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Natural product synthesis facilitated by the deuterium isotope effects (DIE)
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Xiaojuan Chena, Yao Zhub, Muhammad Sulemana, Ranjit Murmub, Hai-Hua Lub, c, Zhiyuan Chena
Chinese Chemical Letters | 2026, 37(9) : 112510
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Chinese Chemical Letters | 2026, 37(9): 112510
• Review •
Natural product synthesis facilitated by the deuterium isotope effects (DIE)
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Xiaojuan Chena, Yao Zhub, Muhammad Sulemana, Ranjit Murmub, Hai-Hua Lub, c, Zhiyuan Chena
Affiliations
  • aSchool of Medicine, Hangzhou City University, Hangzhou 310015, China
  • bZhejiang Key Laboratory of Precise Synthesis of Functional Molecules, Department of Chemistry, and Research Center for Industries of the Future, Westlake University, Hangzhou 310030, China
  • cInstitute of Natural Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China
About Author:

1 These authors contributed equally to this work.

CRediT authorship contribution statement

Xiaojuan Chen: Writing – original draft, Investigation.

Yao Zhu: Writing – original draft, Investigation.

Muhammad Suleman: Writing – original draft, Investigation.

Ranjit Murmu: Investigation.

Hai-Hua Lu: Writing – review & editing, Project administration, Investigation.

Zhiyuan Chen: Writing – review & editing, Supervision, Project administration, Investigation.

Published: 2026-09-15 doi: 10.1016/j.cclet.2026.112510
Outline
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When a deuterium atom (2H or D) replaces a hydrogen atom (1H) in a reactant molecule, the observed change in the rate (kinetic isotope effect, KIE) or equilibrium (equilibrium isotope effect, EIE) of a chemical reaction is known as a deuterium isotope effect (DIE). Because deuterium is twice as heavy as hydrogen, its zero-point energies (ZPEs), which are the lowest vibrational energies that a bond may have, differ significantly. Due to the obvious advantages of deuterium isotope effects (DIE) in total synthesis and mounting importance of deuterated drugs in pharmaceutical industry, development of synthetic routes to these deuterium-based active drugs via DIE is a challenging and important task. The primary goal of this mini-REVIEW is to demonstrate the novel uses of the DIE effect by placing the D atom at specific locations on drug molecules. This has been shown to serve as a "removable blocking group" to enhance yields and selectivity, while suppressing side reactions in the crucial stages of the complete synthesis of certain drug molecules. This review may be served as a perspective or guide for future study as well as inspire further innovative advancements in the field of total synthesis, and stimulate their applications in the related mechanistic studies.

