Total Synthesis of Manzamine A and Related Alkaloids

Total syntheses of three structurally complex marine
natural products,
manzamine A, ircinol A, and ircinal A, are reported. The route pivoted
on the construction of a late-stage protecting-group-free pentacyclic
enol triflate coupling partner, from which all three family members
were accessed divergently via palladium-catalyzed reactions. The rapid
synthesis of this key pentacyclic enol triflate was achieved by a
highly convergent union of five fragments through a stereoselective
Michael addition, a three-component nitro-Mannich lactamization cascade,
an unprecedented and highly stereoselective reductive nitro-Mannich
cyclization cascade, a stereoselective organometallic addition, and
a Z-selective alkene ring-closing metathesis. Altogether
this chemistry has allowed the shortest synthetic route to date for
manzamine A (18-step longest linear sequence) via a late-stage diversification
point that is ideal for future manzamine A analogue synthesis.