A [3+3] cyclization strategy for asymmetric piperidin synthesis using 1,2-cyclic sulfamidates

Activation of vicinal aminolalcohols toward nucleophilic substitution through formation of 1,2-cyclic sulfamidates provide a potential alternative to the reactivity profile of aziridines. In addition the chemistry of 1,2-cyclic sulfamidates has several advantages. These are the regioselective nucleophilic ring opening of cyclic sulfamidates at the C-O bond and no requriment of the presence of activating groups on the nitrogen. Reactions of cyclic sulfamidates with a variety of nucleophiles have recently began to be employed in a range of areas in synthesis. Of great value is the ring opening reactions with carbon-based nucleophiles that enable the synthesis of chiral fuctionalized amines. In this respect, the reactivity of chiral sulfamidates toward synthetically more versatile carbon nucleophiles have been less widely investigated in organic synthesis. Despite a few reported substitution reactions of sülfamidates with some stabilized carbon nucleophiles (mostly enolates), there is no study in the literature about the acetylenic displacement reactions of them.In this study, some basic 1,2-cyclic sulfamidates (phenyl alaninol, alaninol, valinol, norvalinol, prolinol) (3a-e) derived from corresponding L-amino acids have been prepared using lliterature methods. Acetylenic substitution reactions of the sulfamidates synthesized in this work were initially investigated with lithium methylpropiolate, but this anion could not be generated presumably due to the instability of the anion in solution. The use of the carbonyl protetected derivative, triethyl orthopropiolate as the stable propiolate anion equivalent was also studied. This compound was synthesized from triethyl propionate using the literature protocol.Reaction of sulfamidates (3a-d) with lithium triethyl orthopropiolate took place efficiently to furnish N-sulfamate intermadiates(14a-d). Acidic hydrolysis of these intermediates left amino group free while converting orthoesters moiety to ethyl ester. Thus, functionalized ? -amino- ? , ? -unsaturated esters (15a-d) were obtained in high yields (89-91%). Removal of benzyl protecting group and saturation of triple bonds were achieved by palladium catalyzed hydrogenation. During hydrogenation reactions partial cyclization of debenzylated and saturated derivatives to generate piperidine ring systems was observed. Refluxing of the crude reaction mixture was required in order to achieve complete cyclization leading to the synthesis of aminoacids derived piperdine lactams (17a-d) in high yields (83-89 %). This approach presents a [3+3] annulation strategy for asymmetric synthesis of chiral 2-substtitue piperdin ring systems using 1,2-cyclic sulfamidates.Acetylenic substitution reaction of prolinol sulfamidate (3e) proved to be problematic. The reaction formed an intermediate, but the structure of this adduct could not be determined. Further studies is needed to clearify the structure of this intermediate.IR, 1H and 13C NMR were used for structural characterization of the compounds synthesized in this work. Anaylitical data obtained for the previously synthesized coumpounds are in good agreement with the literature data. Characterization of new coumpounds were carried out with IR, 1H and 13C NMR spectra.