Efficient synthesis of serically constrained smmetrically alpha,alpha-disubstituted alpha-amino acids under operationally convenient conditions.
Homologation of the nucleophilic glycine equivalent Ni-Gly-PABP [Ni(II) complex of glycine Schiff base with 2-[N-(alpha-picolyl)amino]benzophenone (PABP)] 2 via alkyl halide alkylations and Michael addition reactions was systematically studied as a general method for preparing symmetrically alpha,alpha-disubstituted alpha-amino acids (sym-alpha,alpha-AA). The dialkylation reactions are conducted under operationally convenient conditions without recourse to inert atmosphere, dried solvents, and low temperatures, thus enjoying key advantages of the experimental simplicity and attractive cost structure. The method has been shown to be particularly successful for the dialkylation of complex 2 with activated and nonactivated alkyl halides, including propargyl derivatives, affording a generalized and practical access to the corresponding sym-alpha,alpha-AA. This study has also shown some limitation of the method, as it cannot be extended to alpha- or beta-branched alkyl halides or Michael acceptors to be used for the dialkylation of glycine equivalent 2. High chemical yields of the dialkylated products, combined with the simplicity of the experimental procedure, render this method worth immediate use for multigram scale preparation of the sym-alpha,alpha-AA.
Ellis
Trevor K
TK
Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, USA.
Martin
Collin H
CH
Tsai
Gary M
GM
Ueki
Hisanori
H
Soloshonok
Vadim A
VA
D000478:Alkylation; D000596:Amino Acids / Q000138:chemical synthesis*; D005998:Glycine / Q000737:chemistry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation
D000596:Amino Acids; D007202:Indicators and Reagents; D005998:Glycine