Asymmetric synthesis of pyrrolidines, piperidines, and tetrahydroisoquinolines utilizing enantiopure sulfinimines

Addition of the potassium enolate of methyl ketones to sulfinimines afforded N-sulfinyl beta-amino ketones in excellent yield and diastereoselectivity. Treatment of these beta-amino ketones with TsOH-H20 and 1,3-propandiol affords, in one pot, the corresponding beta-amino ketals. beta-Amino ketals are valuable chiral building blocks for the assembly of functionalized piperidines via the intramolecular Mannich cyclization reaction. The asymmetric synthesis of (-)-indolizidene 209B was accomplished using this new methodology in eight steps in 19% overall yield.;Of four possible stereoisomers, addition of the prochiral lithium enolate of 4-heptanone to sulfinimines results in formation of only the syn - and anti-alpha-ethyl beta-amino ketones. These results were interpreted in terms of the E-enolate of 4-heptanone, adding to the re face of the sulfinimine C-N double bond via a six-member chelated transition state, affording syn-alpha-ethyl beta-amino ketone as the major product. Addition of Z-enolate of propiophenone to sulfinimines also gave the syn adduct as the major product. Here a boat-like transition state was proposed to explain these results.;In these studies an unusual solvent effect on the enolate geometry was observed. Using LiHMDS in THF the E:Z ratio of the 4-heptanone enolate was 1:2.5, whereas in diethyl ether the E:Z ratio was 15:1. These results were rationalized in terms of Ireland's transition state model. A tighter Ireland's transition state and the dimeric nature of LiHMDS in the poorly coordinating diethyl ether solvent compared to THF was suggested to favor the formation of E-enolate, due to increased interaction between the ethyl group and the carbonyl-LiN(TMS)2 complex.;The alpha-substituted beta-amino ketone obtained in the addition of the 4-heptanone enolate of to N-(butylidene)- p-toluenesulfinamide, was used in a concise asymmetric synthesis of indolizidine (-)-223A, a 5,6,8-trisubstituted indolizidine. The key step in this synthesis was the intramolecular Mannich cyclization of the crotonaldehyde imine of the syn-alpha-ethyl beta-amino ketone.