Synthesis of substituted pyrrolidines and piperidines from endocyclic enamine derivatives.: Synthesis of (±)-laburnamine

Functionalization of the alpha- and beta-positions of readily available endocyclic enamine derivatives provides a convenient method for the formation of substituted pyrrolidines and piperidines. alpha-Alkoxy-beta-iodopyrrolidines are formed by the electrophilic addition of iodine to the endocyclic enamine double bond of an N-substituted 2-pyrroline, and nucleophillic attack by an alcohol on the intermediate iodonium ion. The resultant alpha-alkoxy-beta-iodopyrrolidines can be used in radical cyclization reactions to give bicyclic hemiaminal compounds, which can be further elaborated using N-acyliminium chemistry to form alpha,beta-cis-dialkylsubstituted pyrrolidines. A strategy for the incorporation of amino functionality at the beta-position was also established by using iodoamination of the enamine double bond, followed by migration of the amine functionality through an aziridination/methanolysis protocol. An alternative method uses an azidomethoxylation protocol using ceric ammonium nitrate (CAN) in the presence of NaN3 and methanol. Formation and trapping of the N-acyliminium ions derived from these substrates, afforded the 3-carbamate and 3-azido-2-substituted products with good diastereoselectivity, with the preferential formation of the trans and cis stereoisomers, respectively. Using the sequential iodoamination, aziridination in methanol and N-acyliminium transformation, trans-3-NHCO2Me-2-allyl-pyrrolidine was prepared, which was used as the key precursor in a synthesis of the natural 1-amidopyrrolizidine alkaloid, (+/-)-laburnamine. (C) 2004 Elsevier Ltd. All rights reserved.