Unified Biomimetic Approach to (+)-Hippolachnin A: In-Depth Insights into Its Biosynthetic Origin.

A formal biomimetic synthesis of (+)-hippolachnin A has been achieved under the guidance of its plausible biosynthetic pathway. Pivotal transformations include an intriguing O-mediated [4 + 2] cycloaddition and a tandem Kornblum-DeLaMare rearrangement/hemiketalization/dehydration reaction. The current work not only offers a unified approach to access skeletally diverse plakortin-type polyketides but also provides convincing evidence to elucidate their underlying biosynthetic network.

Recent advances in the synthesis of plakortin-type polyketides.

Plakortin-type polyketides represent a growing family of sponge-derived marine natural products that display notable structural and biological diversity. In particular, a series of polycyclic plakortin polyketides, namely hippolachnin A and gracilioethers, have been identified in recent years, which attract immense interest from the synthetic community owing to their unique molecular architectures and promising biomedical potential. A number of elegant total syntheses of these targets and some synthetic studies have been performed through either bio-inspired or rationally designed strategies.

Enantioselective Total Syntheses of (+)-Hippolachnin A, (+)-Gracilioether A, (-)-Gracilioether E, and (-)-Gracilioether F.

The Plakortin polyketides represent a structurally and biologically fascinating class of marine natural products. Herein, we report a unified strategy that enables the divergent syntheses of various Plakortin polyketides with high step-economy and overall efficiency. As proof-of-concept cases, the enantioselective total syntheses of (+)-hippolachnin A, (+)-gracilioether A, (-)-gracilioether E, and (-)-gracilioether F have been accomplished based on a series of bio-inspired, rationally designed, or serendipitously discovered transformations, which include (1) an organocatalytic asymmetric 1,4-conjugate addition to assemble the common chiral γ-butenolide intermediate enroute to all of the aforementioned targets, (2) a challenging biomimetic [2+2] photocycloaddition to forge the oxacyclobutapentalene core of (+)-hippolachnin A, (3) a [2+2] photocycloaddition followed by one-pot oxidative cleavage of methyl ether/Baeyer-Villiger rearrangement to access (-)-gracilioether F, and (4) an unprecedented hydrogen-atom-transfer-triggered oxygenation of vinylcyclobutane to afford (+)-gracilioether A and (-)-gracilioether E in one pot.

Total synthesis and preliminary SAR study of (±)-merochlorins A and B.

A modular synthesis of merochlorins A and B, two naturally occurring antibiotics, has been achieved concisely from readily available building blocks in 4-6 steps. The key steps include the bio-inspired tandem phenol oxidative dearomatization/[5 + 2] and [3 + 2] cycloadditions to construct the tricyclic cores of the targets, and the intermolecular Diels-Alder reaction followed by dehydrogenative aromatization to assemble the remaining aromatic units. The antibacterial activities of merochlorins A, B and some advanced synthetic intermediates were also evaluated, which provided valuable information on the structure-activity relationship (SAR) of this class of new antibiotics.