Oxidation reactions in the current total synthesis of natural products

Abstract

Oxidation and oxidative reactions are fundamental types of transformations in organic chemistry, which are indispensable in organic synthesis, especially in the total synthesis of natural products. Although there are many reviews on a specific oxidation reaction or oxidation reagent, a general review on the diverse oxidation reactions and oxidation reagents in natural product synthesis has not yet been reported. In this review, we selected some total syntheses published during 2020 to 2025 from selected journals and surveyed the oxidation reactions and oxidative transformations employed therein to reflect the current status of oxidation reactions. This article is organized by functional groups for oxidation and subcategorized by reagents/methods used in natural product synthesis. In addition to the categorized reactions, we selected twenty total syntheses (in Sections 2 and 7) and analysed and discussed all the oxidative transformations involved. The information provided will not only be helpful for chemists in the field of total synthesis of natural products and medicinal chemists to plan their syntheses but also prompt synthetic organic chemists in general to develop modern oxidation reactions/reagents to suit the increasing needs of sustainable organic synthesis.

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Jian-Feng Zheng

Jian-Feng Zheng is an Associate Professor at the College of Chemistry and Chemical Engineering at Xiamen University. He received his PhD degree in 2004 from Xiamen University under the supervision of Professor Pei-Qiang Huang. During 2009–2010, he joined Professor Jianrong “Steve” Zhou's group at Nanyang Technological University, Singapore, as a Postdoctoral Fellow. His research interests mainly focus on the development of novel and efficient synthetic methodologies for amides and the total synthesis of bioactive natural products.

Anqi Chen

Anqi Chen received his PhD in 1992 from Bristol University, UK. He subsequently moved to Manchester University for postdoctoral research in natural product total syntheses. He began his professional career at Xiamen University, China as a faculty member in the College of Chemistry and Chemical Engineering in 1997. In 2004, he relocated to the Institute of Chemical and Engineering Sciences (ICES) in Singapore. After two decades of service across diverse research and leadership roles in the ICES and the Institute of Sustainability for Chemicals, Energy and Environment (ISCE^2), he retired in 2024. Currently, he remains engaged with sustainable chemistry and continues to track emerging advancements in the field, and serves as a guest researcher at the Fujian Key Laboratory of Chemical Biology (Xiamen University).

Yan-Jiao Gao

Yan-Jiao Gao is a Senior Engineer at the Fujian Key Laboratory of Chemical Biology (Xiamen University). She received a Bachelor's degree in Chemistry in 2003 and Master's degree in Inorganic Chemistry in 2006 from Fujian Normal University, with Professor Rong-Fang Liu as her Master's supervisor. After graduation, she worked at the College of Chemistry and Chemical Engineering, Xiamen University, and joined Professor Pei-Qiang Huang's group in 2014. Her current research interests focus on nuclear magnetic resonance spectroscopy.

Pei-Qiang Huang

Pei-Qiang Huang is a Nanqiang Professor at Xiamen University (China). After completing research work at the Institut de Chimie des Substances Naturelles (ICSN), CNRS under the direction of Professor H.-P. Husson, he received his PhD from the Université de Paris-Sud (Orsay) (France) in 1987. In 1988, he joined Professor W.-S. Zhou's group at the Shanghai Institute of Organic Chemistry (SIOC), CAS as a Postdoctoral Fellow. In 1990, he returned to Xiamen University. Huang's research focuses on synthetic methodologies and the total synthesis of natural products. He has co-edited several books including ‘Efficiency in Natural Product Total Synthesis’ (Wiley). He was elected as a fellow of RSC and CCS, respectively. Currently, he serves as an Associate Editor of Org. Chem. Front.

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1. Introduction

Oxidation reactions are one of the most important types of transformations in organic synthesis, as can be seen from the fact that there are more than 25 named oxidation reactions and reagents in organic chemistry,¹ such as the Baeyer–Villiger oxidation, Moffatt (Pfitzner–Moffatt) oxidation, Swern oxidation, Dess–Martin periodinane (DMP) reagent, Corey–Kim oxidation, Ley–Griffith oxidation, Sharpless asymmetric epoxidation, Sharpless asymmetric dihydroxylation, Shi asymmetric epoxidation, and Davis reagent. Sharpless was awarded the 2001 Nobel Prize in Chemistry for his outstanding contribution to catalytic asymmetric oxidation reactions.

As a class of fundamental organic transformations, oxidation reactions serve to introduce oxygen atoms in a selective site within a molecule and adjust the oxidation state, ranging from alcohols to aldehydes/ketones, aldehydes/ketones to acids and derivatives, and alcohols to acids and their derivatives. Moreover, oxidation reactions are a class of reactions enabling subsequent C–C bond forming reactions, such as aldol reactions and Grignard additions from alcohol to aldehyde/ketone transformations. Additionally, oxidation reactions can be used to create chirality in a catalytic enantioselective manner. Thus, oxidation reactions are indispensable for constructing complex molecules, particularly in the total synthesis of natural products. Indeed, a brief survey of the publications on total synthesis between 2015 to 2025 using SciFinder® revealed that 16% of them contain the term “oxidation” in their abstract, indicating its crucial role in natural product synthesis. Although many reviews have been reported on a specific oxidation reaction or oxidation reagent,² a general review on diverse oxidation reactions and oxidation reagents in natural product synthesis, to the best of our knowledge, has not yet been reported. However, this is very important because very often, several oxidation reactions and reagents are required for total synthesis.

To bridage this gap, this review aims to cover the applications of diverse oxidation methods in the synthesis of natural products, guiding readers to select suitable reactions, reagents and conditions for oxidative transformations. Nonetheless, considering the huge number of publications in this field, this article will be restricted to selected examples chosen from papers published in selected journals during 2020 to 2025 on the total synthesis of natural products to reflect the current status of oxidation reactions. This article is organized by functional groups for oxidation and subcategorized by reagents/methods used. Prior to the categorized oxidation reactions, we selected ten total syntheses and analysed and discussed all the oxidative transformations involved. The information provided will not only be helpful for the chemists in the field of total synthesis of natural products and medicinal chemists to plan their syntheses but also prompt synthetic organic chemists in general to develop modern oxidation reactions/reagents to suit the increasing needs of high chemo-, regio- and stereo-selectivity,³ efficiency,⁴ mild reaction conditions, reduced waste formation and environmental friendliness.⁵

2. Survey of oxidation reactions in ten selected total syntheses

To provide an overview on the diverse roles played by oxidation reactions in total synthesis, we selected ten cases from the recent literature. A closer inspection of these examples revealed unexpected and surprising results, where the oxidation steps comprised more than 40% of the total steps. Moreover, some oxidation reactions and oxidative transformations can constitute the basis of a synthetic strategy or be used as a key step of the total synthesis. Additionally, oxidation reactions are not only limited to adjusting the oxidation state of a specific site or a functional group but also play vital roles in enabling transformations. These recent examples cover a variety of oxidation reactions and oxidation transformations, which serve, at least in part, to reflect the current status of oxidation chemistry.

2.1. Enantioselective total synthesis of (−)-novofumigatonin

Isolated in 2008, novofumigatonin 1 represents one of the most structurally complex and most highly oxidized members of the 3,5-dimethylorsenillic acid (DMOA)-meroterpenoid class of natural products isolated to date. In 2025, Carreira and co-workers achieved its first and enantioselective total synthesis (Scheme 1).⁶ The central role of oxidation reactions in their total synthesis is highlighted by one of their conclusions, as follows: “A powerful anionic fragment coupling followed by a series of oxidative transformations led to the rapid construction of the highly oxygenated backbone of 1”.

