Total Synthesis

Total Synthesis of Natural product:

Inspired by the rapid and efficient construction of molecular complexity from simple precursors in natural living system by enzymatic pathway, our lab is mainly focused on the biocatalysis development and the utilization of biomimetic synthesis of natural products and biologically valuable small molecules. The utility of biomass-derived building blocks will be demonstrated by the synthesis of a variety of natural products through environmentally friendly organocascade process that involve the formation of several chemical bonds and stereogenic centers simultaneously with excellent stereoselectivity. Structurally complex natural products are naturally produced in microorganisms through a series of elaborate biological pathways, so its biomimetic synthesis will be incorporated with organocascade transformations in the lab.(“天然产物合成之道在于道法自然”!)

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 total synthesis of sp3-carbon enriched natural product through sp2 to sp3 carbon skeleton transfer strategy and exampled by successful total synthesis of alkaloids with a variety of bioactivities.

In most cases, however, little is known about the exact mechanism by which these natural products produce the observed bioactivity. Thus, mode of action studies is required to reveal the protein target(s) of each natural product. Nature continually presents compounds that do not function through known mechanisms/pathways. These studies serve to illustrate the role that natural products have and will continue to play in mapping important biochemical networks and identification of novel therapeutic strategies.

Our Targets, Ongoing…..