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.

In addition to innovations in the carbonylation methodology and strategy, our synthesis enabled better understanding of the target molecule’s function. For example, in 2018, we reported an efficient and scalable carbonylation approach to synthesize three Abies Sesquiterpenes: beshanzuenones C and D and abiespiroside A. Structurally, these molecules share a common tricyclic core and feature one or two alpha,beta-unsaturated carbonyl groups (Michael acceptors), which can potentially form a covalent bond with certain cellular proteins. Beshanzuenones C and D were isolated from the critically endangered Abies beshanzuensis fir tree from Zhejiang, China and there are only three such fir trees remain in the entire world. It is impossible to obtain sufficient amount of materials from their natural sources. Our total synthesis offers a sustainable supply of abiespiroside A and beshanzuenones C and D. In collaboration with Professor Zhong-Yin Zhang’s group at Purdue, our total synthesis and analog synthesis led to the identification the first selective covalent inhibitor of the oncogenic protein tyrosine phosphatase SHP2. Furthermore, in collaboration with Professor Alexander Adibekian’s group at the Scripps Research Institute Florida, our mode of action studies via a chemoproteomic approach using an azide-tagged analog revealed DNA polymerase epsilon subunit 3 (POLE3) as one of the novel cellular targets. We also demonstrated for the first time that targeting POLE3 with small molecules may be a novel strategy for chemosensitizing cancer cells to DNA damaging drugs such as etoposide.

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.

Total Synthesis and Biological Study of Polycyclic Diterpenes

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. In 2017, we reported 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.

In 2021, we reported the first total synthesis of curcusones A and B in only 9 steps, C and D in 10 steps, and dimericursone A in 12 steps. The chemical synthesis of dimericursone A from curcusones C and D provided direct evidence to support the proposed Diels-Alder dimerization and cheletropic elimination biosynthetic pathway. We also prepared an alkyne-tagged probe molecule of curcusone D. In collaboration with the Adibekian’s group, BRCA1-associated ATM activator 1 (BRAT1), an important but previously “undruggable” oncoprotein, was identified as a key cellular target via chemoproteomics. We further demonstrate for the first time that BRAT1 can be inhibited by curcusone D, resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown.  

(Hydroxy)Cyclopropanol Ring-Opening Chemistry

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 novel palladium-catalyzed carbonylative lactonization of hydroxycyclopropanols and copper-catalyzed hydroxycyclopropanol ring opening cyclizations to facilitate natural product synthesis and O-heterocycle synthesis.

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.

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. The project was funded by the Keck foundation.

We have also been collaborating with other research groups to advance new lead molecules for the treatment of cancer, infectious disease, and neurological disorders. For examples: with the Hu group at Purdue, we have identified novel inhibitors to target the PRMT5:MEP50 protein-protein interaction (J. Med. Chem. 2022, 65, 13793); with the Seleem group at Virginia Tech, 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; J. Glob. Antimicrob. Res. 2019, 1.); with the Zhang group at Univ. of Toledo, we have created novel inhibitors to target survivin dimeric protein-protein interaction for cancer treatment (J. Med. Chem. 2020, 63, 7243.); with the Watts group at Purdue, potent and selective AC1 inhibitors have been identified for chronic pain treatment (Org. Lett. 2015, 17, 892; Science Signaling, 2017, 10, eaah5381).