The selectivity observed can be explained via chair-like transition state• In ketones cis-enolate favoured if R is large but trans-enolate favoured if R is small

4

if R is large, this TS‡ is destabilised by R–Me

interaction and cis predominates

R = small

RMe

OLi

cis

O

H

NLiMe

H

i-Pr

i-Pr

R

R = large

• With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls...geometry - hence trans-enolate predominates

predominates

X


Et2NMe

O

O

H

NLiH

Me

i-Pr

i-Pr

N

O

H

NLiMe

H

i-Pr

i-Pr

REt2N

MeOLi

Et2N

OLi

Metrans

cis

Et

Et

LDA

Enolate formation and geometry IV

• Amides invariably give the cis-enolate; remember restricted rotation of C–N bond

• The previous arguments are good generalisations, many factors effect geometry• Use of the additive HMPA (hexamethylphosphoric triamide) reduces coordination and

favours the thermodynamically more stable enolate

5

predominates

EtOMe

O 1. LDA2. TBSCl

EtOMe

OTBS+ EtO

OTBS

Me

THFTHF / HMPA

cis682

trans9418


H

R2O

R1

H RH

H

R2O

R1

X

H HR

≡H

R2O

R1

X

H HR

Addition of an electrophile to an enolate

• Finally, need to know the trajectory of approach of the enolate and electrophile• Reaction is the overlap of the enolate HOMO and electrophile LUMO • Therefore, new bond is formed more or less perpendicular to carbonyl group• Above is simple SN2 with X = leaving group

6

X = leaving group

σ* orbital (LUMO electrophile)

π orbital (HOMO nucleophile)


Enolate alkylation

• Simple alkylation of a chiral enolate can be very diastereoselective• As we have a cis-enolate diastereoselectivity can be explained in an analogous

fashion to simple alkenes via A(1,3) strain• Larger the substituent, R, greater the selectivity

7

R OEt

Me O

LDA[Li–N(i-Pr)2]

R OEt

Me OLi

Me I R OEt

Me O

R OEt

Me O

+

Me Me

syn778395

anti23275

::::

RR = PhR = BuR = SiMe2Ph

HOOEt

HMe

R

Me

≡ R OEt

Me O

MeMeI

OOEtH

HMe

R Li

most stable conformation; C–H

parallel to C=C

alkylation on face opposite to R

• Note: minor diastereoisomer probably arises from electrophile passing by R group• Therefore, size does matter...


EL OEt

OS H

E H

OEt

OLi

HS

LOLi

OEt

HS

L

≡ ≡

L OEt

OS H LDA

L OLi

OEtS H

L OEt

OLiS H

(E)-enolatetrans

(Z)-enolatecis

Enolate alkylation II

• In this example enolate geometry is not important - both are cis-alkenes• Therefore, selectivity the same in both cases• If we want to reverse selectivity, change the electrophile to H • This route far less selective as H is small so less interaction with substituents

8

MeOOEtMe

HMe

R Li

H

OOEt

HMe

R

H

≡R OEt

Me O

MeLDA R OEt

Me O

H Me

preferred approach

preferred approach


H Ph

O

t-Bu

O

Ph

OH

Mesyn aldol

t-BuMe

O LDA

t-BuMe

OLi

cis-enolate

H Ph

OO

Ph

OH

Hanti aldol

OLDA

OLi

trans-enolate

The aldol reaction

• The aldol reaction is a valuable C–C forming reaction • In addition it can form two new stereogenic centres in a diastereoselective manner• Most aldol reactions take place via a highly order transition state know as the

Zimmerman–Traxler transition state• It will not come as much surprise that this is a 6-membered, chair-like transition state

9

O

R1 R3

R2

OHO OM

R1

R2R3

Zimmerman–Traxler

R1

OM

R2

+O

R3

• Interestingly, enolate geometry effects diastereoselectivityonly possible

enolate


The aldol reaction II

• Generally speaking the above guideline sums up aldol chemistry!• To understand why this happens we need to examine Zimmerman-Traxler TS‡

• You must learn to draw chair-like conformation of 6-membered rings

10

XMe

OLi H R

O

X

O

R

OH

Me

trans-enolate anti aldol

cis-enolate syn aldol

X

OLiH R

O

X

O

R

OH

MeMe


X

O

R

OH

Mesyn aldol

OO

MX

H

Me

HR

OO

MXH

Me

HR

XMe

OLi H R

O

cis-enolate

Zimmerman-Traxler transition state

• We only have one choice in the aldol reaction - the orientation of the aldehyde• Enolate substituents are fixed due to the double bond• Aldehyde substituent is pseudo-equatorial to avoid 1,3-diaxial interactions

