Enantioselective synthesis of benzocyclic alpha,alpha-dialkyl-amino acids:new insight into the solvent dependent stereoselectivity of the TMSCN addition to phenylglycinol derived imines

Different benzocycloalkane-1-amino-1-carboxylic acids 1a-e have been synthe sized via an asymmetric Strecker reaction using (S)-alpha -methylbenzylamin e and (R)-phenylglycinol as chiral auxiliaries. The Zn2+-catalyzed addition of HCN to (S)-alpha -methylbenzylamine derived ketimines of 1-tetralone (8 a) and 1-benzosuberone (8b) yielded mixtures of diastereomeric aminonitrile s (1S,1 'S)-10a/(1R,1 'S)-10a (10:1 ratio) and (1R,1 'S)-10b/(1S, 1 'S)-10b (56:44 ratio), respectively. These aminonitriles are converted to amino ac ids la,b in two steps. The addition of TMSCN to the (R)-phenylglycinol deri ved ketimines of 8a, 8b, 1-indanone (8c), 7-fluoro-1-tetralone (8d), 7-fluo ro-1-benzosuberone (8e) yielded mixtures of diastereomeric trimethylsilylat ed aminonitriles (1S,1 'R)-14a-e/(1R,1 'R)-14a-e. The addition proceeded wi th diastereofacial selectivities ranging from 1:2.9 to 1:25. The selectivit y was found to be temperature and solvent dependent. The diastereomeric rat io (dr) of aminonitriles (1S,1 'R)-14a/(1R,1 'R)-14a increased in different solvents in the order methanol < methanol/ CH2Cl2(1:2.5)< THF < toluene < CHCl3< CH2Cl2. In the pure THF, toluene, CHCl3, or CH2Cl2 kinetic product m ixtures were formed, whereas the presence of methanol led to thermally equi librated product mixtures. This solvent dependent change of the product dr is interpreted with a change in the TMSCN addition mechanism. Hydrolysis of the aminonitrile mixtures (1S,1 'R)-14a-c/(1R,1 'R)-14a-e and oxidative cl eavage of the auxiliary yielded 1a-c, which showed the (S)-configuration as the major isomer. (C) 2001 Elsevier Science Ltd. All rights reserved.