Cyanogen Bromide as Dehydrosulfurizing Agent for the Synthesis of Nβ-Fmoc-Amino Alkyl Isonitriles from Nβ-Fmoc-Amino Alkyl Thioformamides

Abstract

Synthetically useful N b -Fmoc amino alkyl isonitriles are prepared conveniently from N b -Fmoc amino alkyl thioformamides via a cyanogen bromide mediated dehydrosulfurization. The reaction is fast, clean, and yields are good.Key words: N b -Fmoc-amino alkyl thioformamides, isonitriles, dehydrosulfurization, cyanogen bromideIn recent years, the synthetic utility of isonitriles 1 in organic reactions has been exploited. Compounds containing an isocyano group find use as antibiotics, 2 antineoplastics, 3 and antianaesthetics. 4 The synthetic utility of isonitriles arises from their divergent character 5 and this functionality has wide utility, such as in the preparation of isothiocyanates, 6 N,N-dialkylcarbodiimides, 7 1-substituted tetrazoles, 8 [16][17][18][19][20] has been well demonstrated.In peptide chemistry, the application of isonitrile derivatives of amino acids has led to a variety of peptidomimetics 21 and other useful products such as blactams, 22 glycopeptides, 23 depsipeptides, 24 peptide nucleic acids, 25 and N-hydroxy peptides. 26 Amino acid ester derived isonitriles are the known entities, which are prepared from corresponding formyl amino acid esters. 27A recent entry into this new class of amino acid derived isonitriles has been described by our group wherein N bFmoc amino alkyl isonitriles were obtained through carboxyl group modification. 28Of the many methods available for the preparation of isonitriles, dehydration of formamides is the widely followed route in amino acid chemistry, showing general applicability and reproducibility. 29 Reaction of alkyl halides with heavy metal cyanide salts, 30 addition of dichlorocarbene to amines, 31 reduction of isocyanates and isothiocyanates 32 are other available routes. Dehydration of formamides has been carried out by using tosyl chloride, phosphorus oxychloride (POCl 3 ) in the presence of a base, cyanuric chloride, triphenyl phosphine-CCl 4 , phosgene, diphosgene, and triphosgene. 33 The method employing POCl 3 being quite harsh is found to cause racemization and therefore is not applicable in peptide chemistry, and isolation of enantiomerically pure isonitriles is always challenging and demanding. Danishefsky and co-workers have isolated enantiomerically pure aisocyanoesters 34 derived from formyl amino acid esters, employing triphosgene/N-methylmorpholine (NMM) at -78°C. Nenajdenko's group has synthesized the amino acid derived nonracemic isonitriles employing the less commonly used 4-methyl-2,6,7-trioxabicyclo[2.2.2] octyl-protected formyl amino ester.35 Sureshbabu et al. reported the synthesis and isolation of enantiomerically pure N-Fmoc-amino alkyl isonitriles by the dehydration of the corresponding N b -Fmoc amino alkyl formamides under neutral conditions employing Burgess' reagent.28 In a continuation of our current studies on isonitriles, we sought a simple and economically viable route involving dehydrosulfurization of N b -Fmoc amino alkyl thioformamides using cyanogen bromide (CNBr, Scheme 1). Scheme 1There has been a sur...