Electrochemical Decarboxylation of L-Threonine and Oligopeptide Derivatives with Formation of N-Acyl-N,O-acetals: Preparation of Oligopeptides with Amide or Phosphonate C-Terminus

Article abstract of DOI:10.1002/hlca.19890720302

Derivatives of α-amino acids with two stereogenic centers (cf.L-threonine) and di-, tri- and tetrapeptides are electrolyzed in MeOH or AcOH, with formation of N-acyl-N,O-acetals (1b - 15b, 20b), in an anodic oxidative substitution of the COOH by an OR group.The amine ends of the oligopeptides may be benzyloxycarbonyl(Z)- or (tert-butoxy)carbonyl(Boc)-protected.With unprotected dipeptides, an electrolytic decarboxylative cyclization to imidazolidinones (18c, 19c) may also occur (in H2O/NH4OAc).The electrolyses are carried out in simple flasks with cooling jackets ('undivided cell'), using constant current conditions and anodes of Pt or glassy C.The electrolyte is generated in situ by adding 10 - 20 mol-percent of a tertiary amine.Mild acidic hydrolysis of electrolysis products thus obtained may lead to amino-acid amides or peptide amides (10c, 11c, 12c, 17c) with one amino acid less than the starting material.The N,O-acetals from L-threonine and the oligopeptides also react with organometallic nucleophiles such as Grignard compounds (->21 - 26, 29), with formation of products in which the original COOH group has been replaced by alkyl or allyl (sometimes even with moderate stereoselectivity).By treatment of the peptide-derived (open-chain) N,O-acetals with trialkyl or triaryl phosphites/TiCl4, the RO group is replaced by a phosphodiester group in a (non-diastereoselective) Michaelis-Arbuzov-type reaction (1d, 1e, 2d - 9d, 5e).Thus, the two-step sequence of electrolysis and phosphonation converts an oligopeptide derivative to an analogue with a phosphonic-acid end group.The diastereoisomeric N-protected dimethyl and diethyl dipeptidephosphonates (also prepared from the corresponding diaryl esters by Ti(OR)4-mediated transesterification) could be separated by preparative HPLC (SiO2, Lichrosorb Si 60, 10 μm); the dextrorotatory isomers of 1d - 3d were assigned L,D-, the laevorotatory ones L,L-configuration by hydrolysis to and identification of the known amino and aminophosphonic acids.The results described demonstrate a new simple route leading, from a give oligopeptide, to pure peptide analogues of known configuration.