Elektrochemische Decarboxylierung von L.‐Threonin‐ und Oligopeptid‐Derivaten unter Bildung von N‐Acyl‐N, O‐acetalen: Herstellung von Oligopeptiden mit Carboxamid‐oder Phosphonat‐C‐Terminus

Electrochemical Decarboxylation of L-Threonine and Oligopeptide Derivatives with Formation of N-Acyl-N, O-acetals: Preparation of Oligopeptides with Amide or Phophonate C-Terminus Derivatives of α-amino acids with two stereogenic centers (cf.L-threonine) and of 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-% 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nucleophiles such as Grignard compounds (21–26, 29), with formation of products in which the original COOH group has been replaced by alkyl or allyl (sometimes even with moderate stereoselectivity).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 laevoratory 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 given oligopeptide, to pure peptide analogues of known configuration.

[1]  S. Mahboobi,et al.  Synthesis of Esters of 3‐(2‐Aminoethyl)‐1H‐indole‐2‐acetic Acid and 3‐(2‐aminoethyl)‐1H‐indole‐2‐malonic acid (= 2‐[3‐(2‐aminoethyl)‐1H‐indol‐2‐yl]propanedioic acid) 4th communication on indoles, indolenines, and indolines , 1988 .

[2]  D. Seebach.  Struktur und Reaktivität von Lithiumenolaten, vom Pinakolon zur selektiven C‐Alkylierung von Peptiden – Schwierigkeiten und Möglichkeiten durch komplexe Strukturen , 1988 .

[3]  D. Seebach.  Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C‐Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures , 1988 .

[4]  N. Sampson,et al.  Synthesis of phosphonic acid derivatives by oxidative activation of phosphinate esters , 1988 .

[5]  H. G. Thomas,et al.  Zum Reaktionsablauf der anodischen Oxidation N‐acylierter α‐Aminocarbonsäuren , 1988 .

[6]  K. Yamauchi.  Aminophosphonic acids - Synthesis and biological activities of phosphonopeptides. , 1988 .

[7]  L. Gráf,et al.  Inhibition of angiotensin-converting enzyme by angiotensin I analogue peptide inhibitors. A kinetic study. , 2009, International journal of peptide and protein research.

[8]  D. Seebach,et al.  Elektrochemische Oxidation von (S)-Äpfelsäure-Derivaten: ein Weg zu enantiomerenreinen alkylierten Malonaldehydsäure-estern , 1987 .

[9]  D. Rich,et al.  Total synthesis of the unusual cyclosporine amino acid MeBMT , 1987 .

[10]  M. Thaning,et al.  Synthetic applications of electrochemically produced α‐methoxyamides. Part 2. Oxidation of hydroxyproline derivatives , 1986 .

[11]  D. Seebach,et al.  Enantiomerenreine Pyrrolidin‐Derivate aus trans‐4‐Hydroxy‐L‐prolin durch elektrochemische oxidative Decarboxylierung und Titantetrachlorid‐vermittelte Umsetzung mit Nukleophilen , 1986 .

[12]  D. Seebach,et al.  Preparation of Chiral Building Blocks from Amino Acids and Peptides via Electrolytic Decarboxylation and TiCl4-Induced Aminoalkylation†‡ , 1986 .

[13]  D. Seebach,et al.  Herstellung chiraler Synthesebausteine aus Aminosäuren und Peptiden durch oxidative elektrolytische Decarboxylierung und TiCl4‐induzierte Umsetzung mit Nucleophilen , 1986 .

[14]  T. Shono,et al.  Synthesis of optically active piperidine and pyrrolidine alkaloids from L-lysine, L-ornithine, or L-proline using anodic oxidation as key steps , 1986 .

[15]  C. Holzapfel,et al.  Antineoplastic agents. Par 108. Structural biochemistry. Part 23. Synthesis of the dolastatin thiazole amino acid component (gln)Thz , 1985 .

[16]  A. Vasella,et al.  Nucleophilic Additions to N-Glycosylnitrones. Asymmetric Synthesis of α-Aminophosphonic Acids†‡ , 1985 .

[17]  C. Holzapfel,et al.  Synthesis of the dolastatin thiazole amino acid component (gln)Thz , 1985 .

[18]  H. Hiemstra,et al.  Intramolecular reactions of N-acyliminium intermediates , 1985 .

[19]  P. Kafarski,et al.  Chromatographic assignment of the configuration of 1-aminoalkane-phosphonic acids , 1985 .

[20]  T. Shono.  Electroorganic chemistry in organic synthesis , 1985 .

[21]  T. Shono.  Electroorganic Chemistry as a New Tool in Organic Synthesis , 1984 .

[22]  P. Mastalerz,et al.  Synthesis of phosphonic analogs of enkephalins. Pentapeptides with COOH replaced by PO3H2 group. , 2009, International journal of peptide & protein research.

[23]  J. Tronchet,et al.  Structural analysis of 3-C-phosphonates, -phosphinates, and -phosphine oxides of branched-chain sugars , 1983 .

[24]  J. Szewczyk,et al.  Phosphonodipeptides: synthesis and separation of diastereoisomers , 1982 .

[25]  Peter Schnurrenberger,et al.  Herstellung von Methylestern durch Umesterung funktionalisierter Substrate mit Titalsäureestern als Katalysatoren , 1982 .

[26]  H. Schneider,et al.  The differentiation of diastereomers by 13C NMR spectroscopy , 1981 .

[27]  P. Bartlett,et al.  A phosphonamidate dipeptide analog as an inhibitor of carboxypeptidase A , 1981 .

[28]  H. Horikawa,et al.  Synthetic electroorganic chemistry. 11. Electrochemical synthesis of semicyclic and cyclic N-acyl N,O-acetals , 1979 .

[29]  S. W. Holmes,et al.  Phosphonopeptides, a new class of synthetic antibacterial agents , 1978, Nature.

[30]  E. V. Arx,et al.  Das 4,4′-tetramethyldiamino-diphenylmethan reagens (TDM) , 1976 .

[31]  C. Benezra.  NMR of phosphonates. VI. Variation of vicinal phosphorus-31-carbon-carbon-proton couplings with dihedral angle in phosphonates , 1973 .

[32]  T. Kitahara,et al.  The Synthesis of α-Amino Phosphonic Acids , 1973 .

[33]  H. Hellmann.  Neuere Methoden der präparativen organischen Chemie II. 8. Amidomethylierungen , 1957 .