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 O O (EtO)2C=O reduction K CO Ph OH 2 3 HN O Ph OH NH2 NH2 Ph (S)-phenylalanine oxazolidinone chiral auxiliary • Enolate formation gives the cis-enolate (remember enolisation of amides) • Two possible conformations exist - but chelation results in one being preferred Li O O O O Me Me N O LDA N O O Me Me Me 1. n-BuLi Me HN O 2. EtCOCl Me Me Me O O Me Li valine LDA derivative O N O O N O Me Me Me Me 123.702 Organic Chemistry 2 Diastereoselective alkylation of Evan’s enolate Li O O O O Me Me N O PhCH2I N O Ph Me Me Me Me I Ph Li O Bn O O O O O H H Me N Me N H Me Me Me Me 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 123.702 Organic Chemistry 3 Diastereoselective alkylation of Evan’s enolate Li O O O O Me Me N O PhCH2I N O Ph Me Me Me Me I Ph Li O Bn O O O O O H H Me N Me N H Me Me Me Me 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 123.702 Organic Chemistry 4 Diastereoselective functionalisation Li O O O O Br LDA Me Me N O N O H Ph Ph 96% de H O Na O O O O N O O Me NaN(SiMe3)2 Me Ph SO2Ph Me N O N O N O HO H Ph Ph i-Pr i-Pr Ph >90% de K O O O O SO2N3 KN(SiMe3)2 KHMDS Me i-Pr Me N O N O N3 H Ph Ph >90% de • A range of electrophiles can be used with predictable selectivity 123.702 Organic Chemistry 5 Removal of the auxiliary O LiOOH Me OH Ph O O O O Me N O LiOBn Me Bn HN O O + Ph Me Ph Me Me Me H H LiAlH Me 4 OH Ph • For an auxiliary to be of any use in synthesis it must be readily removed • Oxazolidinones are easily converted to carboxylic acids, esters and alcohols 123.702 Organic Chemistry 6 α-Substitution of prochiral aldehydes & ketones H H N N NH2 OMe OMe NH2 SAMP 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 • Hydrolysis is not always possible & the auxiliary must be removed via ozonolysis OMe OMe N Li O H LDA + N N Ni-Pr2 Me Me N N Me H NH2 OMe Me Me Me Pr–Br + OMe H3O OMe O or O N N Li Me Pr 3 N N Br Me Pr Me Pr Me Me Me 123.702 Organic Chemistry 7 Chiral auxiliaries in total synthesis Me Me O O Me H N Me O N O H H H H O OH O Me Me C 31 H Me bistramide A OH Me i-Pr 1. LiBH4 Me NaHMDS, 2. DMSO, H THF, –78°C (COCl)2, Et3N C C H 31 N O 31 H N O I BnO 96% (2 steps) BnO BnO 81% O O O O O 96%de • 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, 4936 123.702 Organic Chemistry 8 Chiral auxiliaries & the aldol reaction Bu Bu Ph Bu Bu O O B O O Bu BOTf O B Me Me Me 2 H O O N O i-PrNEt2 Me Ph H N O Me N Me O Me Me O Me OH O O Me Bu Me Bu O O O O B B Ph N O Ph Ph H Bu H Bu Me Me Me H N H N Me O O Me Me Me 500:1 O O (opposite syn isomer) Bu Me disfavoured O O B Ph Me Bu H N O H Me O • 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 123.702 Organic Chemistry 9 Reversal of diastereoselectivity Bu Bu Bu Bu O B B OH O O O O RCHO R O Me Et2AlCl Me R N O N O N O Me O H H Me H Me Me Me Me Et2AlCl Me • 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 123.702 Organic Chemistry 10 Chiral auxiliaries, the aldol reaction & total synthesis 1. Bu2BOTf, Et3N Ph O 2. O O O Me O OH Me Me Me O C29 Me H N Bu O N N C28 C30 Me B Ph O Bu Me H O Ph Me O O Me 92% 100%de 1. Bu2BOTf, Et3N 2. O O O Me O OH C17 Me OPMB O N N C21 C19 OPMB Ph 87% Me 100%de O Ph Me O Me C29 C H 21 • Cytovaricin is an antineoplastic (anti-tumour) O OH Me O C30 H antibiotic isolated from Streptomyces OH H O O Me diastatochromogenes H C Me Me H 19 OH Me O H • Chiral auxiliaries used to set a number of HO C17 OH H stereocentres OH MeO O O Me • D. A. Evans, S. W. Kaldor, T. K. Jones, J. Clardy, Me OH OH Stout, T. J. J. Am. Chem. Soc. 1990, 112, 7001 cytovaricin H 123.702 Organic Chemistry 11 Chiral reagents and enolate chemistry Me Me Cl Cl Li O N O O O S Et Et LDA Et OO OH OMe OMe OMe 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 123.702 Organic Chemistry 12 Chiral reagents in the aldol reaction OH O (–)-Ipc2BOTf O Ipc2B i-Pr2NEt O RCHO Me R Me Me Me Me Me ≡ ≡ Me Me Me Me Me Me Me B H O H O Me B H Me O Me OH H Me O Me R 2 R Me Me Me • Hopefully 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 123.702 Organic Chemistry 13 Chiral reagents in the aldol reaction II O R*2BBr i-Pr2NEt OH O O OBR*2 CH2Cl2 Ph H Me Me Ph SPh SPh SPh Me 97% ee 96% de Ph Ph F3C O O CF3 N N S S R*2BBr = B O O Br F3C CF3 • Once 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 O R*2BBr Et N OBR*2 OH O O 3 Tol / hex Ph H Me Ot-Bu Ph Ot-Bu Ot-Bu Me Me 94% ee 96% de 123.702 Organic Chemistry 14 CHiral reagents and total synthesis OTBS OB[(+)-Ipc]2 H OTBS O O H Me H O CO Me Me OH OPMB 2 + H H CO2Me O O OPMB H H O Me Me 86% 62%de OH O H O Me OH O O H H O Me (–)-laulimalide (fijianolide B) Fasciospongia rimosa • (–)-Laulimalide is an antimitotic (prevents mitosis - cancer chemotherapy) isolated from the Pacific sponges Hyatella sp. and Spongia mycofijiensis and the Okinawan sponge Fasciospongia rimosa • I. Paterson, C. De Savi, M. Tudge Org. Lett. 2001, 3, 3149 123.702 Organic Chemistry 15 Chiral catalysis and the aldol reaction Nuc Bu O Re O B Ts SiMe3 H O O cat. (20%) N O OH O + O N Si N B 2 R O H 1 2 Ts R1 H R R R H HN 86-93% ee 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 Me Me O O SiMe3 O O O Me OH Et cat. (10%) Et N N + Cu t-BuS Me t-BuS t-Bu L L t-Bu Me O Me O regioselectivity 98:2 L = CF3SO2 97% ee 86% de amino acid / alcohol derivative 123.702 Organic Chemistry 16 Organocatalysis I O OH O PhO2S SO2Ph cat.