Asymmetric Total Synthesis of Clionastatins A and B

Abstract

Herein we report the first total synthesis of polychlorinated steroids clionastatins A and B, which was accomplished asymmetrically by means of a convergent, radical fragment coupling approach. Key features of the synthesis include an Ireland− Claisen rearrangement to introduce the C5 stereocenter (which was ultimately transferred to the C10 quaternary stereocenter of the clionastatins via a traceless stereochemical relay), a regioselective acyl radical conjugate addition to join the two fragments, an intramolecular Heck reaction to install the C10 quaternary stereocenter, and a diastereoselective olefin dichlorination to establish the synthetically challenging pseudoequatorial dichlorides. This work also enabled us to determine that the true structures of clionastatins A and B are in fact C14 epimers of the originally proposed structures.

Marine natural products

“…495,496 Poly-chlorinated steroids clionastatins A 1169 and B 1170 have been produced synthetically for the rst time, leading to their structure revision. 497 A protocol to prioritise anthelmintic samples from the Australian NatureBank marine invertebrate extract collection (7616 extracts) against the barber's pole worm (Haemonchus contortus) has been published. HTS against this nematode resulted in 58 hit extracts (∼0.8%) showing >70% inhibitory activity.…”

Two-Stage Syntheses of Clionastatins A and B

“…In 2014, Tartakoff and Vanderwal reported the synthesis of the A–B–C tricycle of the clionastatins using Diels–Alder cycloaddition . Recently, Gui and co-workers achieved the first total syntheses of 7 and 8 with an acyl radical conjugate addition and an intramolecular Heck cyclization as key transformations . Furthermore, they revised the configuration of the C14 stereocenter of the natural products from ( R ) to ( S ).…”

“…As outlined in Figure B, our synthetic strategy toward 7 and 8 was divided into two stages: a chlorination stage and an oxidation stage. We anticipated that introducing the C19 chloride in the early stage of the synthesis would prevent susceptibility to aromatization of the advanced intermediates bearing a dienone moiety in the A ring or B ring through either rearrangement or retro-aldol fragmentation. , We envisioned that the C1,C2 trans -dichloride could be introduced through desaturation followed by a conformationally controlled dichlorination. To this end, 10 containing a 4,5-epoxycyclohexene A ring was designed as the dichlorination substrate.…”

“…Et 4 NCl 3 (Mioskowski reagent) was used by Vanderwal and Gui as the dichlorination reagent in their studies; however, toxic Cl 2 was inevitable in the preparation of Et 4 NCl 3 . Considering the safety in large-scale synthesis, we chose in situ-prepared Et 4 NCl 3 as the dichlorinating agent.…”

“…Upon sequential treatment with LiCl/Amberlyst 15 and SeO 2 , 27 was converted to clionastatin B ( 8 ) in 16 steps and 1.6% overall yield. The synthetic samples of 7 and 8 exhibited spectroscopic properties identical to those reported for the corresponding natural products. ,, Notably, most of the steps in the synthetic sequence were conducted on gram scales until the late-stage intermediate 21 .…”