Deuterium  /  Isotope effect  /  Natural product  /  DIE  /  Kinetic isotope effect
Xiaojuan Chen, Yao Zhu, Muhammad Suleman, Ranjit Murmu, Hai-Hua Lu, Zhiyuan Chen. Natural product synthesis facilitated by the deuterium isotope effects (DIE)[J]. Chinese Chemical Letters, 2026 , 37 (9) : 112510 - . DOI: 10.1016/j.cclet.2026.112510
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1　Introduction
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Deuterium was discovered by Harold C. Urey in 1931, which led him to win Nobel Prize in Chemistry in 1934 [1]. Since deuterium has an abundance of 0.0115% in nature, it is a stable isotope that can be handled in a laboratory setting without the need for specific handling authorizations or radiation safety precautions. Deuterated medicines have certain advantages over non-deuterated drugs when it concerns medicinal chemistry, including excellent tolerability, improved pharmacokinetics, and a boost in active metabolites in the body by reducing toxic by-product [2].
When a medication is metabolized by enzymes by a process that includes breaking a C—H bond at a rate-determining step (RDS), deuteration at that location can considerably slow down the reaction due to the fact that C—D bond is stronger than the C—H bond. Because of this, replacing H with D in pharmaceutical sciences usually results in a longer half-life that slows down certain metabolic reactions and permits less frequent dosing. Additionally, the deuterated drugs may improve therapeutic safety in advanced clinical approved trials. For instance, Deutetrabenazine (Austedo®) can be used to treat tardive dyskinesia and chorea associated with Huntington's disease. Donafenib is used to treat hepatocellular cancer. Clinical trials are being conducted on deuterated enzalutamide (prostate cancer) and deuterated linoleic acid (Friedreich's ataxia) (Fig. 1) [3–6]. Because deuterium can be identified by mass spectrometry with a high degree of sensitivity, this makes it an excellent tracer nuclide in organic chemistry. Till date, deuterium labeling applications have significantly increased as a result of this mindset, especially in the multi-step transformations in total synthesis [7,8].
Deuterium isotope effect (DIE), or also known as kinetic isotope effect, is observed in the different reaction rates between the isotopically labelled deuterated molecules and the non-deuterated compounds [9–12]. The lower kinetic acidity but higher activation energy of C—D bond relative to a C—H bond has been particularly useful in understanding the reaction mechanism, because it provides primary DIE evidence if a labelled bond is formed or broken when the rate-determining step is involved through kinetic isotope effect (KIE = KH/KD) [13,14]. A secondary hydrogen isotope effect arises in cases where the C—H or C—D bond remains intact during the rate-limiting step. In this regard, usually, modifications in hybridization or the use of hyperconjugation may result in the production of secondary KIEs [15].
There will be significant variations in the zero-point energy (ZPE) discrepancies between C—H and C—D bonds due to the difference in force constant for the out-of-plane bend of a sp3 hybrid versus a sp2 hybrid. The frequency of the in-plane bend also varies significantly between sp2 and sp hybrids.
Deuteration is a technique that, despite the fact that there are many different ways to do it, is constantly evolving and is employed in many different sectors, including the biological sciences and drug industries. After the approval of deutetrabenazine as first deuterated drug by FDA [16]. The race to develop more efficient synthetic routes to deuterated drugs has resulted in enormous increase in the usage of deuterium isotope effect in chemical and biological synthesis.
The use of DIE during total synthesis has opened up new possibilities for the development of affordable and effective approaches to get naturally occurring compounds of biological and pharmacological importance [17–19]. NMR along with GC–MS or LC-MS measurements of a deuterium labeled species can be utilized to investigate electronic, steric, and related effects, due to the sensitive properties of DIEs toward substrates or transition-state of the intermediate species [20]. As a result, DIE has recently been used as an important tool in the total synthesis of valuable natural products, most occasionally with the aim to suppress side product formation in organometallic reactions [21–24], or to facilitate C—H bond functionalizations (Fig. 2) [25–30]. Due to the importance of DIE and the advantages of deuterated drugs in medicinal chemistry, substantial advancement has been made toward the development of quick and practical methods for the late-stage incorporation of deuterium in organic compounds. In a recent summary, Atzrodt and Marc Reid have summarized the advancements in the application of hydrogen isotopes in the life sciences [31]. The catalysts/immobilization strategies or visible light-induced deuteration enforced in the D-labelled organic compounds were also demonstrated [32,33]. However, the significant advances in synthetic chemistry for the complete synthesis of physiologically natural compounds by deuteration or with the aid of DIE, have not yet been fully explained.
