Phosphono peptides

Peptides of aminoalkanephosphonic acids (Phosphono-peptides 4,are now receiving considerable interest because some representatives of this class were found to repress,bacterial growth at very low concentration levels 1. Literature data on the synthesis of dipeptides containing aminoalkylphosphonic acids are scarce and very little information is avaiable,on blocking and deblocking of the phosphonate moiety ... 

The BOP- or PyBOP-mediated SPPS of phosphinot or phosphono peptides can be carried out without protecting the phosphinic or phosphonic acid group. Indeed, phosphinic acids are activated, but the P—N bond is not formed. Phosphonic acids are also acti-vatedt and in fact an amide of methyl phenylphosphonic acid has been obtained, however, in the case of protected a-amino phosphonic acids, phosphonamides are only obtained by using AT-phthalyl protection. Side-chain unprotected phosphorylated tyrosine [Tyr(P03H2)] can be coupled by solid-phase synthesis using BOP (PyBOP), but pyrophosphate formation is also observed and some particular Tyr(P)-peptide syntheses are prone to total failure. ... 

Weigele M, Bohacek R, Jacobsen VA, Macek K, Yang MG, Kawahata NH, Sundaramoorthi R, Wang Y, Takeuchi CS, Luke GP, Metcalf CA III, Shakespeare WC, Sawyer T. Synthesis of phosphono-containing amino acid derivatives and peptides as signal transduction inhibitors. PCT Int Appl W099/24442, 1999. 

The literature data on the preparation of phosphono-dipeptides from 1-aminoalkanephosphonic acids showed 7-7 that the yields of condensation reactions are usually small or moderate. Moreover,the use of bulky N-blocked amino acids drastically decreased the reaction yield. Thus following Martell s method— we wre unsuccesful in the preparation of dipeptides containing N-terminal valine or leucine,while peptides of phenylalanine were obtained in 5—10% yield.Also the active ester method appeared to give small yields of the desired products. Our studies using p-nitrophenyl- and cyanomethyl esters of N-phtaloyl amino acids confirmed these observations. 

Smyth, M. S. and Burke, T. R. Jr. (1994) Enantioselective synthesis of N-Boc and N-Fmoc protected diethyl 4-phosphono(difluoromethyl)-L-phenylalanine agents suitable of the solid-phase synthesis of peptides containing nonhydrolyzable analogs of O-phosphotyrosine. Tetrahedron Lett. 35, 551-554. 

Gordeev, M. F., Patel, D. V., Barker, P. L., and Gordon, E. M. (1994) N-alpha-Fmoc-4-phosphono(difluoromethyl)-L-phenylalanine A new O-phosphotyrosine isosteric building block suitable for direct incorporation into peptides. Tetrahedron Lett. 35, 7585-7588. 

Burke, T.R., Jr., Smyth, M.S., Otaka, A., and Roller, P.P., Synthesis of 4-phosphono(difluoromethyl)-D.L-phenylalanine and A-Boc and A-Fmoc derivatives suitably protected for solid-phase synthesis of nonhydrolysable phosphotyrosyl peptide analogues. Tetrahedron Lett., 34, 4125, 1993. 

Paladino, J., Guyard, C., Thurieau, C., and Fauchere. J.-L., Enantioselective synthesis of (25 )-2-amino-3-(4-hydroxy-3-phosphonophenyl)propionic acid ( = 3 -phosphono-L-tyrosine) and its incorporation into peptides, Helv. Chim. Acta, 76, 2465. 1993. 

Burke, T.R., Jr., Smyth, M.S., Nomizu, M., Otaka, A., and Roller, P.P, Preparation of fluoro- and hydroxy-4-(phosphonomethyl)-D,L-phenylalanine suitably protected for solid-phase synthesis of peptides containing hydrolytically stable analogues of O-phosphotyrosine, J. Org. Chem., 58, 1336, 1993. Burke, T.R., Jr., Smyth, M.S., Otaka, A., and Roller, P.P, Synthesis of 4-phosphono(difluoromethyl)-D,L-phenylalanine and A-Boc and A-Lmoc derivatives suitably protected for solid-phase synthesis of nonhydrolysable phosphotyrosyl peptide analogues. Tetrahedron Lett., 34, 4125, 1993. 

As mentioned in Volume 13 of these Reports, 4-oxoazetidin-2-yl phosphonates and phosphinates (19) can be prepared by Arbusov-like reactions between P compounds and 4-acetoxyazetidin-2-one (20). Acid hydrolysis of (19) yields phosphono- and phosphino-aspartic acids (21) which can be converted into peptides with antibacterial activity. Diastereomeric mixtures of phosphono-dipeptides, which can be prepared from racemic dialkyl 1 -aminoalkylphosphonates, can be separated by ion-exchange chromatography. It appears that it is easier to synthesize phosphonodipeptides from these phosphonates as their P-dialkyl esters rather than as the free phosphonic acids. Phosphonic acid analogues of A-Cbz-alanine and -phenylalanine can be converted into ester and amide fluoridates, e.g., (22, R = OMe or NHCHMeg). These fluoridates are the most potent inhibitors of elastase and chymotrypsin yet reported and seem to mimic the natural substrates of these enzymes. ... 

Scheme 20 yielded the target 3 -phosphono-L-tyrosine as its trimethyl ester benzyl ether (194). The stereoisomeric composition of the product was determined by the generation of the diastereoisomeric peptides (195), the h.p.l.c. of which indicated the S,S)/ R S) ratio as 87.4 12.6. ... 

In 1975, Marthell et al. introduced the term phosphonopeptides for peptide analogues in which an aminocarboxylic residue is replaced by an aminophosphonate at any position in the peptide chain [94]. There is an excellent review by P. Kafarski and B. Lejczak [95] devoted to the synthesis of phosphono- and phosphinopeptides. Here, only references connected with the synthesis of biologically active phosphonopeptides using aminophosphonates based on H-hosphonate diesters have been included. 

Meyer, C. and Kohn, M. (2011) Efficient scaled-up synthesis of Af-alpha-Fmoc-4-Phosphono(difluoromethyl)-L-phenylalanine and its incorporation into peptides. Synthesis, 20, 3255 -3260. 

Williams, T., and Stempel, A., L-(N -Phosphono)Kethionine-S-Sulfoximinyl-L-Alanyl-L-Alanine, An Antimetabolite of L-Gluta-mine Produced by a Streptomycete, Chem. Biol, of Peptides, pp. 415-421, Ann Arbor Science, Publishers (1972). 

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