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Efficient Synthesis of Fmoc-Protected Phosphinic Pseudodipeptides

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Efficient Synthesis of Fmoc-Protected Phosphinic Pseudodipeptides:Building Blocks for the Synthesis of Matrix Metalloproteinase InhibitorsManishabrata Bhowmick,1Ravinder R. Sappidi,1Gregg B. Fields,2Salvatore D. Lepore11Department of Chemistry and Biochemistry, Florida Atlantic University, Boca Raton, FL 33431 -09912Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229-3900Received 16 December 2009; revised 22 February 2010; accepted 6 March 2010Published online 11 March 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/bip.21425This article was originally published online as an acceptedpreprint. The ‘‘Published Online’’ date corresponds to thepreprint version. You can request a copy of the preprint byemailing the Biopolymers editorial office at [email protected] are interested in developing effective matrixmetalloproteinase (MMP) inhibitors as activa-tion of these enzymes have been associatedwith primary and metastatic tumor growth,angiogenesis, and pathological degradation ofextracellular matrix components, such as collagen and lami-nin.1,2Several MMPs have been validated as targets in certaincancers (MMP-2, MMP-9, MT1-MMP), whereas others havebeen found to be host-beneficial and thus antitargets (MMP-3, MMP-8).3A general approach to the design of an inhibitor ofmetallo-proteases involves replacing a trigonal planar amideor ester bond of a substrate with a hydrolytically stable func-tional group possessing tetrahedral geometry in the originalcarbonyl position to mimic the intermediate formed duringenzyme- catalyzed hydrolysis. The phosphinate functionalgroup (Figure 1) with its pair of electronically equivalent ani-onic oxygens (under physiological conditions) has emerge das an effective tetrahedral substitution moti f in peptides lead-ing to potent and selective transition state inhibitors of met-alloproteases such as MMPs.4–7Indeed, due to their growingmedicinal relevance, a number of elegant strategies have beendeveloped over the past few years for the synthesis of phos-phinate dipeptides. Meldal and coworkers, Yiotakis et al.,and Yokomatsu and coworkers reported the synthesis ofdifferent phosphinate dipeptide building blocks by using aprocedure involving the Michael addition of variously pro-tected aminomethyl phosphinic acids to an acrylic acid esterfollowed by protecting group manipulation to afford thedesired product.8Using a creative variation of these methods,FmocNHCH2PO(OAd)-CH2CH(Pri)CO2H(1a, Scheme 2)was prepared and subsequently incorporated into a triple-Efficient Synthesis of Fmoc-Protected Phosphinic Pseudodipeptides:Building Blocks for the Synthesis of Matrix Metalloproteinase InhibitorsAdditional Supporting Information may be found in the online version of thisarticle.Correspondence to: Salvatore Lepore, e-mail: [email protected]:A convenient route for the synthesis of Fmoc-protectedphosphinic dipeptide building blocks is described. Theprotected amino acid isosteres benzyloxycarbonylaminomethyl phosphinic acid (g lycine surrogate), benzyla-isopropyl acrylate (valine surrogate), and benzyla-isobutyl acrylate (leucine surrogate) were sy nthesizedstarting from commercially available materials. Reactionof either the valine or leuc ine surrogate withbis(tr imethylsilyl) phosphonite generated thepseudodipeptide bond. The synthesis concluded with anefficient one-pot three-step procedure involving a bis-deprotection of the N- and C-termini under catalytichydrogenation conditions followed by selective capping ofthe N-terminus with an Fmoc group to yield eitherFmoc-NHCH2PO(OAd)CH2CH(Pri)CO2H or Fmoc-NHCH2PO(OAd)CH2CH(Bui)CO2H.#2010 WileyPeriodicals, Inc. Biopolymers (Pept Sci) 96: 1–3, 2011.Keywords:phosphinic pseudodipeptides; matrix metalloprotei-nase inhibitors; MMPI; peptide synthesis; phosphinatesVVC2010 Wiley Periodicals, Inc.PeptideScience Volume 96 / Number 1 1helical sequence, resulting in a construct, which exhibitedpotent and selective inhibition of MMP-2 and MMP-9.7However, this previously described synthetic route to 1arequired a low yielding (35%) and problematic final stepinvolving a Ru-catalyzed deprotection of an allyl ester.In our continued studies of MMP inhibition involvingthis phosphinate dipeptide system, we required a more scale-able route to 1a. In this communication, we describe anefficient bis-deprotection strategy leading to the desiredphosphinate dipeptide 1a and its Gly-Leu analog 1b.DISCUSSIONOur general strategy for the synthesis of the Fmoc-protectedphosphinic dipeptide 1 entails a Michael-type addition forthe formation of the PC bond pioneered by Regan andYiotakis and subsequently modified by Meldal and Ham-mer.8–10But our initial attempt of Michael-type addition ofFmoc-protected aminomethyl phosphinic acid and electrondeficient acrylate w as not successful.8,11Thus, Cbz-protectedaminomethyl phosphinic acid 3 w as converted to its trivalentstate by the action of HMDS and subsequently reacted withan a-isopropyl-a,b-unsaturated ester12to give product 4 ingood yield (Scheme 1). However, as will be described subse-quently, the Cbz group is very efficiently exchanged for Fmocin the final step of the synthesis.Phosphinic acid 3 was derived from aminomethyl phos-phinate (2) (Scheme 1), which in turn was prepared fromammonium phosphinate using a previously described imineaddition method.10Other reported methods for the synthesisof 2 were less satisfactory.13The main difficulty was in puri-fying highly polar fragment 2 especially on a preparativescale. The use of an ion-exchange resin described by Hammerand coworkers proved least problematic.10,14A subsequentCbz-protection of compound 2 followed by recrystallizationfrom ethyl acetate/light petroleum ether7b,15gave highly purefragment 3 in 65% yield.The adamantyl protection of 4 using AgNO3and AdBrfailed in our hands to provide protected dipeptide 5 (Scheme1).8However, esterification of 4 was achieved by treating thein situ generated phosphinic acid chloride with the sodiumsalt of adamantanol to give fully protected fragment 5a in75% yield.8b,16However, saponification of the ethyl ester unitof 5a by following a previously reported procedure8wasunsuccessful in our hands and led to a complex reaction mix-ture along with a significant amount of Cbz deprotection ofthe starting dipeptide after prolonged reaction time. Othershave also noted the requirement of long reaction times


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