Scheme 1 First and enantioselective total synthesis of (−)-novofumigatonin by Carreira and co-workers.

The first oxidation reaction involved the allylic oxidation of olefin 2 to afford enone 3, which was achieved using catalytic CuI/t-BuO₂H⁷ (68% yield). This oxidation reaction not only introduced the first oxygen atom in the core structure, but also enabled subsequent transformations. Next, after the key anionic fragment coupling reaction, three consecutive oxidation reactions were employed to forge a highly oxygenated intermediate. Firstly, triple ozonolysis of 4 generated four carbonyl groups in the form of diketo hemiacetal 5. Secondly, Ley–Griffith oxidation afforded lactone–acetal 6. Finally, saponification of the δ-lactone followed by oxidation by PhI(OAc)₂ and RuCl₃·hydrate furnished γ-lactone 7a. Because multifunctionalized compound 8 contains both acid-sensitive (ortholactone) and base-sensitive (bicyclic γ-lactone) functional groups, the oxidation method (trichloroisocyanuric acid, TCCA) recently reported by Bao and Wan⁸ was employed for the primary amide (8) to ester (9) transformation. Interestingly, two oxidants were used to complete the total synthesis. One was (PhSeO)₂O⁹ for the desaturation of 9 to afford α,β-unsaturated ε-lactone 10, and the other was 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)¹⁰ used to provide an acidic medium, enabling the selective cleavage of the acetal to afford 1 bearing an embedded ortholactone.

2.2. Asymmetric total synthesis of (−)-cephalocyclidin A

(−)-Cephalocyclidin A (11) is a novel alkaloid isolated from the fruits of Cephalotaxus harringtonia var. nana. Its structure features a unique fused-pentacyclic skeleton and six consecutive chiral centres, making it a challenging target for total synthesis. Its first total synthesis was accomplished by Zhang/Tu and co-workers in 2023 in a quite efficient manner.¹¹ In this 10-step (from known compounds, 12 steps from commercially available materials) total synthesis, four steps involved different types of oxidation reactions, highlighting the crucial role of oxidation reactions in its total synthesis. They first developed a catalytic asymmetric polycyclization of tertiary enamide 12 with silyl enol ether employing Tu's chiral ligand L1 to build tricyclic core 13 as a mixture of inconsequential diastereomers in 90% ee. The latter was subjected to Wilkinson's complex-catalyzed deformylation, Fleming–Tamao oxidation¹² (C–Si to C–OH, 14), and Corey oxidation of the resulting alcohol with pyridinium chlorochromate (PCC) to afford ketone-lactam 15 in 39% yield over three steps. Regioselective α-oxidation of the ketone group was achieved by successive treatment of 15 with TBSOTf (2.1 equiv.) and dimethyldioxirane (DMDO),²ⁱ which afforded tricyclic α-hydroxy cyclopentanone 16 as a pair of inconsequential diastereomers. This transformation probably involved silyl enol ether formation and its oxidation with DMDO. Dess–Martin oxidation of α-hydroxy ketone 16 delivered the corresponding α-diketone in enol form 17, which was benzoylated in one-pot to yield compound 18 in 68% yield. Finally, one-pot radical cyclization–desilylation, and reduction-debenzoylation furnished (−)-cephalocyclidin A (11) (Scheme 2). It is worth noting that in this ten-step total synthesis (from a known compound, not shown), four steps are oxidation reactions covering Si to OH oxidation, alcohol oxidation, ketone α-hydroxylation, and oxidation of α-hydroxyketone.

Scheme 2 First and catalytic asymmetric total synthesis of (−)-cephalocyclidin A (11) by Zhang/Tu and co-workers.

2.3. Divergent, enantioselective total syntheses of three calyciphylline A-type alkaloids

During the last decades, many modern variants of the classic named reactions appeared, which significantly expanded the scope of the original reactions. In this regard, Xu and co-workers developed the oxidative Nazarov-type reaction and used it as a key reaction in the divergent total syntheses of Daphniphyllum alkaloids.¹³ The synthesis started from chiral ketone 22b, which was derived in five steps from (R)-Wieland–Miescher ketone. The Saegusa–Ito oxidation afforded dienone 23 in high yield. For allylic oxidation at C9, the authors tried several reactions and found that Riley oxidation gave the best yield. A tandem oxidation with AZADOL/iodobenzene diacetate (PIDA)¹⁴ afforded enone 25 in 77% yield over two steps. Lower yields were obtained with other oxidation methods. The transformation of enone 25 to 1,3-done 26 also involved Ley oxidation.¹⁵ Two more oxidation reactions were employed for the conversion of 27 to tetracarbonyl compound 28. After the reductive cyclization using Kagan's reagent, the resulting diol was subjected, once again, to Ley oxidation, which afforded α-hydroxyketone 29a. According to their original plan, the subsequent step was the transformation of unfunctionalized tertiary divinyl carbinol to the enone moiety in compound 33. Unexpectedly, Xu discovered that under Iwabuchi's conditions (TEMPO⁺BF₄⁻, MeCN),¹⁶ pentacycle 31 was formed in 80% yield. This reaction was coined as an oxidative Nazarov-type reaction. The resulting product was converted to (−)-10-deoxydaphnipaxianine A (19) in three more steps. Alternatively, treatment of key intermediate 30 with TEMPO⁺BF₄⁻ in dioxane yielded allylic alcohol 32, which was subjected to oxidation with AZADOL/PIDA to give ketone 33 in 98% yield. Finally, chemoselective reduction of the amide carbonyl furnished (+)-daphlongamine E (20), which was further converted to (+)-calyciphylline R (21) via N-oxidation with m-CBPA (Scheme 3). It is worth mentioning that in this 22-step total synthesis of (+)-calyciphylline R (21), more than 40% of the steps involve oxidation reactions. More recently, Xu and co-workers applied their oxidative Nazarov-type reaction to the collective total synthesis of laurane and guaiane sesquiterpenoids.¹⁷

Scheme 3 Divergent, total syntheses of (−)-10-deoxydaphnipaxianine A, (+)-daphlongamine E, and (+)-calyciphylline R by Xu and co-workers.

2.4. First and catalytic asymmetric total synthesis of tri-nor-meroterpenoid janthinoid A

Janthinoid A (34) is a novel 3,5-dimethylorsellinic acid (DMOA)-derived natural product that exhibits in vivo antitumor activities against NSCLC cells A549.¹⁸ Soon after its isolation in 2021, Yang and co-workers accomplished its first catalytic asymmetric total synthesis.¹⁹ This highly efficient 14-step, protecting group-free total synthesis started from the regioselective, catalytic asymmetric dihydroxylation^20,21 of geranylacetone (35) to produce diol 36 (97% yield, 92% ee), setting the stage for epoxide formation and subsequent double cyclization to afford bicyclic intermediate 38. Although the transformation of 38 to 39 involved a routine oxidation (DMP)-reduction strategy to correct the stereochemistry (at C3), the protocol that they developed alleviated the need for protection of the hydroxy group. Another key step in its total synthesis is the regio- and stereo-selective oxidative cascade cyclization reaction of 40 to build the oxabicyclo[3.2.1]octane core. After extensive experimentation, this was achieved by treating bicyclic ketoester 40 with Fe(ClO₄)₃·9H₂O²² in CH₃CN, affording tetracyclic 41 in 55% yield. The latter was converted into janthinoid A (34) in just two steps, completing the highly concise total synthesis (Scheme 4). This total synthesis provides another example²³ demonstrating how oxidative reactions can be used, directly or indirectly, for rapidly building molecular complexity.

