Synthesis of piperidine and quinolizidine alkaloids

Abstract

Natural products have been, and will continue to be, an important starting point for researchers in the quest for novel treatments for today's ailments. While these molecules often have very highly potent or specialised activities, they may not be the perfect drug candidate. Medicinal chemists aim to improve their therapeutic activity and at the same 6 1-11 to give a rather low diastereomeric mixture (2.3:1) of alcohols 1-12 and 1-13 which were separable by silica gel chromatography. Acetonide cleavage of 1-12 by treatment with aqueous HCl followed by the key intramolecular cyclisation step under Mitsunobu conditions furnished pyridinium salt 1-14. Subsequent reduction with hydrogen in the presence of PtO 2 as catalyst produced a 0.8:1 mixture of diastereomers. Subsequent treatment of each diastereomer with concentrated aqueous KOH yielded (-)-lentiginosine, ent-1-1, and its 8a-epimer, 1-15. 1-epi-lentiginosine, 1-16, was also synthesised in a similar fashion. Preparation of the 1-epimer began with alcohol 1-13 and the reduction step proceeded with high yields and diastereoselectivity. Scheme 1.2-2 Fruit's synthesis of (-)-lentiginosine, analogues 1-15 and 1-16 Brandi and co-workers also used a pyridine-based strategy to synthesise racemic lentiginosine (Scheme 1.2-3). 16 Here, pyridyl alcohol 1-17 was identified as a good starting point. Brandi reasoned that the double bond present could undergo electrophilic addition and then cyclise to form the bicyclic skeleton. Bromination of pyridyl alcohol 1-17 with NBS in aqueous THF furnished pyridinium salt 1-18 diastereoselectively with a yield of 53%. Similar to Fruit's work, the pyridinium salt was reduced by hydrogenation with catalytic amounts of PtO 2 to furnish a 0.7:1 mixture of diastereomers 1-19a and 1-19b. The group demonstrated that the presence of a good leaving group i.e. bromine, enabled facile