1 Stereoselective reactions of enolates

M O O O E R2 2 R2 1 R 1 R R1 R H H H E H

• 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)

C-α re face C-α si face

M M O O MO R2 MO H α R2 α α H α R1 R1 1 1 2 H R H R2 R R (Z)-enolate (E)-enolate (cis) (trans) C-α si face C-α re face

• Use terms cis and trans with relation to O–M to avoid confusion 123.702 Organic Chemistry 2 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 enolate C–H σ π orbital orbital C=O π H orbital 2 base 2 O R O R + H base

R1 H R1 H

• 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

base base base H base H H H 2 O R O R2 O R2 R1 O 2 ≡ H R R1 H R1 H R1 H transition (Z)-enolate state (cis) 123.702 Organic Chemistry 3 Enolate formation and geometry II

base base base H base H H H O H O H O H R1 O 2 ≡ R H R1 R2 R1 R2 R1 R2 (E)-enolate (trans)

• 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

LDA Li O Li O THF O + Me –78°C Me R R R Me cis trans R = Et 30 : 70 i-Pr 60 : 40 t-Bu >98 : <2 OMe 5 : 95 >97 : <3 NEt2 123.702 Organic Chemistry 4 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 i-Pr i-Pr destabilised by R–Me H Me OLi interaction and cis O N O N predominates Li i-Pr Li i-Pr Me R = large H H R O R Me R H cis Me LDA R i-Pr i-Pr OLi Me H O N O N if R is small, 1,3-diaxial Li i-Pr Li i-Pr interaction is important as it R R = small ‡ H H destabilises this TS and Me trans predominates R H R Me trans • With esters the R vs OMe interaction is alleviated and 1,3-diaxial interaction controls ...geometry - hence trans-enolate predominates i-Pr Me OLi O N Li i-Pr X Me Me H MeO O O H cis Me LDA i-Pr MeO OLi H O N Li i-Pr MeO predominates Me H O Me Me trans 123.702 Organic Chemistry 5 Enolate formation and geometry IV

i-Pr H OLi O N Li i-Pr Et N Et H 2 N Me O Me Et trans Me LDA Et N 2 i-Pr Me OLi O N Li i-Pr Me predominates H Et2N R H cis

• 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

OTBS O 1. LDA OTBS 2. TBSCl + Me Me EtO EtO EtO Me cis trans THF 6 94 THF / HMPA 82 18

123.702 Organic Chemistry 6 Addition of an electrophile to an enolate

σ* orbital (LUMO electrophile) X = leaving group X X

H H H H R R H H R O R2 ≡ O R2 O R2 R1 H R1 H R1 H

π orbital (HOMO nucleophile)

• 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

123.702 Organic Chemistry 7 Enolate alkylation

LDA R OEt Me Me R OEt [Li–N(i-Pr) ] Me I 2 R OEt + R OEt Me O Me O Li Me O Me O R syn : anti R = Ph 77 : 23 R = Bu 83 : 27 R = SiMe2Ph 95 : 5

• 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

alkylation on face I opposite to R Me Me Me Me H OEt most stable Me OEt O R OEt conformation; C–H H H O ≡ parallel to C=C Li H R R Me O

• Note: minor diastereoisomer probably arises from electrophile passing by R group • Therefore, size does matter... 123.702 Organic Chemistry 8 Enolate alkylation II

S H O LDA S H OEt S H OLi

L OEt L OLi L OEt (E)-enolate (Z)-enolate trans cis ≡ ≡

preferred preferred approach approach

H H S S S H O OEt OLi E L L L OEt E H OLi OEt

• 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

H Me H H Me Me Me OEt Me OEt R OEt LDA R OEt H O H O Me ≡ Me O R Li R Me O

123.702 Organic Chemistry 9 The aldol reaction

M M O OH O O O O + 1 3 1 1 3 R R R R3 R R 2 R2 R2 R Zimmerman– Traxler • 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 • Interestingly, enolate geometry effects diastereoselectivity only possible enolate O O OLi O OH LDA H Ph Ph H trans-enolate anti aldol

