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

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 latency-reversing activity can eliminate viral reservoirs, thereby serving as promising leads for new anti-HIV agents. Herein, we report collective total syntheses of phorbol () and 11 tiglianes - 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 in 15 steps. Second, hydroxylation of and ring-contractive D-ring formation furnished phorbol (). Third, site-selective attachment of two acyl groups to produced four phorbol diesters -. Fourth, the oxygen functionalities were regio- and stereoselectively installed to yield five tiglianes -. Fifth, further oxidation to the most densely oxygenated acerifolin A () and tigilanol tiglate () 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 (- and -) with 20- to 300-fold improved efficacy compared with prostratin (), 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.