Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents

Abstract

Tigliane diterpenoids possess exceptionally complex structures comprising common 5/7/6/3-membered ABCD-rings and disparate oxygen functionalities. While tiglianes display a wide range of biological activities, compounds with HIV latencyreversing activity can eliminate viral reservoirs, thereby serving as promising leads for new anti-HIV agents. Herein, we report collective total syntheses of phorbol ( 13) and 11 tiglianes 14−24 with various acylation patterns and oxidation states, and their evaluation as HIV latency-reversing agents. The syntheses were strategically divided into five stages to increase the structural complexity. First, our previously established sequence enabled the expeditious preparation of ABC-tricycle 9 in 15 steps. Second, hydroxylation of 9 and ring-contractive D-ring formation furnished phorbol (13). Third, site-selective attachment of two acyl groups to 13 produced four phorbol diesters 14−17. Fourth, the oxygen functionalities were regio-and stereoselectively installed to yield five tiglianes 18−22. Fifth, further oxidation to the most densely oxygenated acerifolin A (23) and tigilanol tiglate (24) was realized through organizing a 3D shape of the B-ring. Assessment of the HIV latency-reversing activities of the 12 tiglianes revealed seven tiglianes (14−17 and 22−24) with 20-to 300-fold improved efficacy compared with prostratin (12), a representative latency-reversing agent. Therefore, the robust synthetic routes to a variety of tiglianes with promising activities devised in this study provide opportunities for advancing HIV eradication strategies.

Conversion of Phorbol into Des-D-Ring Tricycle and Crotonianoid B via Peroxidation Reaction

“…Subsequent C12-hydroxylation and D-ring formation from 2 led to 1 . We then established synthetic routes from 1 to 11 structurally distinct tiglianes, represented by tigilanol tiglate ( 8 , also known as EBC-46), which exhibits potent anticancer and HIV-latency reversing activities. , The strategically differentiated functional groups of 2 also enabled us to functionalize the C13 and C14 positions of 2 , culminating in the total syntheses of five natural products, including crotophorbolone ( 5 ), resiniferatoxin ( 6 ), and prostratin ( 7 ), in 2021. − Therefore, ABC-ring 2 served as a common intermediate of 17 natural products …”

“…In 2024, we developed a 22-step total synthesis of 1 (Scheme ). The ABC-ring intermediate 2 was designed and prepared from 3-hydroxy-2 H -pyran-2-one ( 3 ) in 12 steps. Subsequent C12-hydroxylation and D-ring formation from 2 led to 1 .…”