Studies toward Total Syntheses of Prostratin and Related Diterpenes

Pengfei Li, Guanghu Tong

Frontier Institute of Science and Technology (FIST),

Xi’an Jiaotong University, Xi’an

In recent years, diverted total synthesis of biologically important natural products and their structural analogs has been considered as an effective approach for drug discovery and development based on them. Further applications of this approach need more novel strategic practices.

Tiglianes and daphnanes are two families of complex diterpenes sharing the common [5-7-6] tricyclic skeleton which is peripherally highly oxidized and distinguished by either cyclopropane or orthoester unit on the six-membered ring. Because many of the members exhibit versatile and potent biological activities, the basic skeleton has been viewed as a privileged structure in drug discovery. Prostratin, a representative tigliane, has been under preclinical development as a promising drug to help eradicate latent HIV infection. Resiniferatoxin, a typical daphnane, is an attractive candidate for development of novel analgesic drugs. Furthermore, a derivative of the structurally related ingenane natural product ingenol has been approved for treatment of a precancerous skin disease. Therefore, these natural products have been the important targets in organic synthesis community for more than 30 years, and several beautiful syntheses including the ones of phorbol, ingenol and resiniferatoxin, have been achieved. However, a relatively concise and general synthetic strategy toward many of these molecules is still highly desirable.

We have recently commenced a project to address this interesting problem. In our plan, a potentially general, efficient and flexible strategy, involving rapid construction of the skeleton followed by controlled selective peripheral functionalizations for diverted total synthesis of the two families is proposed. Prostratin has been our first synthetic target because of its relatively simple yet representative enough structure. Model studies have produced molecules of the desired tricyclic skeleton with all correct stereogenic configurations, thus providing the viability of the key steps. We have also studied the rest steps with model structures and useful information with the reactivity on the unique structural framework has been obtained.