Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, June 7, 2021
Douglass F. Taber
University of Delaware

The Chen/Yang Synthesis of Haperforin G

Haperforin G (4), isolated from the Southeast Asia liana Harrisonia perforata, is a potent inhibitor of human 11β-hydroxysteroid dehydrogenase type 1. Jia-Hua Chen and Zhen Yang of Peking University envisioned assembling 4 by the late-stage reductive addition of 2 to 1 to give 3 (J. Am. Chem. Soc. 2020, 142, 19487. DOI: 10.1021/jacs.0c10122).

The preparation of the iodide 2 began with the aldehyde 5. Addition of 6 following the Nugent protocol led to 7 in high ee. This was cyclized to 8 by oxidative coupling with t-butyl vinyl ether followed by exposure to a Pd catalyst. Further oxidation with Jones reagent then completed the assembly of 2.

The enone 1 was constructed convergently, starting, following the Paton procedure, with commercial (S)-glycidol 9. Silylation led to 10, that was carried on to the allylic alcohol 11.

The other starting material for 1 was the acid 12. Enantioselective alkylation using a stoichiometric quantity of an enantiomerically-pure tetraamine delivered 14 in high ee. Coupling with 11 followed by ring-closing metathesis led to the lactone 15, that was carried on to the diol 16. Silylation of the alkyne followed by oxidation and methylenation then set the stage for Pauson-Khand cyclization to 18.

The enone 18 was carried on to the epoxide 19. Methylenation required three steps, methylation, then selenylation, then oxidation and elimination of the selenoxide, leading to 1. Many variations of conditions were explored for the reductive addition of 2 to 1. With Bu3SnH, the coupled product with the epoxide intact was isolated. With an Ir catalyst and irradiation using DMF as the solvent, the epoxide was reduced but coupling did not proceed. The best yield of 3 was achieved using 1.5 equivalents of the iodide 2, and DMSO as the solvent.

The cyclization of 3 proceeded on the addition of t-BuOK. The resulting diol was then selectively dehydrated by formation of the cyclic sulfite ester with thionyl chloride followed by β-elimination, to give haperforin G (4).

Massive testing for COVID-19 has underlined the time required for polymerase chain reactions. Hongbin Yan of Brock University reported that under constant temperature conditions, microwave irradiation significantly accelerated such reactions (Tetrahedron Lett. 2019, 60, 151060. DOI: 10.1016/j.tetlet.2019.151060).

We note with sadness the passing of Professor Rodrigo B. Andrade of Temple University, whose work has graced these pages.

D. F. Taber, Org. Chem. Highlights 2021, June 7.