Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings.

Lei Li,Xin-Yuan Liu,Chao Fang,Xiao-Wu Dong,Na Wang,Zhong-Liang Li,Fu-Li Wang,Yong-Feng Cheng,Zhen Guo,Jingjiang Liu,Bin Tan,Chunhui Hou

doi:10.1038/ncomms13852

Abstract

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8–11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations.

Highlights

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents
No radical-based protocol has been available for the conversion of unactivated alkenes into medium- to large-sized and related bridged ring libraries via aryl migration, especially for access to such chiral skeletons
This strategy was realized through a concerted remote 1,4- or 1,5-aryl migration/ring expansion sequence triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation or perfluoroalkylation of unactivated alkenes (Fig. 1b, path 1)

Summary

Introduction

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Several challenges are associated with the development of this reaction, such as (1) the unfavourable kinetic and/or thermodynamic factors to realize regioselective medium ring formation over other competitive 1,2-difunctionalizations of alkenes with oxygen-based nucleophiles[35,36,37,38], (2) the compatibility between unactivated alkenyl substrates and various radical precursors with different reactivity properties, (3) the identification of mild reaction conditions to achieve high degree of enantiocontrol through remote chirality transfer strategy With this strategy, we report a practical strategy for diversity-oriented synthesis of benzannulated 8-11(14)membered cyclic ketones along with concurrent installation of various functional groups from readily available starting materials. Noteworthy is that many formed benzannulated medium-sized or medium-bridged rings constitute the key synthetic intermediates and unnatural analogues of many important naturally occurring and biologically active molecules such as benzannulated cyclooctanes (antiarrhythmic, antidiarrheal, antiallergic and anti-inflammatory)[4], nonadride family (byssochlamic acid, heveadride, rubratoxin B, glaucanic and glauconic acid with antifungal, antimicrobial and antitumor activities)[5,6], isopavine family (neurological disorders inhibition)[7,8] and colchicine derivatives (anticancer activity)[9] (Fig. 2)

Methods

Results

Conclusion