1. Introduction
Natural products exhibit a rich diversity of chemical structures and biological functions
[1],
[2]. Many biologically active natural compounds serve as bridges between chemistry, the life sciences, and medicine (
Fig. 1). Natural products not only provide novel molecules for small-molecule drug development but also inspire new strategies in drug discovery. Important drugs derived from natural sources include morphine, artemisinin, taxol, and many others
[1]. However, one of the challenges in developing natural products into useful medicines is the failure to obtain sufficient quantities of the naturally occurring compounds and their structural analogues to support downstream research, let alone mass production at industrial scale. Another challenge is that natural products are not inexhaustible, and their sustainable supply is often jeopardized due to depletion of natural resources and unpredictable changes in growing environments. To overcome these limitations, scientists from both academia and industry have been endeavoring for centuries to obtain a stable supply of natural products using synthetic approaches
[3],
[4]. Natural product synthesis provides an effective solution to meet such challenges, making it possible to secure an uninterrupted supply of natural products, while preserving biodiversity and natural resources and ensuring sustainable development of the ecological environment.
Natural products can be produced from chemical synthesis or biosynthesis. The chemical synthetic approach involves the rational deconstruction of the target molecule by means of retrosynthetic analysis to guide the design of a synthetic strategy (
Fig. 2)
[5]. Historically, this approach has successfully achieved significant milestones leading to the production of many structurally complex molecules
[6]. However, the field continues to present challenging issues such as the consumption of costly or environmentally unfriendly reagents, the use of harsh or dangerous reaction conditions, difficulty in controlling stereoselectivity, long and tedious synthetic routes, relatively low overall yield, and obstacles in scaling up for industrial production
[7]. On the other hand, the biosynthetic approach represents an interdisciplinary effort in which principles from engineering, chemistry, and biology are integrated to achieve the synthesis of new materials. As far as natural products are concerned, biosynthetic synthesis focuses on manipulating the metabolic pathways and regulatory mechanisms within cells to make the target metabolites (
Fig. 2)
[8]. In recent years, advances in knowledge on biosynthetic pathways and the new development of technologies and tools have become key drivers for new drug discovery. Genome mining and engineering have been crucial in generating new knowledge in the discovery of novel natural products, and manipulations of gene expression and regulation have enabled the biosynthetic production of new natural product analogs. Nevertheless, it should be noted that this approach presents many challenging issues. For example, the biosynthetic generation of natural product analogs has limitations regarding the parts of the molecule that can be modified and the chemical groups that can be introduced or removed. Additionally, the biosynthesis of stereochemically complex compounds is often hindered by low efficiency, unclear mechanisms, and difficulties in pathway optimization.
In the history of natural product synthesis, the synthesis of tropinone by Robinson in 1917 was a milestone marking the dawn of biomimetic synthesis
[9],
[10]. This achievement demonstrated a successful integration of synthetic reactions and biosynthetic transformations, establishing a paradigm for designing a series of chemical processes to parallel biosynthetic pathways. Biomimetic synthesis employs principles from biomimicry, applying inspiration from biogenetic processes to design synthetic strategies that mimic biosynthetic processes (
Fig. 2)
[11]. It is an efficient approach in synthetic chemistry, as it addresses critical challenges in the efficient synthesis of structurally complex natural products with significant biological and medicinal importance
[12],
[13],
[14]. By emulating biosynthetic pathways, this strategy links chemical synthesis and natural biosynthesis, enabling the development of new concepts, strategies, and methods in chemical synthesis. It also advances our understanding of the chemical logic underlying natural product biosynthesis, particularly in complex organisms such as higher plants, while shedding light on evolutionary biosynthetic mechanisms. Beyond its synthetic utility, biomimetic synthesis facilitates the exploration of natural product biology, unlocking the pharmaceutical potential and biological functions of natural products. Consequently, it not only drives innovation in drug discovery but also serves as a cornerstone for advancing the fields of chemistry, biology, pharmacy, and related disciplines. In this perspective article, recent advances and challenges in the biomimetic synthesis of natural products are highlighted, and the significance and prospects of such efforts are outlined.
