Efficient synthesis of Fmoc‐protected phosphinic pseudodipeptides: Building blocks for the synthesis of matrix metalloproteinase inhibitors

Abstract

A convenient route for the synthesis of Fmoc-protected phosphinic dipeptide building blocks is described. The protected amino acid isosteres benzyloxycarbonyl aminomethyl phosphinic acid (glycine surrogate), benzyl α-isopropyl acrylate (valine surrogate), and benzyl α-isobutyl acrylate (leucine surrogate) were synthesized starting from commercially available materials. Reaction of either the valine or leucine surrogate with bis(trimethylsilyl) phosphonite generated the pseudodipeptide bond. The synthesis concluded with an efficient one-pot three-step procedure involving a bis-deprotection of the N- and C-termini under catalytic hydrogenation conditions followed by selective capping of the N-terminus with an Fmoc group to yield either Fmoc-NHCH2PO(OAd)CH2CH(Pri)CO2H or Fmoc-NHCH2PO(OAd)CH2CH(Bui)CO2H.

Synthesis of Fmoc-Gly-Ile Phosphinic Pseudodipeptide: Residue Specific Conditions for Construction of Matrix Metalloproteinase Inhibitor Building Blocks

“…1) involved a Michael-type addition reaction for the formation of a new phosphorous-carbon bond followed by Ad protection and finally Pd(C)/H 2 reduction (Scheme 1) (Bhowmick et al 2011). We successfully synthesized Cbz-protected aminomethyl phosphinic acid 2 starting from commercially available ammonium hypophosphite using previously described literature procedures (Bhowmick et al 2011; Li et al 2007). Z-protected aminomethyl phosphinic acid 2 was then treated with HMDS and converted to its active trivalent state (Georgiadis et al 2001).…”

“…Adamantyl protection of 4 , applying the procedure of Buchardt et al (1999) subsequently used for our prior building blocks (Bhowmick et al 2011), in which in situ generated phosphinic acid chloride is reacted with the sodium salt of adamantanol, failed to provide protected dipeptide 5 (Scheme 1). It was possible that a steric effect of the bulky 2-(2-butyl) and benzyl ester groups prevented the nucleophilic attack of the anionic oxygen of adamantanol to form the Ad ester.…”

“…We recently reported an efficient PPD synthetic method by developing a one-pot reaction procedure utilizing a single step bis-deprotection followed by Fmoc-protection leading to the phosphinate dipeptide 1a and its Gly-Leu analog 1b (Fig. 1) (Bhowmick et al 2011). Surprisingly, synthesis of the Gly-Ile analog ( 1c , Fig.…”

Peptide‐Based Inhibitors of Enzymes

“…Triple-helical conformation is also less susceptible to general proteolysis than peptides and other folded proteins [63,64]. In order to create the desired phosphinate transition state analogs, our laboratory prepared protected Fmoc-phosphinodipeptides [57,[65][66][67]]. An Fmoc-phosphinodipeptide was utilized to create C 6 -(Gly-Pro-Hyp) 4 -Gly-Pro-Pro -GlyΨ{PO 2 H-CH 2 }(R,S)Val-Val-Gly-Glu-Gln-Gly-Glu-Gln-Gly-Pro-Pro-(Gly-ProHyp) 4 -NH 2 [designated 1(V)GlyΨ{PO 2 H-CH 2 }Val THPI] [66], based on the cleavage site in type V collagen by MMP-9 [68].…”

Stabilization of Collagen-Model, Triple-Helical Peptides for In Vitro and In Vivo Applications

“…pressure) in the presence of Fmoc-OSu affords desired N -Fmoc-4-Flp 6 in good yields (Fig. 5) [70]. This one-pot reaction involved the simultaneous removal of the Cbz- and benzyl-protecting groups and re-protection of amine nitrogen with Fmoc group.…”