4.8 Article

Unified Total Syntheses of Rhamnofolane, Tigliane, and Daphnane Diterpenoids

Journal

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 143, Issue 31, Pages 12387-12396

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/jacs.1c06450

Keywords

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Funding

  1. JSPS [JP17H06110, JP17H06452, JP19K15554, JP18H04384, JP18J22552]
  2. Nanotechnology Platform of MEXT [JP12024046]

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Rhamnofolane, tigliane, and daphnane diterpenoids are structurally complex natural products with multiple oxygen functionalities, and a new synthetic strategy was developed for the total syntheses of five representative members of these families. This unified synthetic route required only 16-20 total steps, demonstrating exceptional efficiency.
Rhamnofolane, tigliane, and daphnane diterpenoids are structurally complex natural products with multiple oxygen functionalities, making them synthetically challenging. While these diterpenoids share a 5/7/6-trans-fused ring system (ABC-ring), the three-carbon substitutions at the C13- and C14-positions on the C-ring and appending oxygen functional groups differ among them, accounting for the disparate biological activities of these natural products. Here, we developed a new, unified strategy for expeditious total syntheses of five representative members of these three families, crotophorbolone (1), langduin A (2), prostratin (3), resiniferatoxin (4), and tinyatoxin (5). Retrosynthetically, 1-5 were simplified into their common ABC-ring 6 by detaching the three-carbon units and the oxygen-appended groups. Intermediate 6 with six stereocenters was assembled from four achiral fragments in 12 steps by integrating three powerful transformations, as follows: (i) asymmetric Diels-Alder reaction to induce formation of the C-ring; (ii) pi-allyl Stille coupling reaction to set the trisubstituted E-olefin of the B-ring; and (iii) Eu(fod)(3)-promoted 7-endo cyclization of the B-ring via the generation of a bridgehead radical. Then 6 was diversified into 1-5 by selective installation of the different functional groups. Attachment of the C14-beta-isopropenyl and isopropyl groups led to 1 and 2, respectively, while oxidative acetoxylation and C13,14-beta-dimethylcyclopropane formation gave rise to 3. Finally, formation of an a-oriented caged orthoester by C13-stereochemical inversion and esterification with two different homovanillic acids delivered 4 and 5 with a C13-beta-isopropenyl group. This unified synthetic route to 1-5 required only 16-20 total steps, demonstrating the exceptional efficiency of the present strategy.

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