Research Projects

Expeditious strategies for the rapid generation of molecular complexity are of very high value in organic synthesis due to their relevance in creating complex heterocyclic molecules enriched with C(sp3) atoms. Dearomatization reactions of flat aromatic and heteroaromatic compounds into fully or partially saturated carbo- or heterocyclic systems figure amongst the most promising strategies for rapid assembly of molecular complexity and diversity. However, most dearomatization methods currently focus on single dearomatization reactions. In contrast, there are only a handful of methods available that have utilized double dearomatization of a pair of tethered aromatic/heteroaromatic rings either in a one-pot process or in two separate steps, despite its potential to offer concise routes to the intricate cyclic frameworks found in natural and bioactive compounds. Meanwhile, fused- and spirocyclic indolines featuring a C3 all-carbon quaternary stereocenter have a high 3D character and are encountered in numerous bioactive natural products, pharmaceuticals, and synthetic compounds. Consequently, there has been continuing demand for accessing indolines, driving significant research into their synthesis, with indole-ring dearomatization being a prominent approach. In the past six years, we have been engaged in the synthesis of diverse indoline and indolenine derivatives using dearomative indole C3 alkylation as the key step. We speculated the synthetic utility of dearomative indole C3 alkylation could be further broadened by merging this process with the simultaneous or stepwise dearomatization of another arene/heteroarene ring. Along this line, this research proposal exclusively focuses on the synthesis of indolines with multiple stereocenters and fused/spiro ring systems via double dearomatization of indole-tethered aromatic/heteroaromatic systems like phenols, naphthols, indoles, and pyridines. Conceptually, this approach is appealing because it offers tremendous flexibility in tethering indoles with other electron-rich or electron-deficient arenes/heteroarenes, enables intramolecular reactivity, facilitates conformational preorganization, enhances the possibility of selectivity control through linker design and opens opportunities for reaction cascade development. The proposal is based on several exciting approaches. One strategy involves regioselective electrophilic dearomatization of indoles, which then initiates a tandem dearomatization of a C3-tethered phenol, naphthol, or indole scaffold. A second approach also begins with electrophilic dearomatization of indoles, but the subsequent step is pyridine dearomatization, facilitated by the nucleophilic attack of the pyridine nitrogen on the C2 of the resulting indolenines. Our third strategy focuses on activating the pyridine/quinoline ring to promote tandem nucleophilic capture by a tethered indole moiety. We also propose a sequential double dearomatization reaction for indole–pyridine pairs, where the pyridine is dearomatized in a distinct first step, followed by the indole dearomatization. Additionally, a few sequential double dearomatization reactions in intermolecular versions are proposed. In the last two approaches, even though there are two separate dearomatization steps, the overall process still constitutes a "double dearomatization." All the proposed compounds will be accessed with a variety of substitution patterns and, where appropriate, in both racemic and enantiopure forms. However, the core hurdle will lie in gaining exquisite control over regio-, diastereo-, and enantioselectivity. Overcoming this will allow us to synthesize exceptionally complex, densely functionalized polycyclic and spirocyclic frameworks that would be challenging to synthesize through other methods. The designed molecules are expected to have a broad impact on several areas, from basic synthetic organic chemistry research to chemical biology and drug discovery efforts.