Phosphinic pseudopeptides

N-terminus elongation of the adduct using the mixed anhydride procedure. The latter step appeared to be a suitable method for N-terminal extension of phosphinic pseudopeptide analogues without rearrangement during the hydro-xyphosphinyl protection (Figure 62). ... 

Yamagishi et al. recently presented a novel method for the stereoselective synthesis of phosphinic pseudopeptide isosteres starting from an enantiopure a-aminoalkyl-//-phosphinate on both a-carbon and phosphorus atoms (36, Scheme 18) [99]. In particular, substrates 37 derived from a stereoretentive Michael addition of aminophosphinates 36 to tert-butyl acrylate, were diastereoselectively alkylated in the Pi position with diastereoisomeric ratios (dr) ranging from 14 1 to 29 1. The stereochemical outcome of this process is highly controlled by the chirahty at the phosphorus atom and the nature of the amino protecting group. 

In the past, Jiracek et al. described several selective and potent inhibitors of BHMT, belonging to phosphinic pseudopeptides [158] and S-alkyl derivatives of homocysteine [159, 160]. Among the compounds tested, three of them 235-237 incorporating an S-alkyl homocysteine were detected as potent inhibitors (Fig. 27). 

The synthesis of phosphinic peptides by a reverse sequence of P-C bond formation events (N+PC approach) is a less frequently applied strategy which may offer important diversification possibilities. In particular, an amidoalkylation condensation reaction between amides, aldehydes, and alkylphosphinic acids (the three-component Kabachnik-Fields reaction) affords in a single step the main pseudopeptidic backbone, thus facilitating fast screening of the nature of Pi position. In 1996, Chen and Coward observed that a mixture of benzyl carbamates, aldehydes, and alkylphosphinic acid 23 in AcCl can lead to Cbz-protected phosphinic pseudodipeptides 24 (Scheme 10a) [53]. This method was adjusted by Matziari et al. to the synthesis of Fmoc-protected phosphinic building blocks 25 and peptides thereof (Scheme 10b) [54]. 

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