Synthesis Of Phosphinopeptides Via Multicomponent Convergent Reaction

Phosphonopeptides and phosphinopeptides are importantphosphorus analogues of naturally occurring peptides. They have beenwidely used as enzyme inhibitors and as haptens for production ofcatalytic antibodies because they can be considered as stable mimeticsof tetrahedral transition states in ester and amide hydrolysis andformation. Several phosphonopeptides and phosphinopeptides alsoshowed antibacterial, herbicidal, plant growth regulative andantihypertensive activities. Thus, phosphonopeptides andphosphinopeptides have widely potential application prospects. Besides,sulfonopeptides, as another sulfur analogues of naturally occurringpeptides, have also important biological activities.Nowadays, there were some methods for synthesis ofphosphinopeptides, such as phosphinochloridate method, couplingreagent condensation method, mixed anhydride method, solid phasemethod, enzyme-catalyzed coupling method and Mannich-type reactionmethod and so on. Most of them utilized aminoalkylphosphinic acids ortheir derivatives as starting materials, which were generally synthesized in multi-step procedure, resulting in some disadvantages, such ascomplicated multi-step procedure of preparation, isolation andpurification of products. The overall yields from the desired peptideproducts are seldom satisfactory. In solid phase method, conventionalanalytical tools for assessing the reaction could not be used, intermediatepurifications in a multi-step synthesis were not possible and the synthesisscale was limited. Although the enzyme-catalyzed coupling ofaminoalkylphosphinate and amino ester in satisfactory yields, the methodcould not be widely used due to the restriction by the sort of catalyticalenzymes.The Mannich-type reaction using benzyl carbamate with highlyreactive activities as amide component not only reduced the variety ofphosphinopeptides but also could only extend peptide chain fromN-terminal. The conventional methods can not be applied to giveproducts with peptide chain extending from both sides. Thus, it isnecessary to develop an efficient and facile method to synthesizephosphinopeptides. Recently, we reported the Mannich-type condensationof N-Cbz protected amino amides/peptide amides, aldehydes,aryldichlorophosphines, and subsequent aminolysis with amino acidesters/peptide esters to synthesize phosphinopeptides, in which theaminoalkylphosphinic acid was located in the middle position of thepeptides. We herein present the facile synthesis of phosphinopeptides containing different structures via the multicomponent condensationreactions.Firstly, a series of phosphinopeptides containing C-terminalα-aminoalkylphosphinic acids were prepared directly in one-pot reactionsof2-(N-benzoxycarbonylamino)alkanamides/peptide amides, aldehydes,and aryldichlorophosphines in acetonitrile, followed by hydrolysis. In thecurrent method, the peptide bond was formed in a Mannich-type reaction.Through this approach, phosphinopeptides containing C-terminalα-aminoalkylphosphinic acids which have never been reported can beconveniently prepared in good yields directly from simple chemicals. Wesystematically studied the reaction mechanism through which the ultimatestructure of the product was determined.Secondly, a series of new depsiphosphinopeptides, theaminoalkylphosphinic acids were located in the middle position of thepeptides, were synthesized in satisfactory yields viapseudo-four-component condensation reaction of2-(N-benzoxy-carbonyl-amino)alkanamides/peptide amides, aldehydes, andaryldichlorophosphines, followed by in situ alcoholysis with hydroxylesters. The formation of byproducts was explained and the absoluteconfiguration of the desired products was determined via the mechanismstudies.Thirdly, we synthesized hybrid sulfonophosphinodipeptides composing of taurines and1-aminoalkylphosphinic acids for the first timein satisfactory to good yields via a convenient Mannich-type reaction ofN-benzyloxycarbonylaminoalkanesulfonamides, aldehydes, andaryldichlorophosphines, and subsequent hydrolysis. Hybriddepsisulfonophosphinopeptides were also successfully synthesized via thesimilar preparation method, indicating that the method was alsoapplicable for the synthesis of sulfonophosphinopeptides.The multicomponent convergent methods were utilized to synthesizevarious phosphinopeptides in good yields directly from simple chemicals.The method has several advantages over the traditional preparationmethod, such as short procedure, facile operation, high overall yields,atom-economic strategy. And the peptide chain extending from both sidesof the aminophosphonic acids was achieved. Stereoselectivity in theproducts was also observed. Our work was supplementary to thesynthesis of hybrid sulfonophosphinodipeptides anddepsisulfonophosphinopeptides with C-terminal α-aminoalkyl-phosphinates and offered excellent foundation for the research on thebiological activities of these compounds.Finally, we have developed a highly efficient and convenientmethod for the synthesis of N-Cbz-β-aminoalkanesulfonamides fromvicinal amino alcohols via the N-Cbz protection, the Mitsunobuesterification, N-chlorosuccinimide oxidation, and ammonolysis process. The current method is an efficient, nontoxic, simple, and reproducibleroute to synthesize N-Cbz-β-aminoalkanesulfonamides. And most ofthese sulfonamides are new products.