Stereoselective synthesis of disubstituted piperidines via 1,2-cyclic sulfamidates

This thesis describes the development of a novel method for stereo-selective synthesis of disubstituted piperidines from 1,2-cyclic sulfamidates. Acetylenic ring-opening reactions of 1,2-cyclic sulfamidates was already known in the literature. Giving efficient substitution of 1,2-cyclic sulfamidates with functionalized acetylides and tolerance of the acetal functional group of the N-sulfamate intermediates to the acidic hydrolysis conditions call for the idea that once a phenyl ketal acetylide used in the ring-opening reactions, the alkynlated-ketal-amine products could then be converted to disubstituted piperidines in stereoselective manner using acidic palladyum-catalyzed hydrogenation via the cyclic iminium intermediate in one-pot operation. The present strategy was envisaged to present a novel method for the stereoselective synthesis of disubstituted piperidines. Initially the acidic hydrolysis conditions for the N-sulfamate intermediates of acetylenic ring-opening reactions of sulfamidates with the phenyl ketal acetylides were investigated in order to achieve selectively hydrolysis the N-sulfamates with the ketal group intact. Performing the hydrolsis with standart conditions using 5M HCl led to the isolation of the undesired alkynlated amino ketone derivatives. Use of H2SO4 in a controlled-manner effectivelly hydrolzed selectively N–sulfamates with the ketal group intact to give the desired alkynlated-ketal-amine product in high yields. Application of this protocol to phenylalanine, alanine, valine, norvaline and lactat-derived 1,2-cyclic sulfamidates enabled synthesis of the corresponding chiral alkynlated-ketal-amines in high yields (%83-92). Attempt to construct the piperidine skeleton from the alkynlated-ketal-amines using acidic palladyum-catalyzed hydrogenation in one-pot operation unfortunately failed. Instead all attempts led to isolation of the uncyclized lineer chiral amines. Fortunately performing the cyclization sequence in step-wise manner afforded disubstituted piperidines in highly stereoselective (60-98≥ d.e.) fashion in good yields (%61-86). The configuration of the new stereogenetic centers was observed to possess the cis form on the bases of the spectroscopic results. The rationale for the high stereoselectivity was believed to be based upon the stereoelectronic effects on the half chair transtion state of the cyclic imium intermedites.