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Organic Chemistry Highlights

Total Synthesis

Monday, March 6, 2023
Douglass F. Taber
University of Delaware

The Luo Synthesis of Triptonide

Triptonide (3), isolated from the Chinese herb Tripterygium Wilfordii Hook F, displays reversible male contraceptive effects in both mice and monkeys. A key step in the synthesis of 3 by Tuoping Luo of Peking University was the cyclization of the diene 1 to the aldehyde 2 (J. Am. Chem. Soc. 2022, 144, 2292. DOI: 10.1021/jacs.1c12525).

The convergent assembly of the diene 1 began with commercial 4. Nitration followed by reduction and diazonium salt formation led to the phenol 5. Protection, addition of vinyl magnesium bromide and brominative rearrangement then completed the preparation of the allylic bromide 6.

The construction of the lactone began with the inexpensive diol 7. Johnson-Claisen rearrangement led to racemic 8. Opening with 9 led to the expected 1:1 mixture of diasteromers, from which the desired 10 could be crystallized. Treatment with acid reformed the lactone, that on cross metathesis with the acetal 11 gave the lactone 12. Alkylation with 6 followed by acid hydrolysis then completed the synthesis of 1.

The authors envisioned a free radical cyclization of 1 initiated by hydrogen atom transfer to the styrenic alkene, to give 13. In the event, it took considerable experimentation to define conditions for efficient cyclization to 2.

Deprotection of the phenol of 2 followed by Ti-mediated cyclization delivered the secondary benzylic alcohol with high diastereocontrol. Followed previous syntheses in this series by others, peridoate oxidation then gave the epoxide 14, that could be sequentially epoxidized to 15. Selenation and elimination completed the synthesis of triptonide 3.

The H-atom transfer conditions developed by the authors in the course of this synthesis will have many other applications. They briefly explored some of that scope, and report their findings.

D. F. Taber, Org. Chem. Highlights 2023, March 6.