Scheme 4 14-step, protecting group-free, total synthesis of janthinoid A by Yang and co-workers.

2.5. Divergent, enantioselective total syntheses of bryostatins 1, 7, 9 and an analogue

Bryostatins are a class of structurally complex marine macrolides displaying diverse and potent biological activities with more than 40 clinical trials conducted. In 2025, Song and co-workers achieved the divergent and scalable enantioselective total synthesis of bryostatins 1, 7, 9 and unnatural 9-N₃.^24,25 The synthesis of the southern fragment involved several oxidation reactions. Firstly, in situ-formed dihydropyran 45 was subjected to epoxidation with magnesium monoperoxyphthalate (MMPP) hexahydrate, in situ methanolysis, and Dess–Martin oxidation of the resulting C20 hydroxy group²⁶ to afford pyranone 46 in high yield. Secondly, oxidative deprotection of the PMB group in 47 with DDQ followed by Dess–Martin oxidation afforded enal 48. Thirdly, Sharpless asymmetric dihydroxylation²⁷ (dr = 11 : 1) and selective protection of the C26 hydroxy group produced 49 in 72% yield (Scheme 5).

Scheme 5 Later stage of the gram-scale enantioselective total synthesis of bryostatin 1 and its congeners by Song and co-workers.

2.6. Modular, enantioselective synthesis of marine natural products dragocins A–C and analogues

In the recent modular synthesis and cytotoxicity evaluation of dragocins A–C disclosed by Liu/Li et al.,²⁸ one of the key reactions involved oxidation of the benzylic C–H bond. After attempting several methods, DDQ-induced CDC etherification was found to be suitable for the intramolecular cross-dehydrogenative etherification at the benzylic position,²⁹ which afforded the desired compound 54 and its C-5 epimer epi-54 (dr = 1 : 1) in a combined yield of 56%. Employing the TEMPO/BAIB (bis(acetoxy)iodobenzene) combination, primary alcohol 54 was oxidized smoothly to carboxylic acid 55 in 87% yield. The decarboxylative chlorination reaction can be viewed as an oxidative transformation because the oxidation state of the carbon increased. This was achieved by employing Li's method³⁰ with minor modification. The desired mono-chlorination product 56, formed in 60% yield, was converted into dragocin A (50) in two steps. Selective removal of the N-protecting group in 56 afforded 58 in 84% yield, which was converted to dragocin B (51) by reductive debenzoylation. On the other hand, subjecting 58 to Huang's N-methylation reaction (MeOH, H₂, Pd/C)³¹ and reductive debenzoylation of the resulting N-methylpyrrolidine product produced dragocin C (52) in 59% yield over two steps (Scheme 6). It is worth noting that although Huang's N-methylation reaction using MeOH as the methylating agent appears to be performed under reduction conditions, the first and key step involves Pd/C-catalyzed dehydrogenation of MeOH to generate formaldehyde.³¹

Scheme 6 Collective enantioselective synthesis of dragocins A–C and their analogues by Liu/Li and co-workers.

2.7. Twenty-step enantioselective total synthesis of tigliane diterpene (+)-phorbol

Tigliane diterpenes are a family of natural products possessing diverse and potent bioactivities, among which tigilanol tiglate (Stelfonta®) has been approved by the FDA to treat non-metastatic mast cell tumors in dogs. As a representative member, the total synthesis of (+)-phorbol (60) has attracted considerable attention. Very recently, Jia and co-workers disclosed a 20-step (longest linear steps) enantioselective total synthesis,³² which represents one of the shortest total syntheses after Baran's elegant 19-step total synthesis of this natural product.³³ As a highly oxygenated molecule, it is not surprising that the total synthesis of (+)-phorbol (60) heavily relied on oxidation reactions. Indeed, in Jia's total synthesis, 35% of the steps (7 steps) are oxidation reactions. The synthesis commenced with the direct epoxidative transformation of (+)-carvone (61) to 3,4-epoxycaranone 62 by a known method. Because direct hydroxylation of 62 proved to be challenging, inspired by Fuchs’ approach,³⁴ a pentamethyldisilyl group was introduced as a masked hydroxy group. Chemoselective oxidation of the less hindered C9 alcohol versus that at C12 in diol 63 was achieved using Mukaiyama reagent (64).³⁵ Subjecting silyl derivatives 66aandb to Tamao–Fleming oxidation³⁶ delivered alcohols 67aandb in 63% yield, respectively. Subsequent Swern oxidation yielded 68aandb, respectively. Treatment of ketone 69 with LiHMDS and Mukaiyama reagent (64) was performed again for the generation of enone 70 from ketone 69.³⁷ α-Hydroxylation of the fused cyclic enone proved to be challenging. After extensive experimentation, t-BuOK/O₂/P(OEt)₃ was found to be the reagent system of choice for this transformation, which afforded α-hydroxylated product 72 and its epimer 73 in a combined yield of 90%. Allylic oxidation of 72 with SeO₂ furnished enal 74 instead of the desired allylic alcohol. Finally, reduction and deprotection afforded (+)-phorbol (60) along with (+)-crotophorbolone (75) (Scheme 7).

Scheme 7 Highly efficient asymmetric total synthesis of (+)-phorbol by Jia and co-workers.

2.8. First total synthesis of octacyclic caged Kopsia alkaloid kopsinitarine E

Kopsinitarine E is an alkaloid isolated from the genus Kopsia (Apocynaceae). Its intriguing octacyclic cage structure presents a formidable challenge for its total synthesis, which was overcome by Ma and co-workers in 2020.³⁸ In this total synthesis, only four oxidation reactions were employed, which illustrated the classical role of oxidation reactions in functional group manipulation. However, it is worth noting that in the stepwise transformation of ester 77 to aldehyde 78, the classical Parikh–Doering oxidation showed good chemoselectivity for the oxidation of the primary alcohol intermediate resulting from DIBAL-H reduction, in the presence of an amine group (a piperidine moiety) prone to oxidation. Moreover, the unexpected DMP oxidation (of 80)-triggered cascade Prins-type cyclization to give 81 inspired the authors to develop a method for the direct transformation of 79 to 81. Additionally, successive treatment of ketone 84 with KHMDS and Davis oxaziridine³⁹ allowed the indispensable α-hydroxylation (Scheme 8).

Scheme 8 20-step total synthesis of (±)-kopsinitarine E by Ma and co-workers.