In this mini review, we would like to showcase the rapidly expanding use of DIE in the total synthesis of natural products over the previous few years [34]. We hope that this review may be served as a perspective or guide for future study as well as spark further advancements in the field of applications of DIE in new natural product synthesis and the related mechanistic studies.
2　Applications of DIE in total synthesis of natural products
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2.1　Fredericamycin A
The first demonstration of the utility of deuterium kinetic isotope effects in natural product synthesis is the laboratory synthesis of Fredericamycin A.
Fredericamycin A is a hexacyclic quinone-based natural antibiotic, which was isolated in 1981 from soil bacterium Streptomyces griseus at Frederick Maryland [35]. It was reported to possess potent antifungal, antibacterial activities and exhibits cytotoxic activities against CD8F mammary cell lines, Du-145 prostrate tumor, murine leukemia KB and P338D1 mouse leukemia [36]. Structurally, Fredericamycin A contains two sets of peri-hydroxy tricyclic aromatic moieties joined through a chiral spiroquaternary carbon center. Due to its significant bioactivities and unique molecular architecture, numerous synthetic studies have been reported for the total synthesis of Fredericamycin A [37,38].
Formation of the unusual spiroring system of Fredericamycin A is a challenging task. For this, Clive and co-workers developed an interesting intramolecular 6-endo-trig radical cyclization reaction of 1 (Fig. 3) [39]. Besides the desired product 3a obtained in 48% yield, an unwanted byproduct 2a resulting from intramolecular hydrogen transfer was also produced in comparable amount. The authors then tested deuterium kinetic isotope effects (KIE) to avoid this undesired atom transfer side reaction. Treatment of the deuterated substrate 1 under same conditions, the ratio of desired product 3b to that of the byproduct 2b was now improved to be 9.7:1 and the desired cyclization product 4 was obtained in ≥70% yield. Compound 4 was then conveniently transformed into the spiroquinone 5, a key segment of Fredericamycin A.
2.2　Guanacastepene A
The Guanacastepene diterpenes were discovered by the groups of Clardy and Sterner, respectively (Fig. 4) [40]. They share a tricyclic neodolastane carbon skeleton with two angular methyl groups in an anti-1,4 relationship. In view of their attractive structures and promising biological activities [41,42], guanacastepenes have brought up various interesting synthetic methods and strategies, and continue to synthetic chemists [43–47].
Danishefsky and co-workers reported their synthetic studies for the synthesis of the highly functionalized tricyclic skeleton of Guanacastepene A [48–51]. For the left [5.3]-bicyclic system, they utilized a reductive cyclopeptanone annulation of 6 (Fig. 5). The reaction proceeded well and could provide gram quantities of the desired product 8a. But a considerable amount of the uncyclized byproduct 7a was also obtained. This is presumably due to protium transfer from the α-carbon to the vinyl lithium species. Therefore, the authors prepared deuterated compounds 6b and 6c in the hope of using DIE to suppress this protium transfer process. Pleasingly, the yield of the desired deuterated hydroazulene 8c was greatly improved.
2.3　Aziridinomitosenes
Aziridinomitosenes are a class of clinically used tetracyclic antibiotics, are structurally related to mitomycin C and possess comparable bioactivities [52]. FR66979 (9) and FR900482 (10) are also believed to generate the reduced aziridinomitosene intermediate (11) responsible for their activities [53]. Danishefsky [54] and Egbertson could detect the compound 11 via NMR analysis, but the molecule was too unstable to be isolated [55]. The quinone derivative is considerably more stable. In 1999, Jimenez and Dong reported total synthesis of aziridinomitosene A having a quinone structure [56]. Thus, the development of efficient method to access aziridinomitosenes with good stability as well as activity becomes an important and challenging task.
In 2002, Vedejs and Little reported total synthesis of aziridinomitosenes by a novel anionic cyclization strategy (Fig. 6) [57]. Subjecting compound 13, easily prepared through a SN2 reaction, they obtained the desired product albeit with low yields. Careful deuterioethanol quenching experiments allowed them to isolate compounds 18b and 18c as the major products. This revealed that the indole C—H lithiation dominated over the desired tin-lithium exchange and suppressed the desired intramolecular cyclization. To their delight, treatment of the deuterated compound 14 under same reaction conditions as for 13, followed by trapping with PhSeCl for elimination, they could get 15 in 71% yield. Deuterium served to block the undesired indole C—H lithiation and was smoothly removed during the elimination step. Further simple transformations then provided new aziridinomitosenes 16 and 17.
2.4　Norzoanthamine
Marine natural products usually have interesting structures and possess unique their biological activities. They play an important role in modern drug discovery. Zoanthamine alkaloids are a group of structurally diverse marine natural products (Fig. 7), mainly found from colonial zoanthids of the genus Zoanthus [58]. Biological studies revealed that norzoanthamine (19) is capable of suppressing the loss of bone strength and mass caused by ovariectomy in mice [59,60]. This suggests that norzoanthamine might be applicable as an anti-osteoporotic drug. Due to its unique structural features and promising biological activities, norzoanthamine has attracted much attention from the synthetic community. To date, the groups Miyashita, Kobayashi and Gao had achieved its total synthesis [61].
