Phosphonic peptides

Phosphonate peptides can be synthesized either by formation of the P—O bond or the O—C bond. The former coupling is typically carried out via reaction of an alcohol (e.g., an a-hydroxy acid) with an activated phosphonyl spedes in a manner similar to phosphonamidate synthesis (Section 10.10.2.1). The latter process employs the phosphonate anion as a nucleophile in a displacement reaction on an ester with a leaving group in the a-position. 

As a general rule, phosphopeptides elute earlier in TFA-containing buffers from reverse-phase supports than the corresponding unphosphorylated and //-phosphonate peptides. In situations where these are poorly resolved, better separations can often be achieved by using ammonium acetate or triethylammonium acetate buffers at pH 7.0. 

New amidophosphonates (161) (phosphonic peptide analogues) have been prepared via multicomponent two step Mannich/Ugi one-pot procedure involving isocyanides under solvent free conditions (Scheme 56). ... 

Figures. Inhibition of pepsin by phosphonate peptide analogs the identity of the varied residues in structure 2 is indicated by each point...

Hoveyda and coworkers [142] developed the Cu-catalyzed allylic substitutions of phosphonate derivatives with pyridinyl peptide structures as efficient ligands. The structure of the ligands was chosen through synthesis, and analysis of libraries. Optimized compounds were used as ligands for the... 

Other interesting examples of proteases that exhibit promiscuous behavior are proline dipeptidase from Alteromonas sp. JD6.5, whose original activity is to cleave a dipeptide bond with a prolyl residue at the carboxy terminus [121, 122] and aminopeptidase P (AMPP) from E. coli, which is a prohne-specific peptidase that catalyzes the hydrolysis of N-terminal peptide bonds containing a proline residue [123, 124]. Both enzymes exhibit phosphotriesterase activity. This means that they are capable of catalyzing the reaction that does not exist in nature. It is of particular importance, since they can hydrolyze unnatural substrates - triesters of phosphoric acid and diesters of phosphonic acids - such as organophosphorus pesticides or organophosphoms warfare agents (Scheme 5.25) [125]. 

Similarly, Pei and co-workers [66] explored the feasibility of using an H-phosphonate head group on a peptide cassette (4) to inhibit PDF activity. While inhibitor (4) was not highly potent (if,- = 76 pM versus E. coli... 

In a related series of reactions, Seebach and coworkers decarboxylated amino acids to make peptide-based building blocks (Scheme 18) [42, 43], In this work, 13 examples were tried with yields ranging from 25 to 98%. Treatment of the methoxylated products with Lewis acid was used to introduce both aUyl and phosphonate-based nucleophiles into the molecules. 

Supported reagents have found application in many areas of synthesis including the construction of small peptides, the traditional foundation stone of solid phase synthesis. For example a recent paper describes the preparation of dipeptide p-nitroanilide and phosphonate libraries by supported carbodiimide coupling and scavenger purification (Scheme 2.52) [79]. 

The so-called Weinreb amides (or Af-methoxy-A-methylamides) are versatile building blocks in organic synthesis . Their preparation can be accomplished by coupling carboxylic acids and Af,0-dimethylhydroxylamme. The majority of the methods reported use peptide coupling reagents such as chloroformates , BOP , DCC and others "" or phosphonic derivatives ". These reactive reagents are expensive in some cases, and the removal of their excess (and/or the removal of byproducts) from the reaction mixtures may be difficult. Additional purification of the reaction product is often required. 

Synthesis of Peptides Using Fmoc-Protected Phenylalanine (Difluoromethyl)phosphonate Dialkyl Ester Derivatives... 

Cleavage of the phosphonate allyl esters from Abu[PO(OAl)2]-peptide-resins is accomplished by treatment with Pd(PPh3)4 (50 °C, 5 h)[103l followed by acidolytic deprotection of the Abu[PO(OH)2]-peptide from the resin support. The viability of employing allyl phosphonate protection for phosphopeptide synthesis has been demonstrated by the Fmoc solid-phase synthesis (DIC/HOBt couplings) of several 6-9-mer Abu[PO(OH)2]-containing peptides and has been extended to the synthesis of a 19-mer caldneurin-related Abu[PO(OH)2]-peptide.[104 ... 

Synthesis of (Difluoromethyl)phosphonate Mimetics of Phosphoserine and Phosphothreonine Peptides... 

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