Chem. Pharm. Bull. 53(5) 555—560 (2005)

found in amphibian skin, and the 5,8-disubstituted indolizidines, one of the largest subclass of these alkaloids, were detected from skin extracts of the poison-frog. Quite recently, we have found the synthetic 5,8-disubstituted indolizidine 235B (1), isolated from Dendrobates pumilio, acted as a potent noncompetitive and selective blocker of a4b2 nicotinic receptor (IC50 74 nM). The sensitivity of 235B for a4b2 receptors was comparable with that of the best characterized antagonist of a4b2 nicotinic acetylcholine reseptors (nAChRs), dihydro-b-erythroidine (DHbE) (IC50 0.11 mM). This result shows that poison-frog alkaloids such as indolizidine 235B alter the function of nicotinic receptors in a subtype-selective manner, suggesting that an analysis of these alkaloids may aid in the development of selective drugs to alter nicotinic cholinergic functions. As part of our ongoing program at directing the synthesis of biologically active alkaloids, we planned the synthesis of 237D (2, saturated congener of 1), 207A (3, bis-nor congener of 1), nor congener of 235B (4), and homo congener of 1 (5) as potent blockers for nAChRs. This paper describes a full account of the experiments, some of which were reported in a preliminary communication. The synthesis of 2 began with trisubstituted piperidine 6, which was converted to the a ,b-unsaturated ester 7 in 2-step sequence. Hydrogenation of 7 over Pd–C under medium pressure followed by reduction of the ester moiety with Super-Hydride gave rise to the alcohol 8. Treatment of 8 with MOMCl in the presence of Hünig base provided the MOM ether 9, which was treated with TBAF to afford the alcohol 10. Swern oxidation of 10 followed by Wittig olefination of the resulting aldehyde provided the olefin, which was hydrogenated over Pd–C to give rise to the alkaloid 237D (2). The absolute stereochemistry of natural 237D was determined to be 5S, 8S, 9R by the present synthesis (see Experimental and reference 9). Swern oxidation of 10 followed by the Wittig reaction of the resulting aldehyde provided the olefin 12, which was converted to the alcohol 13. Swern oxidation of 13 and Wittig reaction of the resulting aldehyde afforded the terminal olefin 14. Deprotection of the urethane moiety in 14 using Corey’s procedure, and cleavage of the MOM ether with acid followed by indolizidine formation under the bromination reaction condition provided the alkaloid 207A (3), whose spectral data were identical with those of reported values. On the other hand, the alcohol 13 was converted to the iodide 15, and the cross coupling reaction of 15 using the dibutenyl cuprate gave rise to the homologated olefin 16. Indolizidine formation reaction of 16 furnished 5. Finally, the nor-congener of 1 (4) was synthesized from the May 2005 Chem. Pharm. Bull. 53(5) 555—560 (2005) 555