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

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Different benzocycloalkane-1-amino-1-carboxylic acids 1a– e have been synthesized via an asymmetric Strecker reaction using ( S)-α-methylbenzylamine and ( R)-phenylglycinol as chiral auxiliaries. The Zn 2+-catalyzed addition of HCN to ( S)-α-methylbenzylamine derived ketimines of 1-tetralone ( 8a) and 1-benzosuberone ( 8b) yielded mixtures of diastereomeric aminonitriles (1 S,1′ S)- 10a/(1 R,1′ S)- 10a (10:1 ratio) and (1 R,1′ S)- 10b/(1 S,1 ′S)- 10b (56:44 ratio), respectively. These aminonitriles are converted to amino acids 1a, b in two steps. The addition of TMSCN to the ( R)-phenylglycinol derived ketimines of 8a, 8b, 1-indanone ( 8c), 7-fluoro-1-tetralone ( 8d), 7-fluoro-1-benzosuberone ( 8e) yielded mixtures of diastereomeric trimethylsilylated aminonitriles (1 S,1′ R)- 14a– e/(1 R,1′ R)- 14a– e. The addition proceeded with diastereofacial selectivities ranging from 1:2.9 to 1:25. The selectivity was found to be temperature and solvent dependent. The diastereomeric ratio (dr) of aminonitriles (1 S,1′ R)- 14a/(1 R,1′ R)- 14a increased in different solvents in the order methanol<methanol/CH 2Cl 2 (1:2.5)<THF<toluene<CHCl 3<CH 2Cl 2. In the pure THF, toluene, CHCl 3, or CH 2Cl 2 kinetic product mixtures were formed, whereas the presence of methanol led to thermally equilibrated 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 (1 S,1′ R)- 14a– c/(1 R,1′ R)- 14a– c and oxidative cleavage of the auxiliary yielded 1a– c, which showed the ( S)-configuration as the major isomer.