Total Syntheses of Ningalin A, Lamellarin O, Lukianol A, and Permethyl Storniamide A Utilizing Heterocyclic Azadiene Diels−Alder Reactions

Abstract

Concise, efficient total syntheses of ningalin A (1), lamellarin O (2), lukianol A (3), and permethyl storniamide A (5) are detailed on the basis of a common heterocyclic azadiene Diels−Alder strategy (1,2,4,5-tetrazine → 1,2-diazine → pyrrole) ideally suited for construction of the densely functionalized pyrrole cores found in the three classes of marine natural products. Examination of the natural products and a number of synthetic intermediates revealed that some including lamellarin O (2) and lukianol A (3) exhibit modest cytotoxic activity against both wild-type and multidrug-resistant tumor cell lines. Fundamentally more important, a new class of agents including permethyl storniamide A (5) and its precursor 30, which lack inherent cytotoxic activity, are disclosed which reverse the multidrug-resistant (MDR) phenotype, resensitizing a human colon cancer cell line (HCT116/VM46) to vinblastine and doxorubicin at lower doses than the prototypical agent verapamil.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…Selective hydrolysis of the symmetrical diester provided the monoacid. The subsequent hydrogenolysis afforded lamellarin 41 (Scheme 7c) [108]. In 2012, Vazquez et al used the Paal-Knorr pyrrole synthesis to synthesize 41 in 25% yield in seven steps, and 43 in 28% yield in six steps [94].…”

“…Therefore, increasing the steps of reaction did not increase the reaction yield. Boger et al described the synthesis of lamellarin 41 using an azadiene Diels-Alder reaction named as 1,2,4,5-tetrazine-1,2-diazine-pyrrole transformation with the overall yield of 34% within seven steps [108]. The pyrrole moiety was assembled by a [4+2] cycloaddition/ cycloreversion reaction, followed by a reductive ring transformation.…”

The application of vinylogous iminium salt derivatives and microwave accelerated Vilsmeier–Haack reactions to efficient relay syntheses of the polycitone and storniamide natural products

“…2), which are further elaborated to the desired natural products. Interestingly, the conversion of the 2-carboalkoxy-3,4-diarylpyrroles (11) to the 2,5-dicarboalkoxy-3,4-diaryl-pyrroles (12) has not been utilized presumably due to the surprising lack of reactivity of these 2,3,4-trisubstituted pyrroles (11) at the 5 position with carbon bearing electrophiles. Such a transformation becomes quite significant for the preparation of the 2,3,4,5-tetrasubstituted pyrrole core, which is found in the majority of the natural products that have been previously mentioned.…”

Metal-mediated synthesis of furans and pyrroles

“…11 The reactions were conducted in the presence of 5 mol% AgBF 4 and at room temperature. Not only acetate group but also -OP(O)(OEt) 2 and -OTs group were migrated, however, somewhat high temperature (60 °C) was needed in order to complete the reaction. The reaction involves the intermediacy of allene 21.…”