RESEARCH

Our group has made significant strides in synthesizing complex and biologically active natural products and their derivatives through innovative strategies and the discovery of new chemical methodologies. Documented in 247 publications, our research merges expertise in target-oriented synthesis with an increasing emphasis on biological and drug discovery applications. Additionally, we have published six review articles (Nat. Prod. Rep. 2014, 31, 489–503, Chem. Rec. 2014, 14, 606–622, Synthesis 2014, 46, 2007–2023, Nat. Prod. Rep. 2015, 32, 1584–1601, Eur. J. Org. Chem. 2016, 2356–2368, and Chem. Eur. J. 2024, 30, e20230437) and two comprehensive accounts that focus on our contributions to the synthesis of terpenes and meroterpenes (see: Acc. Chem. Res. 2019, 52, 480-491 and Acc. Chem. Res. 2021, 54, 556−568). Figure 1 showcases representative structures of the compounds synthesized by our group.

 

Figure 1: Total synthesis of natural products (2010–2024).

uApplication of Photosynthesis in the Synthesis of Biologically Important Natural Products:

Since the beginning of this century, photochemical reactions have emerged as powerful tools for synthesizing complex molecules. Utilizing visible light as a driving force for chemical transformations generally provides a more environmentally friendly alternative to traditional synthetic methods. Recently, our group has concentrated on employing photosynthesis as a key step in the synthesis of biologically significant natural products. Typical contributions are detailed below:

1: Total synthesis of Meroterpenoid Scaffolds: We explored various strategies to construct diverse, sterically congested meroterpenoids from a p-benzoquinone via Norrish-Yang photocyclization (2a, Figure 1, Angew. Chem. Int. Ed. 2024, e202415249). This study represents first use of Norrish-Yang photocyclization of quinones for the total synthesis of complex natural products through the formation of a C–C bond.

2: Semi-synthesis of Abeo-steroid Bufospirostenin A: A photosantonin rearrangement reaction catalyzed by Co(salen) was utilized to achieve regioselective double-bond isomerization for the synthesis of bufospirostenin A (2b, Figure 1, JACS 2022, 144, 2479).

3: Total Synthesis of (+)-Cyclobutastellettolide B: We attained regio- and stereoselective Norrish−Yang intramolecular cyclization to establish the congested motif containing three vicinal quaternary centers in cyclobutastellettolide B (2c, Figure 1, JACS, 2021, 143, 18287).

4: Total Synthesis of (+)-Haperforin G: We expanded the capabilities of visible light-mediated photocatalysis for the convergent and asymmetric cross-coupling of an iodide-derived unstabilized C(sp3)-radical with an enone (2d, Figure 1, JACS, 2020, 142, 19487). Notably, this synthesis was featured on the cover of "Organic Synthesis – State of the Art 2020–2021," edited by Dr. D. F. Taber.

5: Total Synthesis of (+)-Waihoensene: We completed a 15-step asymmetric total synthesis of (+)-waihoensene, a challenging compound with a highly congested tetracyclic core containing four contiguous all-carbon quaternary carbon atoms. Key steps included the Pauson-Khand reaction and hydrogen-atom transfer for the stereoselective installation of the C9 stereogenic center (2e, Figure 1, JACS 2020, 142, 6511).

 

Figure 2: Application of photosynthesis to synthesize biologically active natural products.

uDevelopment of Novel Types of Pauson-Khand (PK) Reactions and Exo-selective Diels–Alder Reactions:

Our group has also developed synthetic strategies to access biologically active complex natural products while searching for methods to enhance the efficiency of Pauson-Khand (PK) reactions. We identified Co₂(CO)₈/tetramethyl thiourea (TMTU) as a new catalyst that facilitates PK reactions under balloon pressure of CO at 70 °C (3a, Figure 3) (Org. Lett. 2005, 7, 593−595). Furthermore, we explored the first Pd-catalyzed PK reaction (3b, Figure 3). The application of these PK reactions as key steps has enabled us to achieve the total synthesis of a range of complex natural products (3c, Figure 3) (Eur. J. Org. Chem. 2016, 2356−2368; Acc. Chem. Res. 2021, 54, 556−568), as well as by other groups (Synthesis 2014, 46, 2007−2023).

Figure 3: Navigating the Pauson−Khand reaction in the total syntheses of complex natural products.

Recently, our group serendipitously isolated bispyrrolidine diboronate (BPDB) species from the reaction of prolinol with boronic acid (4a, Figure 3), This compound catalyzed a highly enantioselective catalytic system for the exo-Diels–Alder reaction (4b, Figure 3) upon activation by various Lewis or Br➢nsted acids (4c, Figure 3), forming a complex between BPDB and Lewis acid, along with the dienophile (4d, Figure 3). This work was published in ACIE (2023, 62, e202303075), leading to an invitation for our group to write a review article on the exo-Diels–Alder reaction (Chem. Eur. J. 2024, 30, e20230437). The developed chemistry has allowed us to create novel synthetic methodologies for the total synthesis of complex natural products via the exo-Diels–Alder reaction as a key element.

 

Figure 4: Highly stereoselective Diels–Alder reactions catalyzed by the BPDB.

uMedicinal Chemistry of Natural Products:

In addition to our total synthesis research, our group has continued and accelerated collaborative programs with drug discovery companies under the auspices of the State Key Laboratory of Chemical Oncogenomics at Peking University Shenzhen Graduate School. We have collaborated with Pfizer Inc. and the Shenzhen Bay Laboratory to design a new strategy for developing “non-immunosuppressive” cyclosporine as an anti-inflammatory drug (5a, Figure 5). In this initiative, we developed a novel and concise semi-synthesis of CRV431 (a potential drug candidate for metabolic dysfunction-associated fatty liver disease, MAFLD) in four steps, achieving a total yield of 35% from cyclosporine (see OL 2021, 23, 3421). Our group also extended this “non-immunosuppressive” strategy by targeting extracellular cyclophilin A, resulting in the synthesis of a novel non-immunosuppressive cyclosporine derivative, 4MCsA (5a, Figure 5). This derivative covalently binds to albumin, forming an albumin-binding cyclosporine A, which inhibits chemotactic activity and inflammation by targeting extracellular Cyclophilin A (CypA) without inducing immunosuppressive effects or cellular toxicity (ChemMedChem, 2021, 16, 3649).

 

Figure 5: Natural product-based drug discovery.

During the COVID-19 pandemic, our group also investigated potential antiviral compounds and isolated (–)-anisomelic acid from the traditional Chinese medicine of Anisomeles indica (L.) Kuntze (Labiatae) in 2020. (–)-Anisomelic acid effectively inhibited COVID-19 replication and viral-induced cytopathic effects, with EC₅₀ values of 1.1 and 4.3 μM, respectively. Challenge studies in SARS-CoV-2-infected K18-hACE2 mice demonstrated that oral administration of anisomelic acid and subcutaneous dosing of remdesivir reduced viral titers in lung tissue comparably. To facilitate drug discovery, our group developed an enantioselective semi-synthesis of (–)-anisomelic acid from the naturally enriched and commercially available starting material (+)-costunolide in five steps with an overall yield of 27%, providing (–)-anisomelic acid at a kilogram-scale. Recently, in collaboration with the prestigious Henan Pingyuan Laboratory in China, we developed a potent, orally bioavailable (–)-anisomelic acid-derived antiviral agent against hand, foot, and mouth disease (HFMD), achieving potencies of EC₅₀ = 314 nM and CC₅₀ = 393 M. Currently, no effective drug exists for treating HFMD. During this research, our group also began exploring AI-assisted proteomics for target identification, which is currently underway in our lab.