The Aminative Rearrangement of Dihydropyrans: A Novel Route to Substituted Proline Derivatives

Abstract

This thesis describes the investigation of the aminative rearrangement of 2-alkoxy dihydropyrans, which presents a novel route to substituted proline derivatives. Aziridination of the dihydropyran results in a ring-opening and subsequent ring contraction to afford pyrrolidines with distinctive diastereoselectivity across the 2,3- position. This selectivity is controlled by the manner of aziridination, and initially, studies concentrated on the optimisation of the rearrangement in regard to the conditions of aziridination. Following the establishment of the optimal conditions, a range of substrates were subjected to the aminative rearrangement reaction, followed by the in situ reduction of the 5-ethoxy group, to furnish an array of 2,3-substituted 7V-tosyl-protected pyrrolidines. This proved the tolerance of the procedure to various alkyl, aryl and heteroatom substituents and allowed for the synthesis of either the 2,3-ds or 2,3-trans isomers in reasonable to good diastereoselectivities, depending on the conditions of aziridination. Finally, the application of this methodology to the synthesis of enantiomerically enriched substituted prolines was demonstrated though the initial application of an asymmetric hetero-Diels-Alder reaction to form the dihydropyrans. Employing the Wada chiral titanium TADDOL catalyst resulted in the enantioselective formation of 2-alkoxy-6-(phenylsulfonylmethyl)3,4-dihydro-2//-pyrans. Rearrangement of the pyran and subsequent manipulation of the pyrrolidine allowed for the diastereo and enantioselective synthesis of the proline derivative.