11

OO

MX

H

Me

HR

cis-enolate

R pseudo-equatorial

OO

MX

R

Me

HH

cis-enolate

R pseudo-axialdisfavoured

1,3-diaxial interaction

OO

MXH

Me

HR

to ‘see’ relative stereochemistry

consider S as plane and see which groups are above and which

belowre face of enolate attacks

si face of aldehyde


Zimmerman-Traxler transition state II

• Attack via the enantiomeric transition state (re face of aldehyde) gives the enantiomeric aldol product

• This differs only by the absolute stereochemistry - the relative stereochemistry is the same

12

XMe

OLi H R

O

X

O

R

OH

Mecis-enolate syn aldol

X

O

MO

Me

H

RH

si face of enolate attacks re face of aldehyde

X

O

MO

Me

H

RH

X

O

MO

Me

H

RH

visualising relative stereochemistry


Zimmerman-Traxler transition state III

• The opposite stereochemistry of enolate gives opposite relative stereochemistry• Once again the enolate has no choice where the methyl group is placed

13

trans-enolate anti aldol

X

OLiH R

O

X

O

R

OH

MeMe

X

O

MO

H

H

RMe

re face of enolate attacks re face of aldehyde

X

O

MO

H

H

RMe visualising relative

stereochemistry

X

O

MO

H

H

RMe


Enolisation and the aldol reaction• Hopefully, all the previous discussion highlights that selective enolisation is essential

for diastereoselective aldol reaction• Each geometry of enolate gives a different relative stereochemistry• With the lithium enolates of ketones the size of the non-enolised substituent, R, is

important

14

RMe

O LDA

RMe

OLi+ R

OLi

MeR = t-BuR = Et

98%30%

2%70%

• With boron enolates we can select the geometry by altering the boron reagent used

Ph

O

Me

B

trans-enolate

PhMe

O+

BCl

Et3N H Ph

O

Ph Ph

O

Me

OH

anti aldol (>90% de)bulky

substituents

forces enolate to adopt trans geometry


Enolisation and the aldol reaction II

• 9-BBN (9-borabicyclononane) looks bulky• But most of it is ‘tied-back’ behind boron thus allowing formation of the cis-enolate

15

PhMe

O+

Et3N H Ph

O

Ph Ph

O

Me

OH

syn aldol (96% de)

BTfO

Ph

O

cis-enolate

B

Me


H

OMg O

H

H

MeL R1

R

Me

OR1

HH

OMg

MeMe

O

Me

OH

O

Me

Me

Me

83%93% d.e.

MeMgBrCH2Cl2

C13

C10

C9

H

O

Me

O

O

Me

Me

Me

OBnMe

O

MeMe

OH93%

97% d.e.

C13

C10C9

OO

B

H Cy

H

CyMe R

H Me

BnO

OO

B

HCy

H

Cy MeR

HMeBnO

re-face favoured

disfavouredlone-pair interaction?

versus

MeCHOC9

OBnMe

OBCy2

MeOBn

Me

O

Me Cy2BCl Et3N

C13

C10

Substrate control in total synthesis I

16

C13

OHMe

O

OO

Me

OR

ORMe

O

Me

Me

Me

C1

Oleandomycin aglycon(R=H but should be a sugar)

C9

C7

trans-enolate gives anti-aldol product


OSnO

Me

H

H

R

TfO

BnO MeH

O SnO

Me

H

H

R

OTf

OBnHMe

re-face attackfavouredversus

CHO

MeC7 C5

O

Me

MeOBn

SnOTf

OBnMe

O

Me Sn(OTf)2Et3N

C1

C4

Substrate control in total synthesis II

• Seen oleandomycin earlier• Here see the opportunities offered

by the aldol reaction• It creates 1 C–C bond and 2

stereogenic centres per reaction• Ian Paterson, Roger D. Norcross,

Richard A. Ward, Pedro Romea and M. Anne Lister, J. Am. Chem. Soc., 1994,116, 11287

17

C13OHMe

O

OO

Me

OR

ORMe

O

Me

Me

Me

C1

C9

C7

stereogenic centres setup by

aldol reaction

C–C bonds formed by aldol

reaction

OBnMe

OH

Me

O

Me

90%93% d.e.

C7 C1

C4C5

cis-enolate gives syn-aldol product

Stereoselective reactions of enolatesgjrowlan/stereo2/lecture7.pdf · Addition of an electrophile...

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