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

Article abstract of DOI:10.1016/S0040-4020(01)00505-1

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 Zn²⁺-catalyzed addition of HCN to (S)-α-methylbenzylamine derived ketimines of 1-tetralone (8a) and 1-benzosuberone (8b) yielded mixtures of diastereomeric aminonitriles (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 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 (1S,1′R)-14a-e/(1R,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 (1S,1′R)-14a/(1R,1′R)-14a increased in different solvents in the order methanol2Cl₂ (1:2.5)32Cl ₂. In the pure THF, toluene, CHCl₃, or CH₂Cl₂ 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 (1S,1′R)-14a-c/(1R,1′R)-14a-c and oxidative cleavage of the auxiliary yielded 1a-c, which showed the (S)-configuration as the major isomer.