Formal Synthesis of (+)- and (-)-Perhydrohistrionicotoxin: A "Double Henry"/Enzymatic Desymmetrization Route to the Kishi Lactam(1).

Both antipodes of the Kishi lactam (3), the versatile intermediate for the synthesis of the perhydrohistrionicotoxin (pHTX) alkaloids, have been prepared. The synthetic route involved a "double Henry" condensation between glutaraldehyde and nitroacetal 5 giving meso dioxanyldiol 4 which was acetylated and reduced to afford meso dioxane amide 8. Ultrasound-promoted deacetalization of 8 followed by Wittig olefination and reduction provided meso amide ester 10. Hydrolysis of 10 with aqueous acid followed by dehydrative cyclization with dicyclohexylcarbodiimide gave lactamdiol 11. Acetylation of 11 gave meso diacetate 2 which was an excellent substrate for esterase-mediated hydrolysis to hydroxyacetate 12. Deoxygenation of 12 using a Barton protocol, followed by Zemplén deacylation and Swern oxidation, gave the (-)-antipode of the Kishi lactam (3). Moffatt oxidation of hydroxyacetate 12 followed by ketal protection and Zemplén deacylation gave ketalalcohol 19. Barton deoxygenation of 19 followed by ketal hydrolysis gave (+)-3.