An intramolecular nitrone-olefin dipolar cycloaddition-based approach to total synthesis of the cylindricine and lepadiformine marine alkaloids

A synthetic route to the cylindricine skeleton as well as to the reported s tructure of the marine alkaloid lepadiformine has been achieved using an in tramolecular nitrone/1,3-diene dipolar cycloaddition as the key step. The s ynthesis began with sequential alkylations of acetone oxime to afford key i ntermediate oxime 30, which contains all of the carbons necessary to form t he tricyclic skeleton of the alkaloids. Nitrone 40, available from oxime 30 by standard transformations, underwent an intramolecular 1,3-dipolar cyclo addition to provide isoxazolidine 43. Related 1,3-dipolar cycloadditions we re also explored on two additional nitrone-olefin substrates 41 and 42, whi ch were prepared in a manner similar to that of 40. The tricyclic alkaloid core 52 was formed stereoselectively by a tandem oxidation-Michael addition of amino alcohol 49 derived from isoxazolidine 43. Cleavage of the O-pheny l ether of 52 provided 2-epi-cylindricine C (53). Several unsuccessful atte mpts were made to convert 52 to cylindricine C by epimerization at C2. Tric yclic ketone 52 was deoxygenated to give amine 59, whose structure and rela tive stereochemistry were confirmed by single-crystal X-ray analysis of its picrate salt. Removal of the O-phenyl protecting group from 59 provided tr icyclic amino alcohol 60 having the putative structure of lepadiformine, bu t whose NMR data did not correspond to those of the natural product.