Enantioselective synthesis of polycyclic aromatic tetralinyl lignans based on symmetry-directed strategy

Based on a symmetry-guided synthesis strategy, the research group of Professor Yefeng Tang at Tsinghua University recently achieved the efficient construction of the tricyclic core skeleton of polycyclic aromatic tetralin-type lignans by using as key steps the chiral phosphoric acid-catalyzed photoasymmetric [2+2] cycloaddition and ring strain-driven oxidative ring expansion reactions. They also achieved the efficient enantioselective total synthesis of multiple aromatic tetralin-type lignan natural products through subsequent biomimetic cyclization and local desymmetrization reactions. These results were published as an open access article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background:

Lignans are a class of natural products composed of two or more phenylpropanoid units linked in various ways. Lignans can be divided into various structural subtypes based on their linkage patterns. The most common are aryltetralin lignans, characterized by C8–C8′ and C2–C7′ linkage patterns. Aryltetralin lignans and their derivatives exhibit a wide range of biological activities and are considered important sources for new drug discovery and lead compound development. For example, podophyllotoxin is clinically used as an anti-human papillomavirus (HPV) drug, while etoposide, a topoisomerase II inhibitor, is widely used in cancer treatment.

In recent years, researchers have discovered a series of structurally more complex polycyclic aryltetralin-type lignans, including representative molecules such as Ovafolinins A, B, and D, Lirionol, and Gaultheroside G (Figure 1). These molecules not only possess the typical aryltetralin core skeleton but also form novel C–O or C–C bonds between the side chains and the parent nucleus, thereby constructing a highly congested polycyclic system. Due to their remarkable structural complexity and synthetic challenges, these lignans have become an important research target in synthetic chemistry.

Highlights of this article:

Based on an in-depth analysis of the structural characteristics and biosynthetic pathways of polycyclic aryl tetralin-type lignans, Yefeng Tang's research group cleverly exploited the inherent symmetry within the molecules and proposed an innovative synthetic strategy: "Symmetrizing the Unsymmetrical" (Figure 2). This strategy first homodimerizes the phenylpropanoid units via a photoinduced [2+2] cycloaddition reaction to yield a symmetrical diarylcyclobutane intermediate. Next, a ring-strain-driven oxidative ring expansion reaction desymmetrizes the two aryl units, thereby constructing the tricyclic core skeleton of the aryl tetralin-type lignans (17). On this basis, the side chain aromatic group was converted into a diketene structure through oxidative dearomatization/intramolecular cyclization reaction 13 (18); this intermediate was further subjected to local desymmetrization through a diketene-phenol rearrangement reaction involving C–C or C–O bonds, ultimately obtaining two polycyclic aromatic tetralin-type lignans in the form of heterodimers and homodimers, respectively.

To validate the feasibility of this design strategy, the research team first synthesized a series of meso-diarylcyclobutane derivatives and systematically investigated key oxidative ring-expansion reactions (Table 1). The experimental results demonstrated that the target oxidative ring-expansion reactions proceeded smoothly under the action of the hypervalent iodine reagent PIFA. Notably, the reaction exhibited excellent chemoselectivity for both homodimeric and heterodimeric substrates, primarily yielding a single isomer. For heterodimers, chemoselectivity was closely related to the electrical properties of the two aromatic rings (Ar¹ and Ar²), and in some cases, selectivity reversal was observed.

Building on this foundation, the research team employed a chiral phosphoric acid-catalyzed asymmetric [2+2] cycloaddition followed by an oxidative ring expansion reaction as key steps to efficiently construct the key chiral intermediate, (−)-18a , which possesses an aryl tetralin skeleton (Figure 3). Subsequently, through oxidation state adjustment, selective oxidative cyclization, and skeletal rearrangement, the team completed the total synthesis of the natural products ovafolinins A, B, and D, respectively. Furthermore, starting from intermediate (−)-18a, the natural product lirionol was successfully synthesized through a key Friedel-Crafts acylation reaction followed by oxidative modification.

It is worth noting that during the synthesis of the ovafolinins series of molecules, they observed that the expected C–C bond-involved diketone-phenol rearrangement reaction proceeded smoothly, but no C–O bond rearrangement product corresponding to gaultheroside G was detected. It is speculated that the glycoside portion of gaultheroside G may actually be the C–C rearrangement product ovafolinin B, rather than the structure proposed in the original isolation literature. Finally, through total synthesis verification, the research team confirmed that the connection method of the glycoside portion of gaultheroside G is different from the original reported structure (8), and its absolute configuration is opposite, based on which the correct chemical structure of the molecule was proposed (8′′) (Figure 4).

Summary and Outlook:

In summary, the authors developed a novel "symmetry-guided" synthetic strategy, successfully achieving the enantioselective total synthesis of several complex aryl tetralin-type lignans, including ovafolinins A, B, D, lirionol, and gaultheroside G. This strategy efficiently constructs a chiral core skeleton through catalytic asymmetric [2+2] cycloaddition and oxidative ring expansion reactions. Leveraging subsequent biomimetic transformation and locally desymmetric diketene-phenol rearrangement reactions, it enables the precise synthesis of structurally diverse natural products from common intermediates. This study not only provides a universal synthetic route for complex polycyclic lignans but also demonstrates the powerful combination of biomimetic strategies and rationally designed synthetic methods in natural product synthesis research.

This work was independently conducted by Yefeng Tang's research group, with Professor Tang as the corresponding author and doctoral student Yi Chen as the first author. Important contributions were also made by doctoral student Zhenyu Yun, undergraduate graduate Jia Wang, and Truc Quynh Nguyen, a master's exchange student at RWTH Aachen University in Germany. This research was funded by the National Natural Science Foundation of China, the Beijing Natural Science Foundation, the Beijing Center for Advanced Research in Biological Structures, and the RWTH Aachen University-Tsinghua University Young Researcher Scholarship.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.