Novel Synthetic Methodology

Saturation of carbon or heteroatoms, especially sp3-hybridized and stereogenic atoms in pharmacophore allows the preparation of architecturally more complex molecules for the exploration of more diverse chemical space. While biological activity of small molecule and clinical success are highly correlated with greater complexity of the molecule, the increasing sp3 character of carbon may improve the complexity and therefore increase the opportunity to adjust molecular shape by out-of-plane 3-D interaction of receptor/ligand that are not accessible for a flat aromatic ring, and thus improve potency and selectivity. While aromatic features can provide an opportunity to develop π-π interactions or π-cation interactions, an overall level of saturation may provide the molecule with an opportunity to better place these types of moieties in a 3D environment, which is generally observed in binding pockets of target proteins.

These criteria have also been applied to molecular complexity of natural product-like drug candidates by reducing the aromatic character of a molecule, which might further improve physical characteristics not only for better druggability, but also for better bioavailability. In our lab, we mainly focus on the synthetic logic and strategy for the activation, functionalization and formation of sp3-carbon-carbone single bond.

Carbon-carbon single bonds are among the most abundant and the strongest inert bonds in organic compounds. Activating them for chemical modification is one of the most challenging problems in organic synthesis. Furthermore, the selective activation or cleavage of the terminal vs. internal C-C single bonds of aliphatic chain is still unsolved! In addition, the presence of more active C-H bond is superimposed obstacle for selective activation of C-C bond.

SP3-C-C single bond activation:

SP3-C-C bond formation:

Powerful AlkylZr chemistry:

Transition-metal-catalyzed cross-coupling reactions between naturally abundant sp3-hybridized carbon centers facilitate access to diverse molecules with complex three-dimensional structures. Organometallic compounds are among one of the most powerful reagents that are broadly used in carbon–carbon bond formations. Although sp2-hybridized organometallic compounds are widely employed in cross-couplings, sp3-hybridized organometallic coupling partners are less developed. Herein, we report visible-light-induced single nickel-catalyzed C(sp3)–C(sp3), C(sp3)–C(sp2), and C(sp3)–C(sp) cross-coupling reactions using alkylzirconocenes, which are easily generated in situ from terminal or internal unactivated alkenes through hydrozirconation and chain walking. This method is mild and applicable for a large range of substrates including primary, secondary, tertiary alkyl, aryl, alkenyl, alkynyl halides and a variety of alkenes. Mechanistic studies suggest a novel nickel-catalyzed radical cross-coupling pathway, which represents the first visible-light-induced transformation of alkylzirconocenes.

We made it!

Ongoing more challenging strategies……