Miyashita and co-workers devised their synthesis by means of an alkyne segment to join the other aldehyde segment (Fig. 8) [62]. In the final alkyne formation step by elimination (24 to 25), they found that a 1,5-HAT process happened to give undesired byproduct 26a in 30% yield, which greatly influenced the yield of the desired alkyne product 27a. To solve this issue, they prepared the deuterated compound 24b and subject to the same reaction conditions. Due to deuterium kinetic isotopic effects (KIE), the 1,5-HAT process was substantially slowed, and the yield of the desired alkyne 27b was improved to be 81%. The deuterium atoms could be easily removed in the later stage of oxidation to acid, and the first total synthesis of norzoanthamine (19) was finally completed in impressive overall yields by Miyashita and co-workers.
2.5　Oxidized welwitindolinones and (−)-N-methylwelwitindolinone C isonitrile
Welwitindolinone natural products possess unique [4.3.1]-bicyclic bridged ring systems with various stereogenic centers and functional groups [63]. Some of them showed promising activity against drug-resistant cancer cells. Since their isolation, welwitindolinones have inspired many synthetic chemists to devise numerous intriguing strategies for their syntheses [64]. In 2011, both the groups of Garg [65,66] and Rawal [67] reported the first total synthesis of oxidized welwitindolinones.
Based on their previous synthetic studies, Garg and co-workers strategically employed KIE to improve the efficiency of forging the C—N bond via the challenging nitrene insertion reaction (Fig. 9) [68]. As shown, with the deuterated compound 32b, the yield of the desired product 34b was significantly improved and the major byproduct ketone 33b, presumably resulting from insertion of the nitrene species into the C—H bond at C-10, was suppressed from 25% yield to 8% yield. From 35, (−)-N-methylwelwitindolinone C isothiocyanate (36), (−)-3-hydroxy N-methylwelwitindolinone C isothiocyanate (37), (−)-N-methylwelwitindolinone C isonitrile (40), and (−)-3-hydroxy N-methylwelwitindolinone C isonitrile (39) were then quickly accessed over several simple transformations.
2.6　Taxol
Taxol (46, paclitaxel), a well-known anticancer medicine used to treat breast, lung, ovarian, and Kaposi's sarcoma, is a natural diterpenoid first isolated from the bark of the Pacific yew tree (Taxus brevifolia) [69]. Structurally, Taxol features [6−8−6−4] carbon skeleton highly oxygenated and functionalized. Taxol represents one of the most formidable challenging synthetic targets, and has attracted significant interest from synthetic chemists, leading to the development of numerous interesting strategies and novel synthetic methods over decades [70].
The Baran group initiated their remarkable two-phase synthesis in 2007, and eventually reported their successful synthesis of Taxol in 2020 (Fig. 10) [71]. At the stage of introducing the oxidation state at C-1 and Δ5,6-olefin simultaneously from 41a by DMDO oxidation, they observed ketone 42a resulting from oxidation of the secondary alcohol, was the major product instead of the desired one 44a. Then, by means of C-2 deuterated substrate 41b, this undesired alcohol oxidation process is pleasingly significantly retarded, due to a β-secondary KIE [72,73]. Furthermore, the intended product 44c was achieved in a better yield of 49% than 9% (44a), while utilizing CHCl3 as the solvent instead of acetone, which probably improves the reactivity of DMDO through H-bonding. Following oxidation by TPAP and NMO then produced ketone 45, an important intermediate en route to Taxol.
2.7　(+)-Mutilin
Antibiotics can effectively prevent and treat bacterial infections. However, bacteria can adapt to the frequent use of them and finally become antibiotic-resistant. Antibiotic resistance [74], with new resistance mechanisms emerging and spreading as well, has thus become one of the biggest threats to global health [75]. The importance of discovering new antibiotics cannot be overstated. Among these efforts, the natural diterpene pleuromutilin (50) was found to be able to inhibit the growth of Gram-positive pathogens through binding to the peptidyl transferase center of the bacterial ribosome [76]. And the development of resistance is slow for this family. Due to promising antibacterial activities and its unique 5–6–8 densely functionalized tricycle, pleuromutilin had attracted significant attention from the synthetic and medicinal community leading to seven elegant total syntheses [77] and the FDA-approved topical antibiotic retapamutilin (51), to date [78,79].
In 2022, Luo and co-workers reported their total synthesis of (+)-mutilin (49), interconvertible with its (+)-pleuromutilin (50), from simple (+)-lactate derivative (47) and chiral enone (48) (Fig. 11) [80]. To construct the key 5–6–8 tricyclic framework, they devised a novel tandem photo-induced transannular [2 + 2]-cycloaddition/retro-aldol fragmentation reaction of 6–9 bicyclic intermediate (53a). The authors could obtain the desired product 61a, but also observed comparable yields of the intramolecular 1,5-HAT side products 58a and 60a, besides the stable [2 + 2]-cycloaddition diastereomeric adduct 59a. To suppress the undesired 1,5-HAT pathway, they then turned attention to deuterium kinetic isotope effect [81]. Pleasingly, with the deuterated compound 52b under same conditions, the yield for the desired product was improved and the yield for the 1,5-HAT side product was significantly suppressed. Subsequent few steps, including exchanging deuterium to hydrogen, then completed the total synthesis of (+)-mutilin (49).
