APPLICATIONS OF INTRAMOLECULAR DIELS-ALDER REACTIONS TO ALKALOID SYNTHESIS - A FORMAL TOTAL SYNTHESIS OF (+/-)-DENDROBINE

A facile synthesis of the tricyclic enone 3 was completed; since 3 was an intermediate in a previous synthesis of (+/-)-dendrobine (1), this achievement constitutes a formal total synthesis of the racemic title alkaloid. The key strategic element of the approach involved the intramolecular Diels-Alder reaction of the olefinic dienamide 10g, which was prepared by N-acylation of imine 9g with acid chloride 8, to furnish the tricyclic cycloadduct 11g as the major product. Subsequent elaboration of 11g into 3 was then consummated by epoxidation, followed by epoxide rearrangement and oxidation of the intermediate allylic alcohol 23. The synthetic investigations were preceded by a series of model studies that were executed in order to assess the viability and to probe the scope and limitations of the crucial intramolecular [4 + 2] cycloaddition. In these preliminary investigations, we discovered that thermolyses of dienamido olefins 10a-f afforded mixtures (3.5-14:1) of epimeric cycloadducts 11a-f and 12a-f. The steric bulk of the N-alkyl substituent on 10a-d exerted considerable influence upon the energy of activation and the stereochemical course of the respective cycloaddition reactions. A cyclopropyl or isopropyl group positioned at C(8) on the diene moiety of the unsaturated dienamides 10e-g also facilitated the cyclization and enhanced the endo selectivity of the process.