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

Abstract

The efficient synthesis of an Fmoc-Gly-Ile phosphinic pseudodipeptide was desired as an eventual building block for construction of matrix metalloproteinase inhibitors. A Michael-type addition reaction of bis(tri-methylsilyl) phosphonite with the appropriate acrylate generated the pseudodipeptide bond. Additional of adamantyl (Ad) protection by our prior route (reaction of in situ generated phosphinic acid chloride with the sodium salt of adamantanol) was surprisingly inefficient. Adamantyl protection was achieved in high yield by refluxing the phosphinic acid, Ag2O, and 1-AdBr in chloroform. Subsequently a concise one-pot three-step reaction comprising a double deprotection of the N- and C-termini under catalytic hydrogenation conditions followed by selective protection of the N-terminus with an Fmoc group yielded Fmoc-NHCH2PO(OAd)CH2CH(2-butyl)CO2H in 41 % overall yield. These results indicate that, as the diversity of phosphinic pseudodipeptides is increased to create selective matrix metalloproteinase inhibitors, different synthetic pathways may be required for efficient building block preparation.

Characterization and regulation of MT1‐MMP cell surface‐associated activity

“…Antibodies were purchased from EMD Millipore and Pierce. The triple‐helical substrate fTHP‐9 [(Gly‐Pro‐Hyp) 5 ‐Gly‐Pro‐Lys(Mca)‐Gly‐Pro‐Gln‐Gly~Cys(Mob)‐Arg‐Gly‐Gln‐Lys(Dnp)‐Gly‐Val‐Arg‐(Gly‐Pro‐Hyp) 5 ‐NH 2 ] and the triple‐helical peptide inhibitor GlyΨ{PO 2 H‐CH 2 }Ile‐Tyr THPI [(Gly‐Pro‐Hyp) 4 ‐Gly‐mep‐Flp‐Gly‐Pro‐Gln‐[GlyΨ(PO 2 H‐CH 2 )Ile]‐Tyr‐Phe‐Gln‐Arg‐Gly‐Val‐Arg‐Gly‐mep‐Flp‐(Gly‐Pro‐Hyp) 4 ‐Tyr‐NH 2 , where mep = 4‐methylproline and Flp = 4‐fluoroproline] were synthesized in house using methods described previously (Bhowmick & Fields, ; Bhowmick et al., ; Lauer‐Fields et al., ; Minond, Lauer‐Fields, Nagase, & Fields, ; Minond et al., ). Marimastat, a nonselective inhibitor of MMPs (Beckett & Whittaker, ; Rasmussen & McCann, ), was purchased from Sigma.…”

“…Standard chemicals were of analytical or molecular biology grade and purchased from Fisher Scientific. Antibodies were purchased from EMD Millipore where mep = 4-methylproline and Flp = 4-fluoroproline] were synthesized in house using methods described previously (Bhowmick & Fields, 2012;Bhowmick et al, 2017;Lauer-Fields et al, 2007;Minond, Lauer-Fields, Nagase, & Fields, 2004;Minond et al, 2006). Marimastat, a nonselective inhibitor of MMPs (Beckett & Whittaker, 1998;Rasmussen & McCann, 1997), was purchased from Sigma.…”

Matrix Metalloproteinase Inhibition by Heterotrimeric Triple‐Helical Peptide Transition State Analogues

“…[8a, 23] Phosphinate pseudodipeptide Fmoc-GlyΨ{P(OAd)(OH)-CH 2 }Ile-OH [O-adamantyl-P-(9-fluorenylmethyloxycarbonyl-aminomethyl)-P-{2-(2-butyl)propionic acid-3-yl)-phosphinate] was synthesized as described. [24] …”

π‐Insertion Reactions of Benzynes into P=N and P=S Double Bonds

“…Fmoc‐4 R ‐methyl‐ L ‐proline (Fmoc‐mep‐OH), Knight SSP [Lys(Mca)‐Pro‐Leu‐Gly‐Leu‐Lys(Dnp)‐Ala‐Arg‐NH 2 ], fluorogenic triple‐helical peptide (fTHP)‐15 [(Gly‐Pro‐Hyp) 5 ‐Gly‐Pro‐Lys(Mca)‐Gly‐Pro‐Gln‐Gly∼Leu‐Arg‐Gly‐Gln‐Lys(Dnp)‐Gly‐Val‐Arg‐(Gly‐Pro‐Hyp) 5 ‐NH 2 ], and α1(I–III)GlyΨ{PO 2 H‐CH 2 }Leu THPI [C 6 ‐Gly‐Pro‐Flp‐(Gly‐Pro‐Hyp) 4 ‐Gly‐Pro‐Gln‐GlyΨ{PO 2 H‐CH 2 }( R , S )Leu‐Ala‐Gly‐Gln‐Arg‐Gly‐Ile‐Arg‐(Gly‐Pro‐Hyp) 4 ‐Gly‐Pro‐Flp‐NH 2 ] were synthesized by methods described previously 8a. 23 Phosphinate pseudodipeptide Fmoc‐GlyΨ{P(OAd)(OH)‐CH 2 }Ile‐OH [O ‐ adamantyl‐P‐(9‐fluorenylmethyloxycarbonyl‐aminomethyl)‐P‐{2‐(2‐butyl)propionic acid‐3‐yl)‐phosphinate] was synthesized as described 24…”