Base-Induced Dimerization of Urethane-Protected Amino Acid N-Carboxanhydrides

Abstract

tert-Butyloxycarbonyl-protected N-carboxanhydrides of amino acids dimerize in the presence of base in aprotic media to form 3,5-dialkyl-2,4-dioxo-1-pyrrolidine analogs. Depending on the nature of the base, different ratios of isomers were obtained. The reaction with lithium bis(trimethylsilyl)amide lead to one isomer only. After deprotection of the tert-butyloxycarbonyl groups and coupling of (benzyloxycarbonyl)valine, a homogeneous product was obtained. Reduction with sodium borohydride again gave a homogeneous product. Nuclear Overhauser enhancement spectroscopy and X-ray crystallography identified the stereochemistry in positions 3 and 5 of the pyrolidine as Z. When 1, 8-diazabicyclo[5.4.0]undec-7-ene was used as the base, the condensation led to a 1:3 ratio of isomers. The major isomer was different from the one obtained with lithium bis(trimethylsilyl)amide. The (benzyloxycarbonyl)valine derivative from this compound was obtained as a 1:1 mixture of isomers, leading to the conclusion that this condensation product was an enantiomeric mixture of the E isomers. The pure Z isomer from the lithium bis(trimethylsilyl)amide reaction was converted to a mixture of Z and E isomers in a ratio of 1:3 when treated with 1,8-diazabizycol[5.4.0]undec-7-ene. The (benzyloxycarbonyl)valine derivative of the E isomer from this conversion was again a 1:1 mixture; therefore, the Z isomer obtained with lithium bis(trimethylsilyl)amide was believed to have been an enantiomeric mixture. Several other examples indicated that this reaction occurred also with other tert-butyloxycarbonyl-protected N-carboxyanhydrides.