TOTAL SYNTHESIS OF QUASSINOIDS AND VIRGINIAMYCIN

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A total synthesis of the highly cytotoxic pentacyclic diterpene, quasimarian is proposed. Starting from D-(+)-glucose, we intend to prepare a monocyclic alpha-methylene-3-oxycyclopentanone which contains a total of three chiral centers together with a remote diene function. The preparation of this monocyclic species will utilize some aldol chemistry which has been developed in our laboratories. Intramolecular [4 + 2] cycloaddition of this monocyclic substance is expected to occur in the exo-mode--closely following the stereochemical outcome of our own work on the sesquiterpene, quadrone as well as the work of others. The cycloaddition reaction yields a total of five chiral centers contained in a tricyclic framework which represents rings B, C, and E of the target natural product. Of particular importance is the securement of all three sites of oxygenation in ring C in the correct stereochemical arrangement. Further, the tircyclic substance contains both functionality and molecular geometry suitable and conducive to the annulative elaboration of the rings A and D present in this pentacyclic diterpene. A new reaction sequence resulting in the formation of ring A will be used. We also propose a total synthesis of the biologically very interesting macrocyclic antibiotic, virginiamycin. We have divided this molecule into two portions and named them the upper and lower halves. The upper fragment utilizes some new and very useful erythro aldol methodology which features the aldol-lactonization reaction of a vinylogous urethane. The methodology should permit an extremely brief and efficient construction of the upper half of virginiamycin. The lower fragment will be prepared from glutamic acid and takes advantage of some sulfur based methodology we, and other, developed some time ago. We have never used this methodology in a serious synthetic setting and hope to do so during the course of our work on this problem.