Synthesis of .alpha.-substituted .alpha.-amino acids via cationic intermediates

• Published in: Journal of organic chemistry Vol. 58; no. 12; pp. 3259 - 3268
• Main Authors: Roos, Eric C, Lopez, M. Carmen, Brook, Michael A, Hiemstra, Henk, Speckamp, W. Nico, Kaptein, Bernard, Kamphuis, Johan, Schoemaker, Hans E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.06.1993; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Exact sciences and technology; Organic chemistry; Physical Sciences; Science & Technology; ASYMMETRIC-SYNTHESIS; N-ACYL; BISLACTIM ETHER; ALKYLATION; ESTERS; AMIDOALKYLATION; EQUIVALENTS; DERIVATIVES; STEREOSELECTIVE SYNTHESIS; ELECTROCHEMICAL SYNTHESIS; Reaction intermediate; α-Aminoacid; Iminium compounds; Silicon Organic compounds; Organic silane; Oxidation; Enol ether; Allylic compound
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo00064a011

A novel synthetic approach to racemic alpha-substituted alpha-amino acids is described. The key intermediates of this methodology are highly electrophilic iminium ions, bearing carbonyl substituents at both the iminium carbon and nitrogen atom. The preparation of precursors 8, 10a-c, and 12 includes electrochemical oxidation techniques according to literature procedures. When an alpha-methyl precursor (8 or 10a) was used, reactions with allylsilanes and silyl enol ethers led to the desired products, but elimination to dehydroalanine derivatives appeared to be an important side reaction. A major improvement in the yields of the desired products could be effected by using longer reaction times. In this way, efficient syntheses of protected alpha-methyl-alpha-amino acids could be developed. The elimination process appeared to be a more serious problem in the alpha-benzyl (10b) and alpha-allyl (10c) cases. On the other hand, the alpha-phenyl precursor 12 appeared to be highly useful, because the elimination is impossible in this case. High yields of alpha-phenyl-alpha-amino acid derivatives were obtained upon reaction of 12 with silicon-activated pi-nucleophiles. Deprotection led to various types of free alpha-substituted alpha-amino acids.