Molecular Editing of Pyrroles via a Skeletal Recasting Strategy

Xueting Zhou; Qingqin Huang; Jiami Guo; Lei Dai; Yixin Lu

doi:10.1021/acscentsci.3c00812

Molecular Editing of Pyrroles via a Skeletal Recasting Strategy

ACS Cent Sci. 2023 Aug 15;9(9):1758-1767. doi: 10.1021/acscentsci.3c00812. eCollection 2023 Sep 27.

Authors

Xueting Zhou^{1

2}, Qingqin Huang^{1

2}, Jiami Guo^{1

2}, Lei Dai², Yixin Lu^{1

2}

Affiliations

¹ Joint School of National University of Singapore and Tianjin University, International Campus of Tianjin University, Binhai New City, Fuzhou, Fujian 350207, China.
² Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore.

Abstract

Heterocyclic scaffolds are commonly found in numerous biologically active molecules, therapeutic agents, and agrochemicals. To probe chemical space around heterocycles, many powerful molecular editing strategies have been devised. Versatile C-H functionalization strategies allow for peripheral modifications of heterocyclic motifs, often being specific and taking place at multiple sites. The past few years have seen the quick emergence of exciting "single-atom skeletal editing" strategies, through one-atom deletion or addition, enabling ring contraction/expansion and structural diversification, as well as scaffold hopping. The construction of heterocycles via deconstruction of simple heterocycles is unknown. Herein, we disclose a new molecular editing method which we name the skeletal recasting strategy. Specifically, by tapping on the 1,3-dipolar property of azoalkenes, we recast simple pyrroles to fully substituted pyrroles, through a simple phosphoric acid-promoted one-pot reaction consisting of dearomative deconstruction and rearomative reconstruction steps. The reaction allows for easy access to synthetically challenging tetra-substituted pyrroles which are otherwise difficult to synthesize. Furthermore, we construct N-N axial chirality on our pyrrole products, as well as accomplish a facile synthesis of the anticancer drug, Sutent. The potential application of this method to other heterocycles has also been demonstrated.