Phosphinic pseudodipeptides

A nonaqueous CEC method for an efficient, simultaneous separation of the four stereoisomers of N-Z-phosphinic pseudodipeptides 54 has been developed... 

Scheme 1 Main synthetic routes toward phosphinic pseudodipeptides by the NP+C approach...

Scheme 2 Main synthetic routes toward phosphinic pseudodipeptides by the NP+C approach (Cbz benzyloxycarbonyl, Brv. benzyl, Tf. trifluoromethanesulfonyl, THF tetrahydrofuran, LDA lithium diisopropylamide)...

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]. 

Scheme 10 Application of the N+PC strategy to the synthesis of phosphinic pseudodipeptides by (a) Chen et al. [53] and (h) Matziari et al. [54]...

Several reports have dealt with the use of phosphinic pseudodipeptide building blocks in peptide couplings where both phosphinic and carboxylic acids are unprotected. Among the coupling reagents used successfully for such transformations are W,W -carbonyldiimidazole (CDl) [66-68], (benzotriazol-l-yloxy)tris (dimethylamino)phosphonium hexafluorophosphate (BOP) [69, 70],... 

One of the most powerful derivatization techniques of Pi position was presented in 2003 by Makaritis et al. They prepared phosphinic pseudodipeptide precursors bearing a propargyl group in their Pi side chain (42) and saw that these molecules can serve as excellent dipolarophiles in 1,3-dipolar cycloadditions with in situ-prepared nitrile oxides (Scheme 21) [74], This approach can be easily applied in both solid phase and solution s5mtheses, and has been successfully used in the discovery of selective inhibitors of several Zn-metalloproteases [38, 84, 92, 103, 104]. 

A -Protected a-aminoalkyl-//-phosphinic acids (857) were found to be novel practical building blocks in three-component Mannich-type A -phosphonomethylation condensations with formaldehyde (858) and secondary amine/amino acids (859). This reaction led to multifunctional phosphinic pseudodipeptides (860), designed to act as extended transition state analogue inhibitors of selected cytosolic leucine and microsomal alanyl aminopeptidases (Scheme 215). ... 

Kaboudin et al. have developed a simple and efficient method for the synthesis of a-aminophosphinic acids (577) in reaction of aromatic aldehydes (576) with ammonia solution and hypophosphorus acid in good yields (40-71%). Novel C2-symmetric phosphinic acid pseudodipeptides (578) have been also synthesized by the Michael addition of (577) to methyl acrylate (Scheme 141). 

Recently, Yamagishi et al. utilized the chemistry of stereoselective alkylations developed in their laboratory to synthesize Phe-Pro pseudodipeptide isosteres (49 and 50, Scheme 25) [109]. By using the fully stereodefined phosphinate 48 as starting material (synthesized as in Scheme 4), the authors observed that the proline ring can easily be produced by an intramolecular substitution reaction and that the stereoselectivity of benzyl group introduction can be reversed, depending on whether this event follows or precedes the cyclization step. 

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