Phosphonopeptides, synthesis

Diphenyl 1-aminoalkanephosphonates (2,Y=C,H ) were not used for the phosphonopeptide synthesis yet.They appeare to be very exciting substrates because these esters can be very easily prepared by the method invented in our laboratory... 

Fig. 4. Solid-phase phosphonopeptide synthesis using modified Mitsunobu coupling procedure.

Shapiro, G., Buechler, D., Ojea, V., Pombo-VUlar, E., Ruiz, M., and Weber, H.-P.. Synthesis of both D- and L-Fmoc-Abu[PO(OCH2CH=CH2)2]-OH for solid phase phosphonopeptide synthesis. Tetrahedron Lett., 34, 6255, 1993. 

Peptides containing a P-terminal aminophosphonic acid have been prepared by coupling protected amino acids with dialkyl or diaryl esters of aminoalkanephosphonic acids or free acids. Protection of the amino phosphonic acid groups is an important step in the phospho-nopeptide synthesis. Aminophosphonates based on the H-phosphonate diesters are used directly for the preparation of phosphonopeptides. Diphenyl aminoalkanephosphonates are attractive starting materials for phosphonopeptide synthesis because they are readily available, and efficient coupling is easily achieved by most methods used in peptide chemistry. 

In this chapter we consider Fmoc solid-phase synthesis of peptide analogs containing the amide surrogate that tend to be isosteric with the natural amide. This includes synthesis of peptidosulfonamides, phosphonopeptides, oligoureas, depsides, depsipeptides, and peptoids. 

Key Words Peptidomimetics pseudopeptides isosteres Fmoc solid-phase synthesis peptidosulfonamides phosphonopeptides oligourea depsides depsipeptides peptoids. 

Particularly good results have been achieved with Cr02 in refluxing acetonitrile, a system that proved effective with a variety of structurally different a-hydroxy phosphonates [17]. Similar conversions can be carried out under surface-mediated solid-phase conditions [18], acyl phosphonates being obtained under mild reaction conditions by treatment of a-hydroxy phosphonates on alumina (neutral-supported Cr03 without solvent. An oxidative method proved successful in the synthesis of novel phosphonopeptides for evaluation as inhibitors of human calpain I [19]. 

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. 

The first efficient synthesis of isocyanide derivatives of a-aminophosphonates diphenyl esters (162) has been described. It permits the generation of an a-aminophosphonate-based library of biologically active phosphonopeptides. The new class of compounds (162) could be used in the preparation of a large number of phosphonic pseudopeptides designed to inhibit enzyme activity or to examine enzyme specificity (Scheme 57). 

Atherton FR, Hassall CH, Lambert RW (1986) Synthesis stnicture-activity relationships of antibacterial phosphonopeptides incorporating (1-aminoethyl) phosphonic acid and (aminomethyl) phosphonic acid. J Med Chem 29 29-40... 

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