Synthesis of azacyclic systems via intramolecular cyclization reactions of carbanions of sulfones, sulfoxides and phosphonates with carbamates and amides

Intramolecular cyclizations of amides and carbamates with carbanions of sulfones, sulfoxides and phosphonates have been shown to be useful in the preparation of various azacyclic systems. The products generated using this methodology are potential intermediates for the preparation of functionalized lactams and bicyclic alkaloids.;The sulfinyl and phosphono carbamates (163a, 165a) underwent intramolecular cyclization upon treatment with LHMDS to give lactams ( 164a, 166a) in high yields. Similarly, N-acyl derivatives of phosphonates 165b-d cyclized to give dihydropyrrolidines 166b-d. Successful cyclization of the corresponding sulfoxides 163b-d occurred when there were no alpha-amido protons that could compete with the required a-sulfinyl deprotonation.;Phosphonolactam 169b readily underwent cyclization to give unsaturated indolizidine 170b. Surprisingly, cyclization of the corresponding gamma-lactam 16% to give the pyrrolizidine 170a was unsuccessful. The cyclizations of carbamates 174, 176 and 177 proceeded to give bicyclic lactams 178a-c. The HWE reaction of bicyclic phosphonolactam 178a gave an unsaturated amide that underwent stereoselective hydrogenation. Thermal elimination of the corresponding sulfoxide gave conjugated amide 181.;The intramolecular cyclizations of phthalimide and imide derivatives (185-186, 192b, 193b) proceeded to give bicyclic and tricyclic systems (188a-c, 189, 194, 195). When subjected to Pummerer conditions, vinyl sulfoxides 194 and 188a gave novel pyrrole ring systems 196a-b.;The intramolecular cyclization of type I oxazolidinones (204-206 ) gave chiral non-racemic hydroxymethyl lactams 207a-f in excellent yields. The cyclization of type II oxazolidinones (227 and 229) proceeded to give products (228 and 230) possessing the structural motif of an important anti-epileptic drug, levetiracetam. Using the methodology, we synthesized 226, a known intermediate for levetiracetam.;The intramolecular cyclizations of type III oxazolidinones 238a-c were especially interesting. The course of the reaction and the nature of the product could be controlled depending on the nitrogen protecting group. The presence of an electron withdrawing group on nitrogen led to the formation of lactones 240b-c whereas N-benzyl oxazolidinone 238a cyclized to give lactam 24%.;An approach to the lasubine alkaloids using this cyclization methodology was examined. While the cyclization of sulfoxide 265 was unsuccessful, the corresponding sulfone 266 did undergo cyclization to give 267, a potential intermediate in the synthesis of lasubine.