Molecular Editing of Pyrroles via a Skeletal Recasting Strategy

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.

Rational Molecular Editing: A New Paradigm in Drug Discovery

“…In the research on the cholesterol-lowering drug atorvastatin (Lipitor), converting disubstituted pyrroles to fully substituted pyrroles led to >30-fold improvement of the inhibitory activity (Figure a). In 2023, Zhou and co-workers reported a one-pot protocol to transform the simple pyrroles into fully substituted pyrroles using azoalkene as the molecular perturbator via a dearomative deconstruction and rearomative reconstruction process (Figure b) …”

Copper-catalyzed atroposelective synthesis of C–O axially chiral compounds enabled by chiral 1,8-naphthyridine based ligands

“…At the outset, we envision that a catalytic system consisting of copper and chiral 1,8-naphthyridine-based ligands, 14 which were not used in asymmetric catalysis to the best of our knowledge (Scheme 1c), may yield an efficient catalytic system that is broadly applicable to asymmetric CuAAC reactions. As part of our continuous interest in axial chirality, 15 herein we report a copper-catalyzed asymmetric CuAAC reaction for the atroposelective synthesis of C–O axially chiral diaryl ethers through the employment of chiral 1,8-naphthyridine based ligands (Scheme 1d).…”

Dearomative spiroannulation of indoles enabled by the diaza-[1,2]-Wittig rearrangement

“…Skeletal rearrangement enables rapid molecular editing to synthesize sophisticated products, making it a powerful method for organic synthesis. 39–45 The [1,2]-Wittig rearrangement is a classic example, where ethers take part in a rearrangement to give their corresponding alcohols via O-to-C [1,2]-alkyl migration (Scheme 2A). 46,47 However, harsh reaction conditions and many competing pathways limit its synthetic utility.…”