2.9. Total synthesis of ophiobolin-derived sesterterpenoids bipolarolide B and bipoladien B

Bipolarolides A and B and bipoladien B are sesterterpenoids that exhibit potent HMGR inhibitory activity and possess intriguing cage-like scaffolds. In 2024, Jia and co-workers accomplished the first and enantioselective total syntheses of bipolarolides A and B via a bioinspired strategy.⁴⁰ Very recently, Fan and co-workers reported a distinct bridgehead enone-directed,⁴¹ divergent total synthesis of bipolarolide B (86) and bipoladien B (87).⁴² The first oxidation reaction in Fan's synthetic approach involves the hydroxy group-directed diastereoselective dihydroxylation of 89 with K₂[OsO₂(OH)₄](cat.)/4-methylmorpholine N-oxide (NMO), which, after subsequent chemoselective silylation of the resulting secondary diols with concomitant silyl enol etherification, and Conia-ene-type cyclization, afforded tricyclic ketone 90 in 51% yield. Next, for the key ketone 90 to bridgehead enone 91 transformation, a two-step protocol was first secured based on the Saegusa–Ito oxidation.⁴³ The moderate yield (43%) prompted them to explore a one-step method. After attempting the one-step method,⁴⁴ and inspired by Shvo's method,^44a the one-step, catalytic dehydrogenation of 90 was achieved in 78% yield using Pd(CF₃CO₂)₂ as the catalyst. Remarkably, the reaction could be performed on a 30 g scale. The oxidative cleavage of the vicinal diol in 92 with NaIO₄ followed by piperidine-mediated regioselective intramolecular aldol condensation afforded the ring-contracted product, which was further transformed into compound 93. Employing Brown's oxymercuration–demercuration method⁴⁵ as the key step, 93 was converted regio- and diastereo-selectively to compound 94 in three steps. Dehydrogenation of 95 by Barton's method [(PhSeO)₂O]⁹ set the stage for conjugate addition to yield 97. The resulting TMS enol ether 97 was subjected to Saegusa–Ito-type oxidation to produce trisubstituted enone 98 in 43% yield and recover ketone from 97 in 37% yield. Interestingly, compound 99 served as the common intermediate for the oxidative divergent total synthesis of bipolarolide B (86) and bipoladien B (87). Thus, regioselective allylic oxidation of 99 with SeO₂/t-BuO₂H⁴⁶ furnished bipolarolide B (86) in 79% yield, whereas Swern oxidation⁴⁷ of 99 afforded bipoladien B (87), completing its first total synthesis (Scheme 9). In this campaign, the ketone to enone transformation was performed three times at different stages of the total synthesis and by using different methods, highlighting the importance of developing versatile synthetic methods.

Scheme 9 Bridgehead enone-directed total synthesis of (±)-bipolarolide B and (±)-bipoladien B by Fan and co-workers.

2.10. Collective total syntheses of nine elisapterane and relevant diterpenoids

Elisapterosins A–F are diterpenoids isolated from the West Indian Sea Whip Pseudopterogorgia elisabethae (Bayer). Among them, elisapterosin B (101) was reported to exhibit strong inhibitory activity against Mycobacterium tuberculosis H37Rv. The total synthesis of elisapterosin B was achieved first by Rychnovsky and co-workers,⁴⁸ and then by other groups. Most of its total syntheses used a similar D-ring first strategy. In 2025, Ding and co-workers conceived an unprecedented bio-inspired late-stage D-ring formation strategy, leading to the divergent syntheses of several elisapterane and relevant diterpenoids (Scheme 10).⁴⁹ The divergent syntheses feature norneoelisabane-like (ABC ring system) tricyclic enone 111 as a common intermediate, readily accessible via Ding's in-house developed oxidative dearomatization-induced (ODI)-(5 + 2) cycloaddition/1,2-acyl migration cascade methodology.⁵⁰ The synthesis of common intermediate 111 relied on the phenyliodine(III) bis(trifluoroacetate) (PIFA) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)-mediated ODI-(5 + 2) cascade⁵⁰ of enantiopure 107, affording tricyclic skeleton 108 in 60% yield. Epoxidation of 108 with urea hydrogen peroxide (UHP)/trifluoroacetic anhydride (TFAA) proceeded diastereoselectively to yield epoxide 109 in 70% yield. Ley–Griffith oxidation¹⁵ of diol 110 furnished common intermediate 111 in 77% yield.

Scheme 10 Bioinspired collective total syntheses of marine natural products elisapterosins A–F, aberrarone, elisabanolide, and 3-epi-elisabanolide by Ding/Xia and co-workers.

For the synthesis of aberrarone (113) from 111, Albright–Goldman oxidation⁵¹ was employed for the oxidation of the C17-alcohol, whereas in the synthesis of elisabanolide (106), three oxidation steps were used. The Mukaiyama hydration of 114 promoted the desired concomitant elimination of the C2-tertiary alcohol to give 115 in 86% yield. Dihydroxylation of 115 with OsO₄/pyridine⁵² afforded 116 in 72% yield. Treatment of 116 with VOCl₃ and O₂⁵³ resulted in the formation of elisabanolide (106) via sequential oxidative cleavage. Treatment of elisapterosin C (102), derived from 116via elimination, with O_SO₄/Pyr., led to stereoselective dihydroxylation and spontaneous hemiketalization, affording the putative structure of elisapterosin F (104). On the other hand, for the conversion of elisapterosin C (102) to elisapterosin A (100), after many unsuccessful trials, benzeneseleninic anhydride⁵⁴ was found to be the reagent of choice, delivering the latter in 88% yield. Similarly, elisapterosin B (101) was oxidized to yield elisapterosin D (103). Employing Woerpel's alkene hydroperoxidation method⁵⁵ by treating elisapterosin B (101) with Co(pic)₂, tert-butyl hydroperoxide (TBHP) and O₂ resulted in an intramolecular oxygen atom transfer to provide 117 in 87% yield. Repeating the same protocol, the latter was further converted to elisapterosin A in 20% yield (25% brsm). Prolonged exposure of 118 to Woerpel's conditions afforded elisapterosin F (105). Similarly, elisapterosin D (103) was converted to elisapterosin A in 38% yield. It is important to note that in this total synthesis campaign, the structures of several natural products were found to be misassigned, which were revised via a combination of total synthesis and computer-assisted structure elucidation (CASE).

3. Oxidation of alcohols

Alcohols are some of the most prevalent functional groups in natural products. Depending on the synthetic purpose, primary alcohols can be oxidized to aldehydes or further to carboxylic acids or esters, whereas secondary alcohols are typically oxidized to ketones. Tertiary alcohols, which lack a hydrogen on the carbinol carbon, are generally resistant to oxidation. In the synthesis of a natural product, the selective oxidation of a specific alcohol in a complex structural setting with multiple functionalities often poses a challenge. Thus, a plethora of methods have been developed for the selective oxidation of alcohols. This section will highlight examples of the total synthesis of natural products and pharmaceutical molecules applying greener, milder and catalytic alcohol oxidation methods, including hypervalent iodine reagents, TPAP/NMO, nitroxyl radicals, and alcohol dehydrogenation.

3.1 Hypervalent iodine(V) reagents (IBX and DMP)

Among the many methods for alcohol oxidation, the hypervalent iodine(V) oxidants 2-iodoxybenzoic acid (IBX, 119) and Dess–Martin periodinane [DMP; 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, 120] have been widely used in natural product synthesis.^56,57 Although both oxidants are effective for the oxidation of alcohols to carbonyl compounds, DMP is usually preferred due to its superior solubility, milder conditions (room temperature), faster reaction rates, and higher yields; whereas the poor solubility of IBX in most organic solvents (except DMSO) limits its use to some extent. Nonetheless, both IBX and DMP are often the choice for alcohol oxidation in natural product syntheses, as highlighted in the selected examples below.