2. Strategies and advances in the biomimetic synthesis of natural products
The biomimetic synthesis of natural products can be dated back to the late 19th century. In 1891, as an early example of mimicking biosynthetic processes, Claisen and Hori
[15] demonstrated the synthesis of citric acid and aconitic acid through condensation reactions of acetic acid and oxalic acid molecules. In 1907, Collie
[16] suggested that acetic acid was a fundamental synthetic unit on natural polyketides and utilized condensation reactions to synthesize pyranone compounds, laying the foundational principles for modern biosynthetic investigations. However, early research only focused on individual compounds and lacked systematic guiding principles. A significant advancement occurred in 1917, when Robinson synthesized tropinone in a single step using methylamine, butyraldehyde, and calcium acetoacetate through the Mannich reaction, thereby validating biosynthetic hypotheses and highlighting the potential of biomimetic synthesis
[9]. Shortly after, Robinson outlined the biogenetic pathways for alkaloids based on structural features and proposed basic building blocks, thus establishing biomimetic synthesis as a viable concept. In 1953, his group further established the structural relationship between terpenoids and polyketides and provided a solid foundation of the structural characteristics and chemical transformations of natural products
[17]. Since then, biomimetic synthesis has proved itself to be a viable approach for natural product synthesis, and various biomimetic strategies have been developed and applied based on biogenetic reactions, relationships, enzymes, and building blocks (
Fig. 3).
2.1. Biomimetic synthesis strategies based on biogenetic reactions
The biomimetic polyene cyclization strategy represents a fascinating intersection of chemical synthesis and natural product biosynthesis. This approach involves mimicking the biogenetic processes used by organisms to produce complex cyclic structures from polyene precursors via concerted and stereospecific carbon–carbon bond formation. The hypothesis proposed by Stork and Burgstahler
[18], and Eschenmoser’s group
[19] in the 1950s on the stereochemical outcomes of polyene cyclization led to the successful biomimetic synthesis of steroidal compounds. By using this strategy, the stereoselective syntheses of progesterone and dammaranedienol were accomplished
[20],
[21]. These studies not only led to the efficient synthesis of a series of steroids but also had a profound impact on our understanding of stereoselective control and the biosynthesis of steroids and terpenoids. In the field of terpenoid alkaloids, the one-step biomimetic synthesis of dihydro-
proto-daphniphyllines by Heathcock
[22] revealed that iminium-ion-induced polyene cyclization is a powerful and efficient strategy. These findings opened up a new avenue for biosynthetic studies of terpenoid alkaloids and offered a new paradigm for the field of biomimetic synthesis by using cascade reactions. In the last several decades, the applications of polyene cyclization have been expanded, and the efficacy of this biomimetic process has been improved. Novel chiral reagents and catalysts designed for enantioselective and regioselective cyclization reactions have also become available
[23],
[24].
The biomimetic oxidative coupling strategy aims to mimic biogenetic oxidative coupling reactions, in which two or more phenol or indole units are usually joined together through oxidative processes
[25]. For example, physiologically active molecules such as morphine and galantamine have been biosynthesized through the oxidative coupling of phenols, phenoxy ethers, and benzyl ethers. As early as in the 1950s, Barton’s group
[26] summarized the structural characteristics of phenolic compounds and proposed reaction rules for the site selectivity of phenolic aryl radical coupling. This biomimetic strategy has been widely applied in the synthesis of natural phenolic products such as carpanone, resveratrol tetramers, and peshawaraquinone
[27],
[28],
[29], as well as indole alkaloids including voacalgine A, bipleiophylline, and spiroindimicins
[30],
[31].
The biomimetic Diels–Alder (DA) reaction strategy emulates the biogenetic DA cycloaddition process
[32], in which a diene and dienophile react to form a cyclohexene ring, often under mild conditions. These reactions can be catalyzed by metals, acids, or bases, emulating the catalytic environments in nature. For example, Sorensen’s group
[33] hypothesized that the biosynthesis of the polyketide FR182877, which has excellent anticancer activity, might proceed through successive transannular DA reactions and successfully achieved the biomimetic synthesis of FR182877’s complex polycyclic rings with multiple stereocenters. Shair’s group
[34] ingeniously utilized intermolecular and intramolecular DA reactions to complete the biomimetic synthesis of meroterpenoid longithorone A. It should be noted that biosynthetic chemists have been searching for DA enzymes in the biosynthetic processes of natural products, and only recently has there been definitive experimental evidence to demonstrate the existence of such biosynthetic enzymes
[35].
