A stereodivergent strategy for the synthesis of skipped dienes is developed. The method consists of hydroboration of allenes and Migita-Kosugi-Stille coupling, which allows for access to all four possible stereoisomers of the skipped dienes. The hydroboration is especially useful for providing both E-allylic and Z-allylic alcohols from the same allene by simply changing the organoborane reagent. The strategy was successfully applied to a unified total synthesis of the madangamine alkaloids via a common ABCE-tetracyclic intermediate with a (Z,Z)-skipped diene. The late-stage variation of the D-ring enabled the supply of synthetic madangamines A, C, and E for the first time.

While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long-standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N-alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N-alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N-alkoxy group formed a five-membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL-H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter- and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α-trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five- and six-membered lactams, and macrolactams.

The full details of a unified total synthesis of madangamine alkaloids are disclosed. Our central strategy is based on the construction of a common ABCE-tetracyclic system, followed by the late-stage installation of various D-rings. The common intermediate is assembled through N-acyliminium cyclization of a propargylsilane, and formation of the (Z,Z)-skipped diene. Stereoselective synthesis of the (Z,Z)-skipped diene is especially challenging, and is accomplished by the combination of Z-selective hydroboration of the 1,1-disubstituted allene and subsequent Migita-Kosugi-Stille coupling. Macrocyclic alkylation enables the late-stage variation of the D-rings on the common tetracyclic intermediate, resulting in the collective total syntheses of madangamines A–E. The synthetic madangamine alkaloids exhibited inhibitory activities against a variety of human cancer cell lines.

A general synthetic route toward a diazatricyclic core common to the madangamine family is described. Ring-closing metathesis and palladium-catalyzed cycloisomerization provided the cis-fused diazadecalin structure, accompanied by formation of the N-Boc-enamine, which was utilized as an N-acyliminium ion equivalent. Direct cyclization from the N-Boc-enamine was achieved through the in situ formation of an N,O-acetal.

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