Novel biomimetic Schenck-ene/Hock/aldol tandem rearrangement reaction and its application in natural product synthesis and scaffold editing

The Jingjing Wu group at the National Key Laboratory of Synergistic Materials Creation/Frontier Science Center for Transformative Molecules (FSCTM) at Shanghai Jiao Tong University, in collaboration with the Xiaosong Xue group at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, recently reported a novel biomimetic Schenck-ene/Hock/aldol tandem rearrangement reaction mediated by singlet oxygen and its synthetic applications. Using this tandem reaction, they synthesized four natural products, alstoscholarinoid A, masterpenoid D, leontogenin, and marsformoxide B, in a clustered, one- to four-step process from readily available, inexpensive naturally resourced molecules. The mild reaction conditions and high functional group tolerance suggest that this strategy could serve as a novel approach for molecular backbone editing of natural products. Computational chemistry studies further revealed the mechanistic details of the rearrangement reaction and the factors that control the different rearrangement pathways of the key intermediate hydroperoxide. This study provides new insights into the synthesis of related natural products and molecular backbone editing and reconstruction 

Background:

Steroidal and terpenoid natural products are mainly divided into different families based on the differences in their core molecular skeletons. These core skeletons are often complex, varied, and differ significantly from each other. Natural product synthetic chemists typically need to design corresponding natural product synthesis strategies for the different core skeletons. Therefore, the collective synthesis of natural products with different molecular skeletons using the same or similar strategies is of great interest to simplify natural product synthesis strategies and improving synthesis efficiency. The natural products alstoscholarinoid A ( 1 ), masterpenoid D ( 2 ), leontogenin ( 3 ) and marsformoxide B ( 4 ) have multiple physiological activities, and these four molecules belong to three different families with obvious differences in core skeleton and oxidation state modification (Figure 1). Recently, the research groups of Jingjing Wu and Xiaosong Xue have developed a new biomimetic Schenck-ene/Hock/aldol tandem rearrangement reaction mediated by singlet oxygen molecules. Not only did they quickly synthesize natural products 1 to 4 through this reaction, but they also deeply explored the potential of this reaction as a new strategy for skeletal editing of natural product molecules.

Highlights of this article:

1. Proposal of the biomimetic Schenck-ene/Hock/aldol tandem rearrangement reaction and the synthesis of alstoscholarinoid A

The authors first studied the biosynthesis of alstoscholarinoid A (1) and designed and synthesized the biomimetic transcyclic aldol reaction substrate 8 based on the biosynthesis hypothesis of 1 (Figure 2A) . However, under various reaction conditions, 8 mainly obtained transcyclic aldol reaction products 9 to 11 through C16 enolization intermediate (Figure 2B). To this end,the authors designed a circuitous synthetic strategy to obtain C19 enolization 12, and after repeated attempts, obtained intermediate13 with the complete carbon skeleton of 1. However,the hydration reaction and deacetylation reaction of 13 to obtain 1 were unsuccessful (Figure 2C) . This shows that the strategy of synthesizing 1 directly through intramolecular transcyclic aldol reaction reached a dead end and needs to be redesigned and optimized.

Given the difficulty of transcyclic aldol reactions in controlling the enolization of the substrate at the C19 position and inspired by the synthesis of clavukerin C by the Pak group ( J. Org. Chem. 1991 ,  56 , 6829-6832), the authors proposed that starting from conjugated diene substrate 14, a Schenck-ene reaction and an acid-catalyzed Hock reaction could provide the C19-enolized intermediate 15, which could then be further subjected to an aldol reaction to generate 1. This strategy is expected to significantly improve the simplicity and efficiency of the synthesis (Figure 3A). Preliminary experiments showed that 14 reacted with singlet oxygen molecules to afford peroxyallyl alcohol 16 , which , in turn, could be converted to 19 (acetylated 1 ) upon reaction with a catalytic amount of protic acid or simply dissolved in deuterated chloroform (typically containing trace amounts of HCl), demonstrating the plausibility of the authors' proposed strategy. Further mechanistic investigations confirmed the stereochemistry of the key intermediate 16 by identifying the structures of intermediates 20 and 21 . Based on the above experimental results, the authors preliminarily believed that the tandem rearrangement reaction was a Schenck-ene/Hock/aldol process, in which the stereochemistry of the key aldol reaction was controlled by the intramolecular hydrogen bond in 18 (Figure 3B). In the extended study, the authors found that the free hydroxyl group in the substrate was not affected by the reaction, so they used the natural product aegiceradienol (23) to optimize the tandem reaction and applied the optimal reaction conditions to the synthesis of 1. Finally, oleanolic acid (5) was used as the raw material to achieve a 100 mg-level unprotected group biomimetic synthesis of 1 through four chemical reactions with a total yield of 44%. Starting from 1, the natural product masterpenoid D was obtained through two steps of reaction (Figure 3C). Based on the above results, the authors also proposed another hypothesis for the biogenic synthesis of 1, namely, the Schenck-ene/Hock/aldol process starting from 23.