Electrocyclic reactions are often observed in biosynthetic processes. In a biomimetic electrocyclic reaction, a conjugated system undergoes ring closure to form a cyclic compound. The reaction mechanism typically involves the rearrangement of π-electrons to form new ring structures. In a representative case of biomimetic synthesis, Nicolaou’s group
[36],
[37] elegantly completed the biomimetic synthesis of a series of endiandric acids through electrocyclic reactions of complex conjugated polyene substrates, providing direct and reliable evidence for the biosynthetic hypothesis. Drawing on the substrate compatibility of electrocyclic reactions, Li’s group
[38],
[39] designed a series of structurally diverse 6π conjugated triene substrates for complex natural products containing multiple substituted aromatic structural units, achieving the convergent and efficient biomimetic synthesis of the
Daphniphyllum alkaloid daphenylline and the azaphilone-type polyketide acremolactone B.
The biomimetic polyether reaction strategy is a synthetic approach that mimics natural biosynthetic processes to create polyether compounds
[40],
[41]. Polyethers are a class of compounds featuring multiple ether groups within their structures; examples include brevetoxin-B and maitotoxin. Nakanishi’s group
[42],
[43] hypothesized that natural polyethers could be biosynthesized from long-chain terpenes via epoxidation followed by ring-opening reactions involving alcohols under certain conditions. However, a long-standing problem for synthetic chemists has been the 6-endo ring-closure mode that violates Baldwin’s rules. Vilotijevic and Jamison
[44] overcame these difficulties by using water as a medium to obtain the four-membered tetrahydropyran ring as the main product; they then created a polycyclic ether system through a biosynthetic cascade of epoxide-opening reactions. Recently, Qu’s group
[45],
[46] developed a novel catalytic system for intramolecular epoxide ring-opening cyclization, achieving a reversal of selectivity from exo to endo for the ring-opening cyclization of epoxyalcohols. This enabled the one-step construction of the 7/7/6/6 tetracyclic structure of the marine polyether hemibrevetoxin B and the 7/7/6/7/6 pentacyclic structure of brevenal, providing new support for Nakanishi’s biogenetic synthetic hypothesis
[42],
[43].
The biomimetic skeletal rearrangement strategy is a powerful approach that mimics natural biosynthetic processes to rearrange the molecular framework of a compound
[47],
[48]. Skeletal rearrangement involves changing the connectivity of atoms within a molecule, often leading to the formation of new ring systems, functional groups, or molecular frameworks. This can significantly alter the molecular properties and biological activity. Baran’s group
[49] utilized the steroid tetracyclic framework to complete the biomimetic synthesis of cortistatin A through an expansion reaction of the B ring. By using the skeletal rearrangement strategy, Gui’s group
[50],
[51] efficiently completed the biomimetic synthesis of the 9,11-secosteroids pinnigorgiol B, pinnigorgiol E, and gibbosterol A.
Dearomatization is a useful strategy inspired by natural processes to convert aromatic compounds into non-aromatic ones, often with more complex structures. By mimicking natural biosynthetic processes, chemists can create diverse and structurally complex compounds. Trauner’s group
[52],
[53] leveraged the biomimetic dearomatization strategy to synthesize santalin Y and preuisolactone A. Porco’s group
[54],
[55] significantly advanced practical application of the dearomatization strategy for the synthesis of polycyclic polyprenylated acylphloroglucinols. More recently, George’s group
[56],
[57] utilized the dearomatization strategy to transform simple aromatic precursors into sophisticated meroterpenoids, showcasing innovative methods for constructing complex natural products.
Tang’s group
[58] adopted a biomimetic strategy for natural product synthesis by integrating biomimetic synthesis and rational design. The core of this strategy philosophy is to imitate the biosynthetic processes of natural products while incorporating rational design. By analyzing and understanding the key steps in biosynthetic pathways, they focus on mimicking and applying biogenetic cascade reactions that exhibit high efficiency in natural product synthesis. This approach not only enhances the effectiveness of the synthetic route but also ensures the rationality of a practical synthetic process, making the synthesis of complex natural products more precise and efficient. In this way, the complexities and challenges of biomimetic synthesis were overcome in the synthesis of a series of xanthanolides and asperchalasines
[58].
