Stereoselective reactions of enolates: auxiliaries

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1 1 Stereoselective reactions of enolates: auxiliaries 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 LDA (Et) 2 C= K 2 C 3 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-buli 2. EtCCl valine derivative LDA Li rganic Chemistry

2 2 Diastereoselective alkylation of Evan s enolate Li C 2 I I Li Bn 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 rganic Chemistry

3 3 Diastereoselective alkylation of Evan s enolate Li C 2 I I Li Bn 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 rganic Chemistry

4 4 Diastereoselective functionalisation LDA Li Br a(si 3 ) 2 a S 2 96% de i-pr i-pr >90% de K(Si 3 ) 2 KMDS K S 2 3 i-pr 3 >90% de A range of electrophiles can be used with predictable selectivity rganic Chemistry

5 5 Removal of the auxiliary Li LiBn Bn + 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 rganic Chemistry

6 6 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 i-pr 2 Pr Br Pr 3 + or 3 Li Br Pr Pr rganic Chemistry

7 7 Chiral auxiliaries in total synthesis C 31 bistramide A Bn C 31 amds, TF, 78 C 81% 96%de I Bn i-pr 1. LiB 4 2. DMS, (CCl) 2, Et 3 96% (2 steps) Bn C 31 Bistramide A was isolated from the marine ascidian (sea squirt) Lissoclinum bistratum and has profound effects on cell cycle regulation & sodium channels It has potential in the treatment of slowly evolving tumours Auxiliary used to control C31 stereocentre M. T. Crimmins & A. C. DeBaille, J. Am. Chem. Soc. 2006, 128, rganic Chemistry

8 8 Chiral auxiliaries & the aldol reaction Bu 2 BTf i-pret 2 Bu Bu B Bu Bu B 500:1 (opposite syn isomer) B Bu Bu Bu B 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 Bu B Bu Bu rganic Chemistry

9 9 Reversal of diastereoselectivity Bu Bu B RC Et 2 AlCl R Et 2 AlCl Bu Bu B 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 rganic Chemistry

10 10 Chiral auxiliaries, the aldol reaction & total synthesis 1. Bu 2 BTf, Et 3 2. Bu B Bu C 29 C 28 C 30 92% 100%de 1. Bu 2 BTf, Et % 100%de PMB C 17 C 21 C 19 PMB C 29 C 30 C 19 C 17 C 21 cytovaricin Cytovaricin is an antineoplastic (anti-tumour) antibiotic isolated from Streptomyces diastatochromogenes Chiral auxiliaries used to set a number of stereocentres D. A. Evans, S. W. Kaldor, T. K. Jones, J. Clardy, Stout, T. J. J. Am. Chem. Soc. 1990, 112, rganic Chemistry

11 11 Chiral reagents and enolate chemistry Cl Et LDA Li Et S Cl Et chiral prochiral chiral 95%ee A number of forms of chiral reagent in enolate chemistry... chiral electrophiles (as shown above) chiral enolates (effectively a very short lived chiral auxiliary - shown next slide) chiral bases for the selective formation of chiral enolates rganic Chemistry

12 12 Chiral reagents in the aldol reaction ( )-Ipc 2 BTf i-pr 2 Et Ipc 2 B RC R 2 B R B 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 Brown allylation Interaction between the enolate and the methyl group of the Ipc moiety is minimised rganic Chemistry

13 13 Chiral reagents in the aldol reaction II S R* 2 BBr i-pr 2 Et C 2 Cl 2 BR* 2 S 97% ee 96% de S R* 2 BBr = F 3 C S B Br 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-bu R* 2 BBr Et 3 Tol / hex BR* 2 t-bu 94% ee 96% de t-bu rganic Chemistry

14 14 Ciral reagents and total synthesis B[(+)-Ipc] 2 TBS C 2 + PMB 86% 62%de TBS PMB C 2 ( )-laulimalide (fijianolide B) Fasciospongia rimosa ( )-Laulimalide is an antimitotic (prevents mitosis - cancer chemotherapy) isolated from the Pacific sponges yatella sp. and Spongia mycofijiensis and the kinawan sponge Fasciospongia rimosa I. Paterson, C. De Savi, M. Tudge rg. Lett. 2001, 3, rganic Chemistry

15 15 Chiral catalysis and the aldol reaction R 1 Si 3 + R 2 cat. (20%) uc Bu Re B R Si Ts R 1 R % ee Ts B Bu Lewis acid derived from tryptophan Si face blocked 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 t-bus Si 3 + Et cat. (10%) t-bus Et regioselectivity 98:2 97% ee 86% de t-bu Cu L L t-bu L = CF 3 S 2 amino acid / alcohol derivative rganic Chemistry

16 16 rganocatalysis I Pr 2 S + S 2 F cat. (10%) F Pr ab 4 F Pr 95% 96% ee 2 S S 2 F Pr Ar Ar F Si Si Pr 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 i-pr + S cat. (10%) i-pr SBn ab 4 SBn i-pr 81% 98% ee rganic Chemistry

17 17 rganocatalysis II + cat (10%) L-proline 88% anti / syn 3 / 1 97% ee acid aids enamine formation acid positions aldehyde acid activates aldehyde Proline 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, Barbas III and the excellent review of Dalko & Moisan (2004Angew5138) rganic Chemistry

18 18 rganocatalysts in total synthesis ( )-brasoside s C 2 D-proline (0.4eq) = 2 C R s 56% C 2 s + Bn Bn 78% 98%ee C 2 Bn Bn TMS R Bn Bn Bn Extracts of Verbena littoralis have interesting activity as enhancers for the neurotrophic properties of nerve growth factor (GF) and contain the compound ( )-brasoside I. K. Mangion and D. W. C. MacMillan J. Am. Chem. Soc. 2005, 127, rganic Chemistry