Enantiomerically pure polyhydroxylated acyliminium ions: Synthesis of the glycosidase inhibitors (-)-swainsonine and (+)-castanospermine.

摘要

Acyliminium ion cyclizations have been employed extensively for the preparation of alkaloid natural products in recent years. This methodology has been widely accepted, in part, due to the ease of preparation of the hydroxylactam precursors via reduction of imides. One disadvantage of this methodology is that no general method exists for the preparation of enantiomerically pure hydroxylactams/acyliminium ions that would be derived from meso-imides.; To address this problem, which presented itself in planned syntheses of ({dollar}-{dollar})-swainsonine and (+)-castanospermine, three new methods of preparing highly substituted, enantiomerically pure hydroxylactams have been developed. A protected cis-dihycroxytartarimide with a chiral auxiliary at nitrogen undergoes highly selective reduction of either carbonyl group. Reduction of the imide 47 with Me{dollar}sb2{dollar}NHB(OAc){dollar}sb3{dollar} gave the hydroxylactam 49a in {dollar}>{dollar}98% de while reduction of the imide 46 with L-Selectride gave the hydroxylactam 51b in {dollar}>{dollar} 98% de, resulting from reduction of the opposite carbonyl. Possible reasons for this remarkable regiochemical control are presented.; The reduction of a meso inside with chiral reducing agents has been found to give the corresponding hydroxylactam in enantiomeric excesses up to 56%. Alternatively, direct synthesis from monosacharide lactones derived from ribose or lyxose affords either enantiomeric series of hydroxy lactams, (+)-55{dollar}alpha{dollar}, 51d, 49d and ({dollar}-{dollar})-55{dollar}beta{dollar}, 67, 51c, 59c, 68, respectively. Yields for the 2 step synthesis were found to be dependent on the steric congestion of the amine: primary amines giving higher yields than more highly substituted amines.; A concise synthesis of the mannosidase inhibitor ({dollar}-{dollar})-swainsonine and the glucosidase inhibitor (+)-castanospermine via the monosacharide lactone route is described. Hydroxylactam 68 has been converted into ({dollar}-{dollar})-swainsonine via a synthetic route that utilizes a novel multiple reduction of a vinylogous {dollar}N{dollar}-acylurethane to establish the correct ring juncture stereochemistry. The analogous polyhydroxylated six membered ring hydroxylactam 77 was prepared from a lactone derived from glucose. The stereochemical outcome of the acyliminium ion cyclization of 77 is presented, and the resulting products (78 and 79) have been carried on to (+)-castanospermine and the new indolizidine alkaloid 1,8a-diepicastanospermine, respectively.