2.2. Biomimetic synthesis strategies based on biogenetic relationships
The biomimetic “two-stage” strategy is a synthetic approach inspired by natural biosynthetic processes that involves a two-step sequence to construct complex molecules such as terpenoids and steroids. Fischbach and Clardy
[59] posited that, during the biosynthesis of terpenoids, the first stage involves cyclization reactions catalyzed by cyclases, which facilitate the formation of complex carbon ring systems from acyclic precursors. In the second stage, the ring systems undergo additional enzymatic modifications such as oxidation, reduction, rearrangement, and further cyclization, leading to a variety of terpenoid structures. Subsequently, the two-stage strategy was successfully applied in the biomimetic synthesis of a number of terpenoids
[60],
[61],
[62]. This approach not only provides new synthetic methods for the rapid synthesis of the core skeleton but also offers in-depth insights into oxidative mechanisms in synthetic biology.
Bioinspired structure network analysis, proposed by Deng’s group
[63],
[64], is a novel strategy that explores the biosynthetic pathways of a family of natural products to construct a molecular network and elucidate the interconnection between natural products and their potential biosynthetic intermediates. This approach allows researchers to design efficient synthetic routes from simple precursors to make complex biogenetically related natural products. Using this strategy, the collective biomimetic synthesis of a family of cytochalasans was accomplished
[63]. These advancements have enhanced our understanding of the structural diversity and biogenetic relationship network of natural products.
2.3. Biomimetic synthesis strategies based on biogenetic enzymes
The chemoenzymatic approach to natural product synthesis is an avant-garde synthetic paradigm that integrates the precision of chemical synthesis with the selectivity of enzymatic catalysis
[65]. A significant application of chemoenzymatic synthesis was the asymmetric synthesis of alchivemycin A, which possesses significant antitumor and antibiotic activities
[66]. Other researchers have also dedicated their efforts to harnessing the power of enzymatic catalysis for the total synthesis of complex natural products
[67]. Collectively, these efforts have demonstrated that chemoenzymatic synthesis is an evolving methodology that is being refined and applied by synthetic chemists through continuous exploration and practice, heralding a new era in the efficient and selective construction of complex molecular architectures. This achievement underscores the formidable potential of chemoenzymatic strategies in addressing synthetic challenges, particularly in the realm of stereoselectivity.
The biomimetic late-stage diversification strategy employs principles inspired by natural biological processes to enhance the chemical diversity and biological function of natural products during their final synthesis stage
[68],
[69]. By emulating enzyme-catalyzed modifications, chemists can generate a broad range of derivatives from a single natural product precursor. This strategy not only amplifies the chemical diversity of natural products but also facilitates the discovery of novel compounds with potentially valuable properties. For example, chemical modifications of the taxane ring system and side chains, guided by natural biosynthetic pathways, have provided derivatives with improved efficacy or reduced toxicity. Similarly, the synthesis of steroid hormones such as cortisol and testosterone often involve biomimetic modification to diversify the steroidal frameworks. By mimicking enzyme-catalyzed hydroxylations and oxidations, researchers have created steroid derivatives with altered biological activities. These examples underscore how nature’s strategies for molecular diversification are being harnessed to advance and expand the applications for natural product modification
[69].
2.4. Biomimetic synthesis strategies based on biogenetic building blocks
Organisms are chemical reactors that can efficiently synthesize complex natural products using their biogenetic building blocks (BBBs)
[70],
[71],
[72]. Recently, a synthetic strategy based on systematic phytochemical investigations, biosynthetic pathway hypothesis, and BBB analysis was put forward for the biomimetic synthesis of natural products. This strategy includes BBB recognition, activation, and combination, enabling the collective and efficient synthesis of biogenetically related and structurally diverse natural products. In such a biomimetic synthesis process, the key step involves the activation of stable BBBs. This approach is characterized by its efficiency, simplicity, atom economy, and diversity-oriented advantages, enabling the rapid construction of natural products with varied structures and complicated stereochemistry. By using this strategy, the collective biomimetic synthesis of a series of complex phloroglucinols was accomplished. Given that most natural products are assembled from specific building blocks, this strategy offers great potential for the biomimetic synthesis of a broad range of natural products.
3. Challenges in the biomimetic synthesis of natural products
The biomimetic synthesis of natural products presents many challenges, despite its potential to offer compact and efficient alternatives to classical total synthesis and biosynthesis methods. Some key challenges are outlined below:
(1) The synthesis of natural products—particularly those possessing multiple chiral centers and unique functional groups—requires sophisticated synthetic techniques and strategies to control regioselectivity, stereoselectivity, and functional group compatibility in the synthetic reactions.
