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

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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(trimethylsilyl) 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.

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Fig. 1
Scheme 1

Abbreviations

Ad:

Adamantyl

Bn:

Benzyl

Z:

N-Benzyloxycarbonyl

Fmoc:

N-(9-Fluorenyl)methoxycarbonyl

HMDS:

Lithium hexamethyldisilazide

MMP:

Matrix metalloproteinase

PPD:

Phosphinic pseudodipeptide

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Acknowledgments

This work was supported by NIH grant CA98799, NIH contract 268201000036C, and the Multiple Sclerosis National Research Institute (to GBF). We thank Dr. Deboprosad Mondal, The Scripps Research Institute/Scripps Florida, Jupiter, FL and The University of Texas Health Science Center at San Antonio, TX for the acquisition of NMR spectra.

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Correspondence to Gregg B. Fields.

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Bhowmick, M., Fields, G.B. Synthesis of Fmoc-Gly-Ile Phosphinic Pseudodipeptide: Residue Specific Conditions for Construction of Matrix Metalloproteinase Inhibitor Building Blocks. Int J Pept Res Ther 18, 335–339 (2012). https://doi.org/10.1007/s10989-012-9307-y

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