Total Syntheses of Phorbol and 11 Tigliane Diterpenoids and Their Evaluation as HIV Latency-Reversing Agents
Ayumu Watanabe, Masanori Nagatomo, Akira Hirose, Yuto Hikone, Naoki Kishimoto, Satoshi Miura, Tae Yasutake, Towa Abe, Shogo Misumi, Masayuki Inoue
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 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 ( 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.