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Concise total syntheses of (–)-jorunnamycin A and (–)-jorumycin enabled by asymmetric catalysis

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Science  18 Jan 2019:
Vol. 363, Issue 6424, pp. 270-275
DOI: 10.1126/science.aav3421

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Journey to jorumycin

Jorumycin is a structurally complex, pentacyclic organic compound produced by a marine mollusk. The success of a similar compound, trabectedin, in treating certain types of cancer has focused attention on exploring jorumycin's pharmaceutical properties. Welin et al. developed a succinct route to synthesizing jorumycin and the closely related jorunnamycin A that deliberately diverges from the putative biosynthetic pathway underlying prior chemical syntheses. This route, which hinges on a carefully optimized asymmetric catalytic hydrogenation, can be easily modified to introduce unnatural structural diversity for functional optimization in further drug discovery research.

Science, this issue p. 270

Abstract

The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong Gram-positive and Gram-negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet–Spengler reaction, that mimics their biosynthetic pathways. Herein, we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of nonnatural analogs.

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