Stereoselective reactions of enolates

Transcription

1 1 Stereoselective reactions of enolates Chiral auxiliaries are frequently used to allow diastereoselective enolate reactions Possibly the most extensively studied are the Evan s oxazolidinones These are readily prepared from amino acids 2 (S)-phenylalanine reduction 2 (Et) 2 C= K 2 C 3 LDA Li oxazolidinone chiral auxiliary Enolate formation gives the cis-enolate (remember enolisation of amides) Two possible conformations exist - but chelation results in one being preferred 1. n-uli 2. EtCCl valine derivative LDA Li

2 2 Diastereoselective alkylation of Evan s enolate Li C 2 I I Li n iso-propyl group blocks bottom face Clearly (I hope) one face of the enolate is blocked Chelation results in a rigid structure that provides maximum steric hindrance The electrophile can only approach from one face

3 3 Diastereoselective functionalisation LDA Li r a(si 3 ) 2 a S 2 96% de >90% de K(Si 3 ) 2 KMDS K S >90% de A range of electrophiles can be used with predictable selectivity

4 4 Removal of the auxiliary Li Lin n + LiAl 4 For an auxiliary to be of any use in synthesis it must be readily removed xazolidinones are easily converted to carboxylic acids, esters and alcohols

5 5 α-substitution of prochiral aldehydes & ketones 2 SAMP 2 RAMP A simple auxiliary for the reaction of the enolates of ketones & aldehydes is Ender s hydrazones, SAMP & RAMP A rigid enolate-like structure allows highly diastereoselective reactions ydrolysis is not always possible & the auxiliary must be removed via ozonolysis + 2 LDA Li 2 r 3 + or 3 Li r

6 6 Chiral auxiliaries & the aldol reaction u 2 Tf Et 2 u u u u 500:1 (opposite syn isomer) u u u Initially, boron-enolate formation gives the chelate This must be broken for the boron to chelate the aldehyde, a requirement of the aldol The auxiliary then rotates to minimise steric and electronic repulsions Aldehyde approaches from the opposite face to auxiliary disfavoured u u u

7 7 Reversal of diastereoselectivity u u RC Et 2 AlCl R Et 2 AlCl u u R The reaction can be made to favour anti diastereoisomer by forcing it to proceed via an open transition state The aluminium Lewis acid preferentially coordinates to the aldehyde instead of the boron

8 8 Chiral reagents in the aldol reaction ( )-Ipc 2 Tf 2 Et Ipc 2 RC R 2 R R opefully it is becoming clear that the use of chiral reagents is more efficient In this reaction, the standard pinene derivative is being utilised The transition state is analogous to that of rown allylation Interaction between the enolate and the methyl group of the Ipc moiety is minimised

9 9 Chiral reagents in the aldol reaction II S R* 2 r 2 Et C 2 Cl 2 R* 2 S 97% ee 96% de S R* 2 r = F 3 C S r S CF 3 F 3 C CF 3 nce again, the geometry of the enolate is important - it controls relative stereochemistry Use of the thio-ester results in the cis-enolate and thus the syn aldol Alternatively, use of the ester & a change of solvent gives the trans-enolate & anti product t-u R* 2 r Et 3 Tol / hex R* 2 t-u 94% ee 96% de t-u

10 10 Chiral catalysis and the aldol reaction R 1 Si 3 + R 2 cat. (20%) R 1 R % ee Ts u Lewis acid derived from tryptophan The Mukaiyama aldol reaction is the reaction of silyl enol ethers with aldehydes The reaction can be catalysed by chiral Lewis acids The above example shows the use of a boron derivative of tryptophan The example below utilises a bis(oxazoline) ligand; these amino acid derived ligands are extremely versatile ligands for enantioselective synthesis (note they are symmetric but chiral) The regioselectivity probably results from attack at the least hindered carbonyl t-us Si 3 + Et cat. (10%) t-us Et regioselectivity 98:2 97% ee 86% de t-u Cu L L t-u L = CF 3 S 2 amino acid / alcohol derivative

11 11 The catalytic direct aldol reaction + cat.(10%) ZnEt 2 4Å MS 5 C 91% ee acetone coordinates to zinc -- proton transfer gives product and generates the enolate Et Zn Zn Et Zn Zn Zn Zn Zn Zn cat All the stereoselective aldol reactions we have looked at so far involve the preparation of activated enolate prior to reaction (metal or boron enolate or silyl enol ether) This adds additional steps to our methodology More attractive is the direct aldol reaction of non-activated carbonyl groups Above shows Trost s bimetallic zinc catalyst for the reaction of acetone Shibasaki has also designed a number of bifunctional catalysts for this reaction

12 12 rganocatalysis I 2 S + S 2 F cat. (10%) F a 4 F 95% 96% ee 2 S S 2 F Ar Ar F Si Si TMS Ar Ar F 3 C CF 3 CF 3 CF 3 Secondary amines can be utilised as catalysts in enolate-like chemistry Initially an enamine is formed that then reacts in a diastereoselective manner Finally, in situ hydrolysis gives the product and regenerates the catalyst + S cat. (10%) Sn a 4 Sn 81% 98% ee

13 13 rganocatalysis II + cat (10%) L-proline 88% anti / syn 3 / 1 97% ee acid aids enamine formation acid positions aldehyde acid activates aldehyde oline can catalyse the direct aldol reaction of simple aldehydes ther simple amino acids can also be used in this reaction In addition a number of derivatives have been prepared that show more practical characteristics Those interested in this are directed towards the work of List, arbas III and the excellent review of Dalko & Moisan (2004Angew5138)