(−)-Alstrostine G (126) is an indole alkaloid isolated from the bark and trunks of Alstonia rostrata. This molecule contains an unusual 6/5/6/6/5/6 hexacyclic ring system with five stereocenters, rendering it a challenging target for total synthesis. Its first asymmetric total synthesis by Ma's group involves three DMP/IBX oxidation steps.⁵⁸ Dess–Martin oxidation of alcohol 121 followed by Horner–Wadsworth–Emmons (HWE) reaction provided α,β-unsaturated ester 122. A subsequent 3-step transformation led to pentacyclic core 123, in which the C19–C20 double bond was dihydroxylated and the resultant C19 alcohol was oxidized with DMP, providing α-hydroxy ketone 124. Final IBX oxidation of the primary alcohol in alstrostine G precursor 125 followed by I₂-mediated oxidative esterification of the resulting aldehyde completed the synthesis of (−)-alstrostine G (126) (Scheme 11).

Scheme 11 IBX and Dess–Martin oxidation in the total synthesis of (−)-alstrostine G.

Although primary and secondary alcohols are generally not differentiable with IBX and DMP, some cases on the selective oxidation of either have been reported. For example, in the synthesis of tetrodotoxin (129) by Qi's group,⁵⁹ the primary alcohol in diol intermediate 127 was selectively oxidized with IBX (1.05 eq.) to the aldehyde (not shown), which was then reacted with the secondary alcohol to form the corresponding hemiacetal. Subsequent acetalization with trimethylorthoacetate provided acetal (128) in 88% yield in a one-pot operation (Scheme 12).

Scheme 12 IBX oxidation in the total synthesis of tetrodotoxin.

In the second example, in the total synthesis of pallamolide A (131) by Jia's group,⁶⁰ the authors found that the rate of Dess–Martin oxidation of the secondary hydroxy group in the pallamolide A precursor 130 was much faster than that of the primary one. Thus, oxidation of 130 with 1.2 equivalent of DMP at 0 °C furnished the total synthesis of pallamolide A in 78% yield, significantly simplifying selective oxidation at the final stage of synthesis (Scheme 13). Although the reason for this subtle selectivity was not clear, it could be due to the steric hindrance around the primary alcohol and its hydrogen-bonding to the tertiary alcohol.

Scheme 13 Selective Dess–Martin oxidation in the total synthesis of pallamolide A.

The selectivity of the oxidation of alcohols could also be influenced by the reaction temperature. For instance, in the synthesis of phomactins by Sarpong's group,⁶¹ oxidation of advanced intermediate 132 with 2.0 eq. DMP at 0 °C selectively oxidized the C2 hydroxy group, providing ketone 133, which was further converted to Sch 49027 (134) by deacetylation–hemiketalization. When the reaction was carried out at 21 °C with 4.0 eq. DMP, both the C2 and C14 hydroxy groups were oxidized with subsequent formation of C2 hemiketal 135 after deacetylation. Final reduction of C14 ketone in 135 by Red-Al® provided a mixture of phomactin A (136) and Sch 49027 (134), which was separated by HPLC (Scheme 14).

Scheme 14 Dess–Martin oxidation in the total synthesis of Sch 49027 and phomactin A.

Additionally, DMP modified with t-butanol as a bulky ligand⁶² has been applied to control the regioselectivity in alcohol oxidation. For example, in the total synthesis of dolabriferol C (139) by Ward's group,⁶³ 1,9-diol (137) was selectively oxidized at the C1 position to provide ketone 138 in >10 : 1 selectivity (Scheme 15), whereas DMP and IBX were much less selective (ca. 4 : 1 and 1.2 : 1, respectively).

Scheme 15 Dess–Martin oxidation in the total synthesis of dolabriferol C.

Apart from alcohols, lactols can also be oxidized by IBX and DMP to form lactones. For example, in the total synthesis of (−)-cephalotanin B (144) by Hu's group,⁶⁴ deprotection of (i-Pr)₂CH in acetal intermediate 140 followed by oxidation of the resulting lactol with DMP provided lactone 141 in 80% yield over 2 steps. The double bond in 141 was stereoselectively epoxidized with H₂O₂/Na₂HPO₄, providing α-epoxide 142. Subsequent reduction of both C8 and C20 carbonyl groups with NaBH₄, followed by AgBF₄-promoted S_N2 displacement of the C3-chloride from the resultant C20-β-alcohol, installed ring G in 143 after reoxidation of the C8-alcohol with DMP. Final two-step transformation completed the total synthesis of (−)-cephalotanin B (Scheme 16).

Scheme 16 Dess–Martin oxidation in the total synthesis of (−)-cephalotanin B.

Thaigranatins V (149) and P (151) and erythrocarpines M (150) and L (152) are phragmalin-type limonoids featuring a complex cage-like tricyclo[3.3.1^2,10.1^1,4]decane core, rendering them challenging targets for total synthesis studies. Two Dess–Martin oxidation steps were employed in the total synthesis of these phragmalin-type limonoid natural products by Newhouse's group.⁶⁵ Firstly, the undesired configuration of C3–alcohol in tricyclic intermediate 145 was corrected by Dess–Martin oxidation, followed by reduction with NaBH₄. Secondly, a one-pot operation on alcohol 146 by TBS deprotection, global TMS protection, selective C9 TMS deprotection and subsequent Dess–Martin oxidation of the resultant C9 alcohol 147 provided ketone 148. Subsequent 6 steps of transformation led to thaigranatin V (149) and erythrocarpine M (150), which upon 1,6-reduction of the dienone with SmI₂/PhSH furnished thaigranatin P (151) and erythrocarpine L (152) (Scheme 17).

Scheme 17 Dess–Martin oxidation in the total synthesis of phragmalin-type limonoids.

More examples on the application of the IBX and DMP oxidation of alcohols in natural product synthesis are provided in Table 1.

Table 1 More examples on the application of IBX and DMP oxidation of alcohols in natural product synthesis

