Li Chuang-Chuang’s Group Completes First Total Synthesis of Cyclocitrinol

2018-04-05

Recently, Li Chuang-Chuang’s Group from the Department of Chemistry of SUSTech used type II [5+2] cycloaddition, to complete the total synthesis of cyclocitrinol for the first time. Their paper was selected as the cover article for Journal of the American Chemical Society (JACS). Dr. Liu Junyang was the first author of this paper andPh.D. students Wu Jianlei and Fan Jianhong also made great contributions to the paper. Professor Li Chuang-Chuang is the corresponding author while SUSTech is the author’s afiliation.

Steroids continue to play a significant role in synthetic organic chemistry and drug discovery, due to their biological importance and structural diversity,. Isocyclocitrinol , an unusual C25 steroid with a novel structure, was isolated by Crews and Clardy et al. in 2003 from sponge-derived Penicillium citrinum. The structure of cyclocitrinol has been revised from the original incorrectly assigned structure. To date, more than 25 diverse cyclocitrinols have been isolated, some of which have exhibited interesting biological activities. Cyclocitrinol can induce the production of cAMP in GPR12-transfected CHO cells at 10 μM, while isocyclocitrinol has shown antibacterial activity against Staphylococcus epidermidis and Enterococcus durans. However, the relative scarcity of these compounds from natural sources has impeded a more systematic evaluation of their biological activity. Structurally, cyclocitrinol comprises a sterically compact 7/7/6/5 tetracyclic skeleton with a unique bicyclo [4.4.1] undecene A/B ring system (highlighted in red), rather than the common decalin system. In particular, cyclocitrinol possesses a strained bridgehead (anti-Bredt) double bond at C1–C10, as also observed in the well-known natural drug taxol, and eight stereocenters, including two quaternary centers. Therefore, cyclocitrinol presents a formidable synthetic challenge.

The fascinating and synthetically challenging structure combined with potential pharmacological properties has prompted much interest in cyclocitrinols from the synthetic community (several publications and 8 dissertations on studies towards cyclocitrinol). However, the total synthesis of any member of the cyclocitrinol family has yet to be reported.

Recently,Li’s group have achieved the first and asymmetric total synthesis of cyclocitrinol in a linear sequence of 18 steps and 1.0% overall yield from commercially available compound. Notably, the synthetically challenging bicyclo [4.4.1] A/B ring system with a highly strained bridgehead double bond found in cyclocitrinols was synthesized efficiently and diastereoselectively using a type II intramolecular [5 + 2] cycloaddition. A unique chemoselective reductive cleavage of the C–O bond of 8-oxabicyclo [3.2.1] octane was successfully realized using Li–EtNH2. Furthermore, the eight stereocenters of cyclocitrinol were constructed in a facile and diastereoselective fashion. This work will serve as a basis for the asymmetric synthesis of other diverse cyclocitrinols  and their analogs to facilitate further biological research.

 

 

https://pubs.acs.org/doi/10.1021/jacs.8b02629