Sulfinimines (N-sulfinyl imines) mediated asymmetric synthesis of alpha-amino acids, piperidine and pyrrolidine alkaloids

Enantiopure sulfinimines (N-sulfinyl imines, p-TolylS(O)N=CR1R2) are versatile chiral building blocks for the asymmetric synthesis of amine derivatives and provide a general solution to the problem of addition of organometallic reagents to chiral imines. In this regard an improved two-step method for their en anti oselective synthesis was devised. This new methodology involves condensing (S)- or (R)-p-toluenesulfinamide [p-TolylS(O)NH2] with aldehydes and ketones in the presence of titanium (IV) ethoxide affording the sulfinimine in excellent yield and ee. The sulfinamides were prepared in an SN2 type substitution reaction of lithium bis(trimethylsilyl) amide (LiHMDS) with the commercially available Andersen reagent.; Several new N-sulfinylaziridine-2-carboxylates were prepared in high diastereoselectivity and good to excellent yields using the aza-Darzens reaction of an alpha-bromo enolate with sulfinimines. Bis-azindine carboxylates were prepared from bis sulfinimines. Reaction of the N-sulfinyl aziridines with MeMgBr affords the valuable 1 H-aziridine 2-carboxylates and avoids the problematic ring-opening observed with more reactive aziridines under acidic conditions. The catalytic hydrogenation ring-opening reaction of 1H-aziridine 2-carboxylates is highly regioselective and affords enantiopure 3-substituted alanines in excellent yield.; N-Sulfinyl delta-amino-beta-ketoesters were introduced for the asymmetric synthesis of piperidine alkaloids. This new polyfunctionalized chiral building is prepared in one-pot from the addition of the enolate of methyl acetate to enantiopure N-sulfinyl beta-amino esters. Concise asymmetric syntheses of all four stereoisomers of 4-hydroxypipecolic acid and SS20846A, a proposed intermediate in the biosynthesis of the anti-microbial agent streptazolin, were accomplished. Importantly, these syntheses were completed with a minimum of chemical manipulation and protecting deprotecting group chemistry with this new chiral building block.; The utility of N-sulfinyl delta-amino-beta-ketoesters was extended to the asymmetric synthesis of pyrrolidine alkaloids using metal carbenoid chemistry. Here the Rh-mediated intramolecular carbenoid N-H insertion reaction of N-Boc delta-amino alpha-diazo-beta-ketoesters was employed to prepare enantiomerically pure 5-substituted 3-oxo prolines. The requisite alpha-diazo compounds were prepared by a diazo transfer reaction from N-Boc delta-amino beta-ketoesters and commercially available 4-carboxybenzenesulfonazide. Methyl cis-(2 S,5R)-(+)-5-phenylpyrrolidine-2-carboxylate, a constituent of the potent cholecystokynin (CCK) inhibitor (+)-RP-66803, was prepared using this new polyfunctionalized pyrrolidine chiral building block. This synthesis represents the most concise asymmetric synthesis of this cis-proline reported to date.