O O OH O OLi LDA H Ph Me Me t-Bu Ph t-Bu t-Bu Me cis-enolate syn aldo123.702l Organic Chemistry 10 The aldol reaction II

O O OH OLi H R Me X R X Me cis-enolate syn aldol O OLi O OH H R X X R Me Me trans-enolate anti aldol

• 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

123.702 Organic Chemistry 11 Zimmerman-Traxler transition state

1,3-diaxial interaction X X H R cis-enolate M cis-enolate M O O H O H O R H Me Me R pseudo-equatorial R pseudo-axial disfavoured

• 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 O O OH OLi H R X Me X R H M X O Me H O cis-enolate syn aldol R Me to ‘see’ relative X X stereochemistry H H consider S as plane M M and see which groups re face of enolate attacks O O are above and which si face of aldehyde H O H O below R R Me Me 123.702 Organic Chemistry 12 Zimmerman-Traxler transition state II

O O OH OLi H R Me X R X Me cis-enolate syn aldol Me H O O R M X Me Me H O O visualising relative H H stereochemistry O O R M R M X X H H si face of enolate attacks re face of aldehyde

• 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

123.702 Organic Chemistry 13 Zimmerman-Traxler transition state III

O OLi O OH H R X X R Me Me H trans-enolate anti aldol Me O O R M X H H H O O visualising relative Me Me stereochemistry O O R M R M X X H H re face of enolate attacks re face of aldehyde

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

123.702 Organic Chemistry 14 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 O LDA OLi + Me Me R R R Me R = t-Bu 98% 2% R = Et 30% 70%

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

O O OH O Et3N H Ph + B Me B O Ph Ph Ph Cl Me Ph bulky Me substituents trans-enolate anti aldol (>90% de) forces enolate to adopt trans geometry123.702 Organic Chemistry 15 Enolisation and the aldol reaction II

O O OH O Et N H Ph + 3 Me B Ph Ph Ph B O Me TfO Me Ph cis-enolate syn aldol (96% de)

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

123.702 Organic Chemistry 16 Substrate control in total synthesis I

BnO Me Me C Me Me Me Cy2BCl Me 9 Me Me CHO H Cy C10 Et3N OBn H OBn Me C9 C10 OBn B C13 R O Cy C OBCy Me 13 O 2 O OH O 93% O H 97% d.e. C O Me 9 re-face favoured trans-enolate gives versus anti-aldol product Me C7 Me Cy Me HH OH BnO C13 B Me O R Me O OR Cy Me O C1 O OR H Me disfavoured Oleandomycin aglycon lone-pair interaction? (R=H but should be a sugar)

Me O Me O Mg H Me C9 R MeMgBr Me OR1 C Me O O CH Cl Me 10 R1 Me 2 2 Me L O Me Me Mg O O H C 13 H H Me H Me OH H O 83% 93% d.e. 123.702 Organic Chemistry 17 Substrate control in total synthesis II

Me BnO H H Sn TfO O H O Me Me R Me Me Me Sn(OTf) C C5 Me Me Me 2 7 re-face attack C Et N Me CHO C 4 OBn 3 favoured C5 4 OBn O OBn C1 versus C7 C1 O Sn OH O H OTf Me OBn 90% H 93% d.e. Sn O OTf cis-enolate gives H O syn-aldol product R Me

• Seen oleandomycin earlier O C–C bonds C O formed by aldol • Here see the opportunities offered Me 9 reaction by the aldol reaction It creates 1 C–C bond and 2 Me C7 Me • OH stereogenic centres per reaction C 13 Me • Ian Paterson, Roger D. Norcross, stereogenic Me O OR Richard A. Ward, Pedro Romea centres setup by aldol reaction O OR and M. Anne Lister, J. Am. Chem. C1 Soc., 1994,116, 11287 Me 123.702 Organic Chemistry