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

Ralf Warmuth, Tamara E. Munsch, Robert A. Stalker, Bing Li, Alicia Beatty

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Abstract

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 methanol<methanol/CH2Cl2 (1:2.5)<THF<toluene<CHCl3<CH2Cl 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.

Original languageEnglish (US)
Pages (from-to)6383-6397
Number of pages15
JournalTetrahedron
Volume57
Issue number30
DOIs
StatePublished - Jul 23 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Asymmetric Strecker reaction
  • Dialkyl-amino acid
  • Solvent effect

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