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)

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

(E)-enolate(trans)

C-α si face

(Z)-enolate(cis)

C-α re face

H R2≡

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

C=O π orbital

C–H σ orbital

enolate π orbital

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

(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

R2 H≡

base base

(E)-enolate(trans)

OLDATHF

–78°C R

R = Eti-Prt-BuOMeNEt2

cis:::::

7040<295<3

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

destabilises this TS‡ and trans predominates

Metrans

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

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

interaction and cis predominates

R = small

R = large

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

predominates

Et2NMe

Metrans

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

predominates

O 1. LDA2. TBSCl

OTBS+ EtO

THFTHF / HMPA

cis682

trans9418

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

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

LDA[Li–N(i-Pr)2]

Me OLi

Me I R OEt

syn778395

anti23275

RR = PhR = BuR = SiMe2Ph

≡ R OEt

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 LDA

OEtS H

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

MeOOEtMe

≡R OEt

MeLDA R OEt

preferred approach

Mesyn aldol

t-BuMe

cis-enolate

Hanti aldol

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

OHO OM

Zimmerman–Traxler

• 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

OLi H R

trans-enolate anti aldol

cis-enolate syn aldol

OLiH R

Mesyn aldol

OLi H R

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

cis-enolate

R pseudo-equatorial

cis-enolate

R pseudo-axialdisfavoured

1,3-diaxial interaction

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

OLi H R

Mecis-enolate syn aldol

si face of enolate attacks re face of aldehyde

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

trans-enolate anti aldol

OLiH R

re face of enolate attacks re face of aldehyde

RMe visualising relative

stereochemistry

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

OLi+ R

MeR = t-BuR = Et

98%30%

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

trans-enolate

Et3N H Ph

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

Et3N H Ph

syn aldol (96% de)

cis-enolate

MeL R1

83%93% d.e.

MeMgBrCH2Cl2

97% d.e.

CyMe R

Cy MeR

HMeBnO

re-face favoured

disfavouredlone-pair interaction?

versus

MeCHOC9

Me Cy2BCl Et3N

Substrate control in total synthesis I

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

trans-enolate gives anti-aldol product

BnO MeH

OBnHMe

re-face attackfavouredversus

MeC7 C5

Me Sn(OTf)2Et3N

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

C13OHMe

stereogenic centres setup by

aldol reaction

C–C bonds formed by aldol

reaction

90%93% d.e.

cis-enolate gives syn-aldol product

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

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