Jiping Hao1, Xueying Guo2, Shijun He1,3, Zhongliang Xu1,3, Lu Chen1,3, Zhongyu Li1, Bichao Song1,3, Jianping Zuo1,3, Zhenyang Lin4, Weibo Yang5,6,7. 1. Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China. 2. Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China. 3. University of Chinese Academy of Sciences, Beijing, China. 4. Department of Chemistry, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China. chzlin@ust.hk. 5. Chinese Academy of Sciences Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China. yweibo@simm.ac.cn. 6. University of Chinese Academy of Sciences, Beijing, China. yweibo@simm.ac.cn. 7. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. yweibo@simm.ac.cn.
Abstract
Biomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we synthesize diverse alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketones carbene precursors. DFT calculations demonstrate that a formal 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams show significant anti-inflammatory activities against TNF-α, IL-6, and IL-1β and the cytotoxicity is comparable to Dexamethasone.
Biomimetic modularization and function-oriented synthesis of structurally diversified natural product-like macrocycles in a step-economical fashion is highly desirable. Inspired by marine furanocembranoids, herein, we synthesize diverse n class="Chemical">alkenes substituted furan-embedded macrolactams via a modular biomimetic assembly strategy. The success of this assembly is the development of crucial Pd-catalyzed carbene coupling between ene-yne-ketones as donor/donor carbene precursors and unactivated Csp3‒H bonds which represents a great challenge in organic synthesis. Notably, this method not only obviates the use of unstable, explosive, and toxic diazo compounds, but also can be amenable to allenyl ketonescarbene precursors. DFT calculations demonstrate that a formal 1,4-Pd shift could be involved in the mechanism. Moreover, the collected furanocembranoids-like macrolactams show significant anti-inflammatory activities against TNF-α, IL-6, and IL-1β and the cytotoxicity is comparable to Dexamethasone.
Authors: Henning S G Beckmann; Feilin Nie; Caroline E Hagerman; Henrik Johansson; Yaw Sing Tan; David Wilcke; David R Spring Journal: Nat Chem Date: 2013-08-25 Impact factor: 24.427