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.

Synthesis of Clionastatins A and B through Enhancement of Chlorination and Oxidation Levels of Testosterone

“…The NMR spectra and optical rotation data of synthetic samples of 3 and 4 agreed with those reported by Gui et al . [ 6 ]…”

“…[ 5 ] In 2021, Gui and co‐workers reported the first total syntheses of clionastatins A and B featuring a regioselective acyl radical conjugate addition and an intramolecular Heck cyclization to establish the tetracyclic scaffold with a cis ‐fused C/D ring system and a diastereoselective olefin dichlorination to install the C1,C2 pseudoequatorial dichloride. [ 6 ] Surprisingly, they found that the diastereomers of 1 and 2 , which contained a cis ‐fused C/D ring system, matched well with the reported spectroscopic data of natural products, including optical rotations and 1 H NMR data. They also corrected the misassignment of 13 C NMR chemical shifts of C3 of clionastatin A and C16 of clionastatin B by Fattorusso et al .…”