Entry	Source and significance of the natural product	Oxidation of alcohols using IBX and DMP
1	Vilmoraconitine (155) is a C19-diterpenoid alkaloid isolated from the traditional Chinese medicinal herb Aconitum vilmorinianum, used to treat rheumatism and pains
		Comment:^66 IBX oxidation of alcohol 153 provided aldehyde 154 in excellent yield
		Other oxidation reactions used: PhI(OAc)2 oxidation of phenol; Dess–Martin oxidation of alcohol to ketone; Ozonolysis of olefin; 2× AZADO oxidation of alcohol to aldehydes; and O2/LDA oxidative decyanation to ketone
2	Rubriflordilactone A (160) is a highly oxygenated polycyclic triterpenoid with anti-HIV activity, which is isolated from the Chinese herbal medicinal plant Schisandra rubriflora.
		Comment:^67 O-TIPS deprotection of 156 followed IBX oxidation of the resultant primary alcohol provided aldehyde 157. Oxidation of the furan in 158 with singlet oxygen followed TBS deprotection and IBX oxidation of the resulting benzylic alcohol afforded ketone 159
		Other oxidation reactions used: 2× photocatalytic singlet oxygen oxidation of furan to butenolid
3	Archangiumide (164) is an unusual allenic macrolide isolated from the myxobacterium Archangium violaceum SDU8 collected in Shandong Province in China
		Comment:^68 DMP oxidation of alcohol 162 provided aldehyde 163 in 98% yield
		Other oxidation reactions used: N/A
4	Neaumycin B (167) was isolated from the marine microbe Micromonospora sp. (strain CNY-010) in the Bahamas Islands. This compound displayed significant potency against several cancer cell lines
		Comment:^69 Dess–Martin oxidation of alcohol 165 followed by Horner–Wadsworth–Emmons (HWE) olefination of the resultant aldehyde provided α,β-unsaturated ester 166 in 79% yield over 2 steps
		Other oxidation reactions used: NaIO4 cleavage of 1,2-diol; 2× MnO2 oxidation of allylic alcohol; TBHP/VO(acac)2 epoxidation of allylic alcohol; TEMPO/PIDA oxidation of alcohol; and Stahl oxidation of alcohol
5	(−)-3-Oxoisotaxodione (172) was first isolated from the plant Taiwana cryptomerioides in 2005. This compound displayed promising anticancer, antibacterial, and antifungal activities
		Comment:^70 Two Dess–Martin oxidation steps were employed in the synthesis of 172
		Firstly, alcohol 168 was oxidized to the aldehyde 169. Secondly, the resultant alcohol after DIBAL-H demethylation-reduction of 170 was oxidized back to ketone 171 after selective triflation of the phenol
		Other oxidation reactions used: m-CPBA olefin epoxidation; HIO5 epoxide cleavage; (PhSeO)2O phenol oxidation to quinone; and DMDO olefin epoxidation-rearrangement
6	Sealutomicin C (175) is an anthraquinone antibiotic isolated from fermentation of the marine actinomycete Nonomuraea sp. MM565M-173N2
		Comment:^71 Dess–Martin oxidation of alcohol 173 provided aldehyde 174 in excellent yield
		Other oxidation reactions used: RuCl3/NaIO4 dihydroxylation of olefin; (NH4)2Ce(NO3)6 oxidation of p-aminophenol ether to iminoquinone; and DDQ deprotection of PMB
7	Principinol B (178) is a member of the grayanoid diterpenoids, isolated from Rhododendron principis growing in Tibet, China
		Comment:^72 Dess–Martin oxidation of alcohol 176 followed by reacting the resultant ketone with methyl cerium generated in situ and further elimination of the formed tertiary alcohol with SOCl2/Et3N provided triene 177
		Other oxidation reactions used: Tamao-Fleming oxidation; Parikh-Doering oxidation; m-CPBA epoxidation of olefin; OsO4 dihydroxylation of olefin; and Mukaiyama hydration of olefin
8	(−)-Sinulochmodin C (186) is a norcembranoid diterpenoid isolated from the genus Sinularia. This compound displayed anti-tumor and anti-inflammatory activities
		Comment:^73 IBX oxidation of alcohols 180 and 184 provided ketones 181 and 185, respectively
		Other oxidation reactions used: DDQ deprotection of PMB; 3× Saegusa oxidation of ketone to enone; Mukaiyama hydration of olefin; and m-CPBA epoxidation of olefin
9	Pepluacetal (193), featuring a 5/4/7/3 tetracyclic core, was isolated from Euphorbia peplus, which is a traditional medicine to treat asthma and psoriasis
		Comment:^74 Three Dess–Martin oxidation steps were employed in the total synthesis of 193. Oxidation of alcohol 187 to ketone 188, the alcohol after PMB deprotection of 189 to ketone 190, and the alcohol from DIBAL-H reduction of ester 191 to aldehyde 192
		Other oxidation reactions used: DDQ deprotection of PMB; Pinnick oxidation; Baeyer–Villiger oxidation; and CrO3 oxidation of allylic methylene to ketone.
10	The cephalotaxus diterpenoids such as cephinoid P (202) are a family of structurally diverse diterpenoids isolated from different species of Cephalotaxus
		Comment:^75 Oxidation of primary alcohols 195 and 198 with DMP provided the corresponding aldehydes 196 and 199, which were transformed to fragments 197 and 201, respectively, for the synthesis of cephinoid P (202) and other members of the cephalotaxus diterpenoids
		Other oxidation reactions used: Lindgren-Kraus oxidation; Swern oxidation; and OsO4/NaIO4 cleavage of olefin.
11	Bipolarolides A (209) and B (210) are sesterterpenoids isolated from Bipolaris sp. TJ403-B1. Structurally they possess a caged 5/6/6/6/5 pentacyclic skeleton bearing seven contiguous stereocenters, making them challenging targets for total synthesis
		Comment:^40 Dess–Martin oxidation of alcohols 204 and 206 provided ketones 205 and 207, respectively. Subsequent Prins reaction-ether formation cascade cyclization of 207 led to the 5/6/6/6/5 pentacyclic skeleton 208 of bipolarolides
		Other oxidation reactions used: Babler-Dauben oxidation; TEMPO/PIDA oxidation of alcohol; K2OsO4/NMO/NaIO4 cleavage of olefin; methylene blue/O2 and Babler-Dauben oxidation of olefin to enone
12	Strasseriolides A (213) and C (215) are 18-membered macrolides isolated from the fungus Strasseria geniculata CF-247, with strasseriolide C (215) displaying inhibitory activities against P. falciparum parasites
		Comment:^76 Dess–Martin oxidation of alcohol 211 followed by hydrolysis of ester 212 using Nicolaou's method provided strasseriolide A (213), while the same oxidation of alcohol 214 and subsequent deprotection of TBS group furnished strasseriolide C (215)
		Other oxidation reactions used: 2× Parikh Doering oxidation of alcohols; 2× ozonolysis; Ti-Salan-catalysed enantioselective epoxidation of unfunctionalized olefin; and MnO2 oxidation of propargyl alcohol
13	Lucidumone (219) is a meroterpenoid isolated from the fruiting bodies of Ganoderma lucidum cultivated in the Yunnan Province in China. Its structure features a complex 6/5/6/6/5 polycyclic ring system
		Comment:^77 Acid-catalyzed O-deprotection/Prins cyclization/cycloetherification sequence on 216 led to hexacyclic alcohol 217, which was oxidized with DMP to ketone 218
		Other oxidation reactions used: Iron-catalyzed Wacker-type oxidation of terminal olefin to methyl ketone.
14	Randainin D (224) is a diterpenoid isolated from Callicarpa randaiensis. This compound inhibits elastase release and superoxide-anion generation
		Comment:^78 IBX (5 eq.) was used to deprotect the primary TES ether in 220 and further oxidized the resulting alcohol to aldehyde 221. Subsequent isopropenylation provided alcohol 222, which was oxidized with DMP to ketone 223
		Other oxidation reactions used: Mukaiyama hydration of olefin to alcohol.
15	Discorhabdin V (227) is a member of the pyrroloimino-quinone alkaloids. This compound inhibits hypoxia-inducible factor 1 (HIF-1), a heterodimeric transcription factor that contributes to tumour development
		Comment:^79 Regioselective IBX oxidation of phenol 225 to o-quinone followed by p-toluenesulfonyl protection of N–H provided tosylamide 226
		Other oxidation reactions used: Air oxidation of o-diphenol to o-quinone; Stahl oxidation of primary alcohol to aldehyde; and Swern oxidation
16	The Malagasy family of alkaloids (e.g., 231 and 232) are polycyclic indoline compounds featuring unique trans-fused C/D rings
		Comment:^80 Mono decarboxylation of 228 followed by DIBAL-H reduction provided alcohol 229. Subsequent TFA-mediated one-pot deacetalization and intramolecular acetalization led to a lactol intermediate, which was oxidized to lactone 230 with DMP
		Other oxidation reaction used: Riley allylic oxidation

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3.2 Ley–Griffith oxidation (TPAP/NMO)

Ley–Griffith oxidation is the oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones, respectively, using a catalytic amount (5–10 mol%) of tetrapropylammonium perruthenate (TPAP) and N-methylmorphone N-oxide (NMO) as the co-oxidant. This reaction is named after William P. Griffith and Steven V. Ley, who first reported it in 1987.⁸¹ This reaction is known for its mild conditions and broad functional group tolerance, though stringently anhydrous conditions are required to achieve the optimal reaction performance.¹⁵ The application of this method in natural product synthesis is highlighted in selected examples below.

