DaiResearch
Group

Research

Acknowledgement

We thank NIH (R35, T32, and P30), NSF CAREER, Keck Foundation, Eli Lilly, Amgen, ACS PRF (DNI), American Cancer Society, Showalter Research Trust, ORAU Powe Jr. Faculty Enhancement Awards, Purdue Research Foundation, H.C. Brown Foundation, Purdue Center for Cancer Research (PCCR), Purdue Institute for Drug Discovery (PIDD), and Purdue University for generously supporting our research!

The goal of our research program is to innovate in both the strategy and methodology of organic synthesis, and apply them to solve problems of biological and medical importance and ultimately impact human health.

We work on both natural and unnatural molecules with particular potential for the treatment of cancer, CNS disorders and infectious diseases. We view the completion of a synthesis as the beginning of a larger and deeper scholarly inquiry. It would enable us to profile the biology of the selected natural products and rationally designed small molecules, decipher their mechanism of actions, and optimize the lead compounds into biological probe and novel therapeutics development. We also use our new synthetic methodologies to create novel, diverse, complex and bio-functional small-molecule libraries in order to target new disease targets, particularly those important, but “undruggable” ones, such as protein-protein interactions and transcription factors.

Our research program involves the fields of organic synthesis, chemical biology, and drug discovery.

Total Synthesis via Catalytic Carbonylation

One major focus in our lab is to develop palladium-catalyzed carbonylation methodologies and strategies to streamline the synthesis of complex bioactive natural products, particularly macrolides and spirocyclic natural products. We use cheap and abundant carbon monoxide as a one-carbon linchpin to stitch relatively simple starting materials into complex structures such as bridged/fused macrolactones and spirocyclic lactones with the aid of palladium catalyst. In the tandem process, highly reactive acyl-palladium species were generated and trapped in situ to form the desired lactone in one step. Therefore, no carboxylate synthesis is necessary and the related protection/deprotection as well as activation are avoided.

Carbonylation-Summary.png

Divergent Total Synthesis via Funtional Group Pairing Strategy

We have been practicing a functional group pairing (FGP) strategy for divergent total synthesis of bioactive natural products and analogs. The central notion of the FGP strategy is to quickly synthesize a pivotal intermediate with requisite functional groups and tune these functional groups into different reaction modes to build diverse structural skeletons which would serve as platforms for the synthesis of the selected natural products and a focused small-molecule library to explore the related chemical space and improve the target molecules’ function. We have successfully used this strategy to complete divergent syntheses of a family of important lyconadin alkaloids with potent neurotrophic activity and a family of novel terpene indole alkaloids (TIA) with potent anticancer activity.

FGP strategy

Polycyclic Diterpene Synthesis via Tandem Gold Catalysis

Polycyclic diterpenes such as the daphnane/rhamnofolane/tigliane diterpenes have demonstrated a broad range of biological activities, including anticancer, antiviral, analgesic and neurotrophic effects. They are promising lead compounds in the drug discovery pipeline. However, their structural complexity, natural scarcity, and unelucidated biosynthesis and mode of actions have significantly hampered their biomedical development. In order to unleash their full therapeutic potential, we recently initiated a function-driven total synthesis program toward these complex bioactive natural products and their analogs. So far, we have developed a gold-catalyzed tandem furan formation and furan-allene [4+3] cycloaddition to facilitate the total syntheses of the reported structures of two rhamnofolane diterpenes curcusones I and J. Our syntheses revealed that the originally proposed structures of both curcusones I and J were incorrect and need revision. We also established a synthetic approach toward the polycyclic core of the daphnane diterpenes such as kirkinine and synaptolepis factor K7.

Diterpene syntheses

Cyclopropanol Ring-Opening Cross Couplings

Alkyl cross couplings play important roles in medicinal chemistry, natural product synthesis, and other related areas. Most of the commonly used alkyl nucleophiles in alkyl cross-coupling processes are alkyl Grignard reagents, alkyl zinc reagents, and alkyl boron reagents. Some of these reagents suffer from poor functional group compatibility, have to be generated in situ or right before use, and are not stable for long-term storage. Stained cyclic alcohols such as cyclopropanols are prone to ring opening reactions and could be viewed as potential alkyl nucleophiles for cross coupling reactions. We have developed novel Cu-catalyzed and Mn-mediated cyclopropanol ring opening cross-coupling reactions to introduce various groups such as CF3, SCF3, amino, (fluoro)alkyl, and heteroaryl groups at the beta-position of ketones. We have also developed a novel palladium-catalyzed carbonylative spirolactonization of hydroxycyclopropanols to facilitate oxaspirolactone-containing natural product synthesis.

Cyclopropanol ring-opening cross couplings

Amphoteric Diamination to N-Heterocycles

Saturated N-heterocycles including piperidine, piperazine, 1,4-diazepane, 1,4-diazocane, and related macrocyclic compounds are privileged scaffolds in medicinal chemistry and exist in over 150 life-saving drug molecules. However, there is a significant lack of substitution diversity on the carbon atoms of these heterocycles due to the limitations of the existing synthetic methodologies. My group is actively addressing this gap. We have developed conceptually novel and practical amphoteric diamination methodologies to provide new avenues toward these medicinally important, but otherwise difficult to access structures.

Amphoteric diamination

Medicinal Chemistry and Chemical Biology

In collaboration with Professor Ji-Xin Cheng's group, we have been designing and developing new probe molecules with Raman tags for real time live cell and in vivo imaging using Stimulated Raman Scattering (SRS) Microscopy.

Raman tags and probe molecules for live cell and in vivo imaging

We have also been collaborating with a few other research groups to advance new lead molecules for the treatment of infectious disease, cancer, and neurological disorders. For examples: with the Seleem group, we have identified a series of aryl isonitrile compounds as potent and novel antibacterial and antifungal leads (Eur. J. Med. Chem. 2015, 101, 384; Bioorg. Med. Chem. 2017, 25, 2926; Bioorg. Med. Chem. 2019, 27,1845); in collaboration with the Watts group, potent and selective AC1 inhibitors have been identified for chronic pain treatment (Org. Lett. 2015, 17, 892; Science Signaling, 2017, 10, eaah5381).