2. Biomimetic Schenck-ene/Hock/aldol tandem rearrangement reaction as a new method for backbone editing

Given the increasing importance of molecular scaffold editing strategies in natural product synthesis and structural modification, the authors explored the potential of the Schenck-ene/Hock/aldol tandem rearrangement reaction for scaffold editing. First, they synthesized derivatives of 1, 24b – 27b, demonstrating the mild conditions and high functional group tolerance of this rearrangement (Figure 4A). For tri- and tetrasubstituted olefin substrates, the TPP/CCl₄ system exhibited superior efficiency. In this system, Δ5 - steroidal substrates 28a to 30a can be converted into abeo -5(6→7) products 28b and 29b and the natural product leontogenin (3), respectively, while Δ9,10 - octahydronaphthalene substrates 31a to 33a can also be converted into conjugated unsaturated ketone products 31b to 33b with a bicyclo[5.3.0]decane skeleton, respectively. Among them, 32b and 33b also have a cis- bicyclo [3.3.0] octane skeleton commonly found in natural products (Figure 4B). These results fully demonstrate that the Schenck-ene/Hock/aldol tandem rearrangement reaction is a new type of skeleton editing method. However, studies have shown that not all peroxyallyl alcohols will undergo this tandem rearrangement reaction. For example, β-amyrin acetate 34 obtained by radical allyl C-H bond oxidation 35 failed to undergo the expected tandem rearrangement reaction under protonic acid catalysis, but instead underwent oleanane→taraxastane rearrangement to obtain the natural product marsformoxide B (4, Figure 4C).

3. Computational study of the mechanism of the Schenck-ene/Hock/aldol tandem rearrangement reaction

Although the authors have thoroughly investigated the Schenck-ene/Hock/aldol tandem rearrangement reaction experimentally, mechanistic details remained, such as whether the oxygen-bridged intermediate 17 is plausible, whether the stereochemistry of the aldol reaction is truly governed by intramolecular hydrogen bonding in 18, and what factors control the outcome of peroxy bond migration. To this end, the authors conducted computational studies of the reaction mechanism using density functional theory (DFT). In the reaction 16 → 19 , the authors used p-toluenesulfonic acid (p-TSA) as a catalyst and CH₂Cl₂ and MeOH as solvents. The calculated results showed that the Gibbs free energy barrier for the Hock rearrangement of 16 to 17 (transition state TS-A) is 20.1 kcal/mol, indicating that the rearrangement can proceed at 273 K. In TS-A , p-TSA promotes the cleavage of the peroxy bond and the formation of a new CO bond by forming a hydrogen bond with the hydroxyl group of the peroxy alcohol. In the subsequent reaction, the oxygen bridge group of 17 undergoes fragmentation under the action of p -TSA to produce 18' (energy barrier 7.5 kcal/mol). Finally, 18' undergoes an aldol reaction to produce 19 (energy barrier 7.2 kcal/mol). In TS-B and TS-C , p-TSA promotes the reaction through proton shuttling. The total Gibbs free energy change of the reaction is −61.6 kcal/mol, making it a strongly exothermic process (Figure 5A).

The authors next evaluated the transformation of 35 → 4 using MeSO₃H as a catalyst. Calculations indicate that 35 fails to form any Hock rearrangement intermediates, but instead initially generates the α-epoxycarbenium ion IM-1 via transition state TS-D. The Gibbs free energy barrier for this reaction is 18.1 kcal/mol, indicating that this rearrangement can also proceed at 273 K. The energy barrier for IM-1 to generate the methyl-migrated carbenium IM-2 via transition state TS-E is 5.8 kcal/mol, while the energy barrier for generating the ring-expanded carbenium IM-2', similar to the Hock rearrangement, via transition state TS-E2 is 8.2 kcal/mol. Therefore, IM-1 transforms toIM-2 and ultimately to 4 in the direction of lower energy barrier. The total Gibbs free energy change for the entire reaction is −53.8 kcal/mol (Figure 6A). The authors further explored factors influencing the subsequent transformation pathways of peroxyallyl alcohols by comparing the relative stabilities of carbenium ions A, B, C, and D (Figures 5B and 6B). The authors propose that two primary factors influence the relative energies of these intermediates: epoxy tension and carbocation stability. The tetrasubstituted epoxy group in B (corresponding to17' in Figure 5A ) is located centrally between the two rings and exhibits higher tension than the cis -1,2-disubstituted epoxy group in C. The tertiary carbocation in C is also more stable than the secondary carbocation in B , while the secondary carbocation in A is also more stable than the primary carbocation in D. Therefore, in Figure 5B,B is difficult to form due to its poor stability, while in Figure 6B, C is more easily formed due to its relatively low epoxy tension and relatively stable carbocation. Therefore, TS-A favors the formation of the oxygen-bridged intermediate 17, which then undergoes a Hock/aldol cascade reaction, while the epoxy intermediate IM-1 generated by TS-D kinetically favors the formation of IM-2, which then further generates 4. This explains the different selectivities observed for these two substrates.

Summary and Outlook:

In summary, in their research on the biomimetic synthesis of natural products, the authors critically considered the biogenesis hypothesis to develop a novel biomimetic Schenck-ene/Hock/aldol tandem rearrangement reaction. Based on this reaction, they synthesized four natural products, alstoscholarinoid A, masterpenoid D, leontogenin, and marsformoxide B, in a clustered 1-6-step process from inexpensive and readily available natural molecules. Alstoscholarinoid A was prepared on a 100-milligram scale. Furthermore, this tandem reaction exhibits mild conditions and high functional group tolerance, suggesting its potential as a novel strategy for molecular backbone editing of natural products. The authors further investigated the mechanistic details of the reaction and the structural factors governing different reaction modes through computational chemistry.

Related results were recently published in CCS Chemistry as Communication. Shanghai Jiao Tong University postdoctoral fellow Ruoxi Li is the first author of the paper, responsible for the chemical synthesis. Postdoctoral fellow Tongkun Wang of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, is the co-first author, responsible for the computational studies. Associate Professor Jingjing Wu of the Frontier Science Center for Transformative Molecular Sciences (FSCTM) at Shanghai Jiao Tong University and Researcher Xiaosong Xue of the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, are the corresponding authors. This research was supported by the National Natural Science Foundation of China (Grant No. 22101173) and the Fundamental Research Funds for the Central Universities (Grant No. 24X010301678).

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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/.