In the synthesis of Taxol (236) by Inoue's group,⁸² the primary alcohol in 233 was oxidized with TPAP/NMO and the resulting aldehyde was reacted with methyllithium to provide alcohol 234 in 76% yield over 2 steps. Secondary alcohol 234 was in turn oxidized with TPAP/NMO, leading to ketone 235 (Scheme 18).

Scheme 18 Ley–Griffith oxidation in the synthesis of Taxol.

In the total synthesis of isoxeniolide A (239) by Altmann's group,⁸³ double oxidation of a lactol and a primary alcohol in intermediate 237 under Ley–Griffith conditions provided the desired lactone-aldehyde 238 in 70% yield (Scheme 19), whereas a number of other oxidants, including DMP, PCC, PDC, and TEMPO/DAIB alone or in combination with Yb(OTf)₃, were ineffective.

Scheme 19 Ley–Griffith oxidation in the synthesis of isoxeniolide A.

Manginoids and guignardones are two types of biogenetically related meroterpenoids found in the fungus Guignardia mangiferae. These natural products possess intriguing architectures and exhibit diverse biological activities. In the combined synthesis of guignardones A/C (242 and 243) and manginoids A/C (244 and 245) by Zong et al.,⁸⁴ oxidation of the secondary alcohol in 240 to the common intermediate ketone 241 was achieved by Ley–Griffith oxidation, while other methods, including PDC, DMP and IBX, failed due to the sensitivity of the other functional groups in the molecule. Treatment of 241 with pyridinium p-toluenesulfonate (PPTS) furnished guignardones A/C, which were separated by silica gel column chromatography. A longer sequence of transformations led to manginoids A and C (Scheme 20).

Scheme 20 Ley–Griffith oxidation in the synthesis of manginoids and guignardones.

(+)-Haperforin G (250) is a potent inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) isolated from Harrisonia perforata. In the total synthesis of (+)-haperforin G by Zhang's group,⁸⁵ two Ley–Griffith oxidation steps were employed. The first oxidation of alcohol 246 provided ketone 247 without affecting the two labile TMS groups. The second Ley–Griffith oxidation of diol intermediate 248 led directly to lactone 249via the lactol intermediate formed from the resultant aldehyde with the tertiary alcohol (Scheme 21).

Scheme 21 Ley–Griffith oxidation in the synthesis of (+)-haperforin G.

19-Nordigitoxigenin (253) is an aglycon of antiroside Y, which is a 19-norcardenolide isolated from the bark of Antiaris toxicaria. Antiroside Y showed potent inhibitory activities against human cancer cell lines with a totally different mode of action, and hence is a potential candidate for cancer therapy. In the total synthesis of 19-norcardenolide by Nakazaki and co-workers,⁸⁶ hydrogenation of the double bond in 251 resulted in an 80 : 20 inseparable mixture of 5-β/α epimers. Interestingly, after Ley–Griffith oxidation of the C17-alcohol, the epimeric mixture was separable, providing the desired 5-β isomer (252) in 56% isolated yield over the two steps (Scheme 22).

Scheme 22 Ley–Griffith oxidation in the synthesis of 19-nordigitoxigenin.

In the concise and divergent total synthesis of brassicicenes by Wang and Chen,⁸⁷ the initial racemic enone [(±)-254] was deracemized by (R)-CBS reduction followed by Ley–Griffith oxidation of the desired isomer, providing the enriched enone 255 in 57% ee. Subsequent two-step reactions led to triene intermediate 256, which was converted to aldehyde 257 by regioselective hydroboration at the C7–C8 olefin and subsequent DMP oxidation. A critical Barbier reaction mediated by SmI₂ formed macrocycle 258, in which the C8-alcohol was oxidized to ketone 259 with DMP. Further transformations led to brassicicene K (260) (Scheme 23).

Scheme 23 Ley–Griffith oxidation in the synthesis of brassicicene.

3.3 Nitroxyl radical TEMPO and related reagents

Nitroxyl radicals are a class of stable organic free radicals used as catalysts for the oxidation of alcohols to aldehydes and ketones.⁸⁸ Among them, the most well-known is 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO, 261)⁸⁹ but it often shows sluggish activity in the oxidation of hindered alcohols. To overcome this limitation, other nitroxyl radicals, such as AZADO (262)¹⁴ and ABNO (263),⁹⁰ have been developed for enhanced reactivity. The nitroxyl radicals require a terminal oxidant (or co-oxidant) for alcohol oxidation to regenerate the active oxoammonium cation species to maintain the catalytic cycle. A variety of terminal oxidants, such as NaOCl, Oxone®, O₂/air, PhIO, phenyliodine(III) diacetate (PIDA or BAIB), trichloroisocyanuric acid (TCCA), t-butyl hydroperoxide (TBHP), and KBrO₃, have been used. The choice of a co-oxidant is often dictated by the specific reaction conditions, desired selectivity, and environmental considerations. Additionally, nitroxyl radicals can be used in combination with a metal co-catalyst, such as copper (Stahl oxidation)⁹¹ or iron (Ma oxidation)⁹² with molecular oxygen as a green oxidant. Apart from the often-used nitroxyl radical catalysts, their oxoammonium salt derivatives such as 4-acetamido-2,2,6,6-tetramethyl-1-oxopiperidinium tetrafluoroborate (Bobbitt's salt, 264)⁹³ have also been used for alcohol oxidation, although a stoichiometric amount of the reagent is required. For primary alcohols, the aldehydes formed can be further oxidized to carboxylic acids in combination with a suitable co-oxidant such as PIDA, providing convenient access to carboxylic acids in an efficient one-step operation.

Alcohol oxidation using nitroxyl radicals has several notable advantages, including high chemoselectivity, mild reaction conditions, use of environmentally benign oxidants (e.g. O₂/air), choice of catalyst (TEMPO, AZADO and ABNO) for optimal outcome, and scalability. Thus, they are often the choice for alcohol oxidation in the synthesis of natural products and pharmaceutical compounds, as shown in the examples below.

In the total synthesis of pedrolide (267) by Li and co-workers,⁹⁴ dihydroxylation of the olefin in 265 followed by regioselective oxidation of the less hindered C13-hydroxy group with TEMPO/KBr-NaOCl provided hydroxy ketone 266 in 85% yield in a one-pot operation (Scheme 24).

Scheme 24 TEMPO oxidation of alcohol in the synthesis of pedrolide.