2.8　Salimabromide
In 2013, König and coworkers discovered the polyketide salimabromide (67), the first secondary metabolite from the Plesiocystis/Enhygromyxa clade of marine myxobacteria [82]. It exhibited potent inhibitory activities of Arthrobacter cristallopoietes but has extremely low natural abundance (only 0.5 mg was obtained from 64 L of culture). Structurally, salimabromide possess a unique benzo-fused [4.3.1] carbon skeleton with four contiguous stereocenters, including two vicinal quaternary ones. These highly compact structural features make salimabromide an appealing synthetic challenge [83]. In 2018, Magauer and coworkers successfully completed its first racemic total synthesis [84]. Meanwhile, Menche and coworkers soon reported their asymmetric synthesis of salimabromide and found that the natural salimabromide is actually in almost racemic form [85]. Strategically, both research groups resorted to an in situ ketiminium-[2 + 2]-cycloaddition of a tetralin-tethered amide to build the central bridged [4.3.1]-carbon framework [86].
Recently, we developed an intramolecular radical cyclization of diene 64 via hydrogen atom transfer (HAT) to construct the benzo-fused [4.3.1] carbon skeleton 66, and finally achieved a concise synthesis of salimabromide 67 (Fig. 12) [87]. Unfortunately, the undesired 1,5-HAT side product 65 always dominated over the desired cyclization product 66. This is presumably due to the steric hindrance associated during the cyclization as well as the proximity of the initially generated radical to the hydrogen atom at the γ-position of the enone moiety. The deuterium kinetic isotope effect (KIE) was then studied for this cyclization. To our delight, the deuterated compound 68 (75% D) to subjected to the same conditions, the desired cyclization product 70 could be obtained as the major product (46% y). Based on these interesting results, a new short asymmetric total synthesis of (+)-salimabromide was completed.
3　Summary and outlook
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The DIE has been demonstrated to be a highly effective method for the cost-effective and selective protection of highly active protons, preventing side reactions and delivering greater yields of the target molecules during total synthesis. DIE is thus the method of choice for protecting active protons due to the benign methods for adding and removing D atom as a "removable blocking group". In this aspect, the typical applications of DIE by using the installation of D at specified places of clinically important drug molecules, such as Fredericamycin A, Guanacastepene A, Aziridinomitosenes, Norzoanthamine, oxidized Welwitindolinones and (−)-N-Methylwelwitindolinone C Isonitrile, Taxol, (+)-Mutilin, and Salimabromide, are summarized herein.
The trend of usage of DIE during total synthesis has seen a sharp increase during the past few years and is expected to continue as this approach. Owing to the importance and usefulness of DIE in organic synthesis, it is expected that more efficient, cost-effective and selective synthetic routes for the total synthesis of valuable natural products would be developed in the future with the help of DIE. It is necessary to develop more commercialized deuterated reagents, new catalytic systems and, optimized synthetic processes with the help of DIE, to efficiently synthesize deuterated drugs.
Moreover, since deuteration is an effective "isotope engineering" method, its principal utility is not only in discovering novel synthetic activities, but also in improving the pharmacokinetic and physicochemical features of molecules. As synthetic methods advance, their function will broaden beyond developing life-saving pharmaceuticals to enabling more stable materials, precise analytical methods, and efficient agricultural goods, making it a critical technology for molecular innovation in a variety of technologies.
In general, there is still plentiful of room for more efficient and goal orientated research in other areas of science with the help of DIE, and this review might help fellow scientists for future endeavors in this regard.
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Year 2026 volume 37 Issue 9
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doi: 10.1016/j.cclet.2026.112510
  • Receive Date：2025-10-30
  • Online Date：2026-10-27
  • Published：2026-09-15
Article Data
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History
  • Received：2025-10-30
  • Revised：2026-02-03
  • Accepted：2026-02-08
Affiliations
    aSchool of Medicine, Hangzhou City University, Hangzhou 310015, China
    bZhejiang Key Laboratory of Precise Synthesis of Functional Molecules, Department of Chemistry, and Research Center for Industries of the Future, Westlake University, Hangzhou 310030, China
    cInstitute of Natural Sciences, Westlake Institute for Advanced Study, Hangzhou 310024, China

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E-mail addresses: (H.-H. Lu)
(Z. Chen)
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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