Heterocycles in synthesis: Part I. Alpha,alpha-dialkylated amino acid derivatives via imidazoles. Part II. Approaches to the cyclopeptide alkaloids

Part I. Improved preparations of N-hydroxy- and N-protio-2-4(5)-disubstituted imidazoles from olefins and nitriles are described. The products of subsequent N or O alkylation are exposed to singlet oxygen to afford N-alkylacylimines 48 and N-alkoxyacylimines 69 respectfully. Although both 48 and 69 are readily reduced with NaBH{dollar}sb4{dollar} to provide alpha-alkylated amino acid derivatives in essentially quantitative yield, 48 does not undergo 1,2-nucleophilic addition with organometallic reagents. In contrast 69 readily undergoes nucleophilic addition with a variety of organometallic reagents at {dollar}-78spcirc{dollar}C in THF to give alpha,alpha-dialkylated amino acid derivatives in good to excellent yields.; Part II. Two approaches to the cyclopeptide alkaloids employing either oxazoles or imidazoles as synthetic equivalents of the diamide/dipeptide segment are described.; In the first route, a general, highly efficient, nine step synthesis of novel oxazolophanes containing all the atoms of the 13- and 14-membered cyclopeptide alkaloid skeleton is achieved via an intramolecular macrocyclization of suitably substituted 5-acylaminooxazoles. The monomeric/dimeric nature of these oxazolophanes is not readily ascertained. The oxazolophanes are inert or unstable to all attempted deprotection/hydrolysis procedures. The search is in progress for a protecting group which allows cyclization of a linear precursor and undergoes mild removal to afford the cyclopeptide alkaloid system.; The second route details the progress made towards the elaboration of simple imidazoles into imidazolophanes, which upon exposure to singlet oxygen and base should provide the cyclopeptide alkaloid ring system. A general three step synthesis of 4(5)-substituted imidazoles has been improved. The {dollar}beta{dollar}-(trimethylsilyl)ethoxymethyl (SEM) group provides a general solution to imidazole N protection. SEM-imidazoles regio-specifically undergo C-2 metallation and subsequent reaction with a variety of electrophiles. Although 2-lithioimidazoles readily undergo 1,2-addition with BF{dollar}sb3cdot{dollar}Et{dollar}sb2{dollar}O activated simple imines, addition to 3-phenoxy-1-pyrrolines is not observed. BF{dollar}sb3cdot{dollar}Et{dollar}sb2{dollar}O promoted nucleopohilic addition to acyclic 3-phenoxyaldimines occurs, albeit low yields. Elaboration of a 1,2 addition product to a linear cyclization precursor is described. Cyclization studies aimed the construction of imidazolophanes are currently in progress.