(2) Many biomimetic reactions suffer from low yields, side reactions, or the need for multiple steps to achieve the desired product. Such shortcomings may hinder downstream development into economically viable industrial production.
(3) Developing biomimetic routes that make use of readily accessible starting materials without sacrificing efficiency and selectivity can be a significant challenge, particularly for routes that require unusual or costly precursors.
(4) Transitioning from laboratory-scale synthesis to industrial-scale production is a nontrivial and arduous task. Ensuring consistent quality, high yield, and cost-effectiveness at larger scales requires robust process engineering and optimization.
Addressing these challenges requires interdisciplinary collaboration among synthetic chemistry, biosynthetic chemistry, chemical engineering, and other disciplines. Currently, advances made in synthetic methodologies, catalyst designs, computational modeling, and biotechnology are continually improving our ability to overcome these obstacles and expand the capabilities of the biomimetic synthesis of natural products.
4. Prospects for the biomimetic synthesis of natural products
The biomimetic synthesis of natural products holds promising prospects in terms of sustainability, efficiency, and innovation. This approach provides access to complex natural products and their derivatives. As our understanding of biosynthetic mechanisms deepens, the biomimetic synthesis of natural products is poised for a new era of breakthroughs following a century of development. Interdisciplinary collaboration continues to drive innovations in this field.
4.1. Creation of complex natural products and their derivatives
Delving into the intrinsic structural and biogenetic relationships within natural product families has opened up new avenues for innovative biomimetic synthesis strategies. By synthesizing all the compounds in a natural product family, a diverse library of complex natural products and their derivatives can be created. This approach not only broadens the scope of available molecules but also enhances our understanding of their varied molecular structures and biological functions.
4.2. Integration of chemical and biological synthesis
Efforts to integrate chemical synthesis with gene mining data are pivotal in advancing the field. This integration facilitates a deeper understanding and development of biomimetic synthesis alongside biosynthetic processes. By unraveling the biogenetic pathway networks and detailed biosynthetic mechanisms of natural products, researchers can uncover new synthesis strategies and enhance efficiency in production.
4.3. Development of new biomimetic synthesis strategies
Continued research is crucial for developing novel strategies and methods specifically tailored for the biomimetic synthesis of natural products. Emphasis should be placed on efficient approaches that merge principles from chemical and biological synthesis, with the aim of streamlining processes and improving yields. These advancements will contribute to expanding the repertoire of accessible natural compounds and facilitating their sustainable production.
4.4. Utilization of big data and deep learning technologies
Harnessing the power of big data and deep learning technologies is instrumental in advancing natural product synthesis. Establishing intelligent prediction systems for biogenetic pathway networks will enable the proactive planning and optimization of synthetic routes. Limited studies have employed advanced artificial intelligence approaches—such as BioNavi-NP with deep-learning-based pathway planning and READRetro with retrieval-augmented dual-view models—to improve biosynthetic pathway predictions
[73],
[74]. However, enhancing accuracy and efficiency, especially in the synthesis of complex natural products, remains a challenge. Similarly, intelligent analysis systems for BBBs will aid in guiding biomimetic synthesis and biosynthesis, optimize production processes, and enhance predictability.
In summary, the biomimetic synthesis of natural products spans several scientific domains, encompassing fundamental, cutting-edge, interdisciplinary, and comprehensive applications. It profoundly supports and broadens the research landscape of modern synthetic chemistry while providing ample opportunities for integrating synthetic chemistry with synthetic biology, artificial intelligence, and other fields. From the biomimetic design of molecular synthesis to the chemical validation of biosynthetic hypotheses, and from the simulation of nature to chemical evolution beyond nature through biomimetic strategies, this field not only underpins the understanding and application of natural product functions but also opens up new avenues for chemical exploration related to the origins of life.
Acknowledgments
This work was financially supported by the National Key Research and Development Program of China (2023YFC3503902), the National Natural Science Foundation of China (82430108, 82293681(82293680), and 82321004), the Guangdong Basic and Applied Basic Research Foundation (2022B1515120015 and 2024A1515030103), the Guangdong Major Project of Basic and Applied Basic Research (2023B0303000026), and the Science and Technology Projects in Guangzhou (202102070001).
Compliance with ethics guidelines
Li-Jun Hu, Zhi-Zhang Duan, Ying Wang, Wen-Cai Ye, and Chun-Tao Che declare that they have no conflict of interest or financial conflicts to disclose.
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