On the conformations of halichlorine and the pinnaic acids: Nitrogen inversion as a possible determinant of biological profile

Although the marine alkaloids halichlorine (1) and the pinnaic acids 2, whi ch contain a quinolizidine ring system, exhibit considerable structural hom ology, they act upon different biological targets (VCAM-1 and cPLA(2), resp ectively). Quinolizidines can exist as cisoid or transoid invertomers. In t he recently reported total synthesis of (+)-halichlorine, it was determined by NMR that advanced intermediates 3 and 4, containing the spiroquinolizid ine core, exhibit the transoid conformation, while the macrolactone-contain ing halichlorine has the cisoid conformation We conclude that constraints i mposed upon closure of the macrolactone ring force adoption of the cisoid c onformation The major conformational reorganization upon macrolactonization has implications for the design of pharmacophors and anticipated structure -activity relationships in their action on biological targets.