Construction of Tetracyclic Core Skeleton of Cephalotaxus Diterpenoids through Diastereoselective Pauson‐Khand Reaction

Abstract

Cephalotaxus diterpenoids represent a class of attractive natural products with diverse chemical structures and valuable biological activities. The Construction of tetracyclic core skeleton plays an important role in synthesizing these compounds. We report here the development of diastereoselective Pauson-Khand reactions as an effective strategy to the core structure, which enabled the total synthesis of (+)-3-deoxyfortalpinoid F, (+)-fortalpinoid A, and (+)-cephinoid H.

Cephalotane diterpenoids: structural diversity, biological activity, biosynthetic proposal, and chemical synthesis

“…27,28 In addition, due to the complex cage-like framework and remarkable bioactivities of cephalotane diterpenoids, they are regarded as excellent targets for total synthesis. The past 30 years have witnessed a multitude of synthetic efforts toward this diterpenoid class, 29–49 leading to a battery of elegant completed total syntheses by the groups of Mander, 50 Tang, 51 Zhai, 52–54 Hu, 55–57 Gao, 58–60 Zhao, 61 Cai, 62 Zhang/Yang, 63 and Sarpong. 64,65…”

Asymmetric Total Synthesis of Cephalotaxus Diterpenoids: Cephinoid P, Cephafortoid A, 14-epi-Cephafortoid A and Fortalpinoids M-N, P

“…The Zhai group disclosed the asymmetric total synthesis of 2 and mannolide C by using a rhodium-catalyzed intramolecular [3 + 2] cycloaddition and double ring closure metathesis to generate the required seven-membered ring, respectively. Recently, Hu and co-workers accomplished the total synthesis of 3-deoxyfortalpinoid F, fortalpinoid A, and cephinoid H ( 4 ) by means of ring-closing metathesis (RCM)/elimination as the key steps . Correspondingly, various efficient strategies have been developed regarding to the total syntheses of the benzenoid cephanolides, without the characteristic cycloheptene ring, by the groups of Zhao, Cai, Yang, Sarpong, , Zhai, and Hu and our group , (Figure B).…”

“…Based on our previous studies, , known vinyl triflate 11 , containing four contiguous stereogenic centers involving a quaternary center, could be prepared in 10 steps from (−)-quinic acid. , Subjection of 11 to Pd-catalyzed hydrogenolysis and direct HCl workup delivered cyclohexene 12 in 88% yield on a large scale. Inspired by Hu and Yang’s pioneer studies, , we realized that a bridging acetal structure with bigger steric hindrance will facilitate the stereogenetic control pattern. Therefore, oxidation of the primary alcohol 12 with Dess–Martin periodinane (DMP) gave an aldehyde, which was directly treated with HCl to remove the cyclic acetal group to form the corresponding diol.…”

“…However, X-ray crystallographic analysis revealed that the configuration at the C1–C10 bond in 29 was opposite to the natural product (Table A). In order to tune and control the stereochemistry of the Pauson-Khand reaction, , we transformed the bridging lactone back to the bulky isopropyl acetal group and obtained 30 in good yield over three steps. Under a N 2 atmosphere, pentacyclic product 32 with desired configuration could be obtained in 21% yield by utilizing NMO at 0 °C (entry 1, Table B).…”