NATURAL PRODUCT SYNTHESIS VIA IMINIUM YLIDE & NITRILIUM

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The objectives will be to develop improved chemical systheses for biologically active natural products and their structural analogs. These syntheses are destined to rely on conceptually novel annulation precedures. Specifically, we propose to develop enantioselective syntheses for the alkaloids dendrobine and pretazettine which rely on oxazolinium ylide 1,3-dipolar cycloaddition reactions. The narcissus alkaloid pretazettine has exhibited remarkable therapeutic potential. This substance has shown marked activity against Ehrlich ascites carcinoma in mice. More importantly, the therapeutic activity of the individual standard drugs adriamycin, and cycloposphamide against the forementioned carcinoma was increased tremendously by the adjuvant therapy with pretazettine. In addition, the independent inhibitory action of pretazettine on cellular protein synthesis in the presence of adriamycin has been demonstrated in KB-cell cultures. Significantly, pretazettine has been revealed to increase both the survival rate and survival time of mice with Lewis lung carcinoma when administered at low levels over several days. In addition, the therapeutic effectiveness of a variety of standard drugs (e.g. cyclophosphamide, actinomycin D, 5-fluorouracil, methotrexate, 6-thioguanine, and vincristine) against i.p. implanted Lewis lung carcinoma was increased synergistically or additively when coadministered with pretazettine. Concise syntheses for the biologically active alkaloids erythraline and eburnamonine are proposed. The intended routes to these natural products will utilize a new procedure for effecting acylnitrilium ion cyclizations which we have recently developed. We predict that this novel means for efficiently constructing heterocycles of variable ring size will create a significant impact in the area of alkaloid synthesis.