TEMPO with a suitable co-oxidant can selectively oxidize a primary alcohol in the presence of a secondary one, whereas it is difficult to achieve by using DMP or IBX. For example, in the total synthesis of (±)-cryptotrione (270),⁹⁵ the primary alcohol in the advance intermediate (268) was selectively oxidized to aldehyde (269) using TEMPO and PIDA in excellent yield without affecting the secondary alcohol (Scheme 25).

Scheme 25 TEMPO-selective oxidation of primary alcohol in the synthesis of (±)-cryptotrione.

In another example, in the synthesis of (+)-davisinol (273) by Ding's group,⁹⁶ selective benzoylation of the equatorial hydroxymethyl group in 271, followed by chemoselective oxidation of the primary alcohol in the resulting benzoate with TEMPO and NCS (N-chlorosuccinimide) at 0 °C provided the aldehyde (272) without affecting the secondary alcohol (Scheme 26).

Scheme 26 TEMPO-selective oxidation of primary alcohol in the synthesis of (+)-davisinol.

As less hindered nitroxyl radicals than TEMPO, AZADO (262) and ABNO (263) have also been used in the selectivity oxidation of alcohols with enhanced activity for sterically hindered secondary alcohols, often in combination with a Cu(I) or Fe(III) co-catalyst. For example, at the final stage in the synthesis of vilmoraconitine (155) by Qin's group,⁶⁶ to overcome the challenge in selective reduction of the amide in the presence of the C14 ketone in 274, both the amide and ketone were reduced with LiAlH₄ and the resulting alcohol (275) was reoxidized to ketone using AZADO/CuCl and air as the co-oxidant, completing the synthesis of vilmoraconitine (Scheme 27).

Scheme 27 AZADO/Cu(I) oxidation of alcohol in the synthesis of vilmoraconitine.

In another example, in the synthesis of C19 diterpenoid alkaloids (−)-talatisamine (278), (−)-liljestrandisine (279) and (−)-liljestrandinine (280) by Reisman and co-workers,⁹⁷ the diol from the deprotection of the cyclic silyl ether (276) was selectively oxidized at the allylic position using an ABNO/Cu(I)-^MeObpy (4,4′-dimethoxy-2,2′-bipyridine) complex and N-methylimidazole (NMI).⁹⁸ Subsequent MOM protection of the remaining hydroxy group led to the common enone intermediate (277) in 75% yield over 3 steps (Scheme 28).

Scheme 28 AZADO/Cu(I) oxidation of alcohol in the synthesis of (−)-talatisamine, (−)-liljestrandisine and (−)-liljestrandinine.

One of the prominent advantages of nitroxyl radical-mediated alcohol oxidation is that oxygen or air can be used as an inexpensive and environmentally benign terminal oxidant. For example, in the synthesis of (+)-discorhabdin V (227) by Burns’ group,⁷⁹ the primary alcohol in diol 281 was selectively oxidized to aldehyde 282 under Stahl conditions (TEMPO, CuBr, bipy, NMI and air).⁹⁰ Subsequent double condensation and cyclization of 282 with NH₄OAc/AcOH/MeOH led to N,O-acetal 283, which underwent reductive demethoxylation, providing cyclic amine 284 in 58% yield in an efficient one-pot operation (Scheme 29).

Scheme 29 TEMPO/Cu(I) selective oxidation of primary alcohol in the synthesis of discorhabdin V.

More examples of the nitroxyl radical-catalyzed oxidation of alcohols are provided in Table 2. Apart from converting primary alcohols to aldehydes, nitroxyl radicals in conjunction with a suitable co-oxidant can also oxidize primary alcohols directly to carboxylic acids, making it a selective and efficient transformation (see Section 4.2).

Table 2 More examples of nitroxyl radical-mediated oxidation of alcohols in natural product synthesis

Entry	Source and significance of natural product	Oxidation of alcohols using nitroxyl radical and related reagents
1	Daphnezomines A (288) and B (289) are daphniphyllum alkaloids isolated from the leaves of Daphniphyllum humile. Daphnezomine B displayed notable cytotoxicity in murine lymphoma L1210 cells
		Comment:^99 Bobbitt's salt (4.0 eq.) cleaved the benzyl ether in 285 and further oxidized the resulting alcohol to carboxylic acid (286), which was further converted to methyl ester 287
		Other oxidation reactions used: Dess–Martin oxidation
2	Neaumycin B (167) was isolated from the marine microbial Micromonospora sp. (strain CNY-010) in the Bahamas Islands. This compound displayed significant activities against several cancer cell lines
		Comment:^100 The primary alcohol in 290 was selectively oxidized to aldehyde 291 without affecting the secondary alcohol and the epoxide
		Other oxidation reactions used: 3× ozonolysis; 5× Dess–Martin oxidation; CF3CO3H epoxidation of olefin; and 2× DDQ deprotection of PMB
3	Cephalotanin B (144) is a member of the Cephalotaxus diterpenoids found in Cephalotaxus plants. This molecule possesses a highly congested heptacyclic skeleton, three lactone units, and nine consecutive stereocenters
		Comment:^64 Alcohols from TBDPS deprotection of 292 and reaction of 293 were oxidized with TEMPO/NaOCl-KBr, providing aldehyde 293 and ketone 295, respectively
		Other oxidation reactions used: 2× Dess–Martin oxidation
4	Pre-schisanartanin C (298) is a nortriterpenoid isolated from the Schisandra genus. This compound exhibited potent anti-hepatitis, antitumor and anti-HIV activities
		Comment:^101 The primary alcohol in 296 was selectively oxidized to aldehyde 297 using TEMPO/PIDA without affecting the secondary alcohol
		Other oxidation reactions used: Riley allylic oxidation; Ley–Griffith oxidation; m-CPBA epoxidation; Upjohn dihydroxylation; and Sharpless AD
5	Batrachotoxin (305) is a steroidal alkaloid isolated as the toxic principle of Phyllobates. This compound is one of the most toxic natural substances known with an LD50 of 2 μg kg^−1 (subcutaneous in mice)
		Comment:^102 AZADOL mediated the oxidation of lactol 299 to lactone 300 and β-diol 301 to β-keto aldehyde 302, which was further converted to lactam 304
		Other oxidation reactions used: RuCl3/NaIO4 cleavage of olefin; Ozonolysis; and VO(O^iPr)3/PhC(Me)2OOH epoxidation of olefin
6	Zephycarinatines C (309) and D (310) are plicamine-type alkaloids isolated from Zephyranthes carinata. They displayed cytotoxic properties against a variety of cancer cell lines and anti-inflammatory activities
		Comment:^103 Oxidation of the primary alcohol in 306 with AZADOL/NaClO2-NaOCl led to carboxylic acid 307, which was further converted to methyl amide 308
		Other oxidation reactions used: TPAP/NMO oxidation of allylic methylene to ketone
7	Hikizimycin (314) is a nucleoside antibiotic natural product isolated from the fermentation broth of Streptomyces A-5. This compound inhibits protein synthesis and exhibits antiparasitic and antibiotic activities.
		Comment:^104 Primary alcohol 312 from the selective deacetylation of 311 was oxidized to carboxylic acid 313 using AZADOL/PIDA
		Other oxidation reaction used: DDQ deprotection of benzyl ether
8	Daphnilongeranin A (317) and calyciphylline A (318) are members of daphniphyllum alkaloids from the genus Daphniphyllum. This class of natural products possesses complex structures and diverse biological activities
		Comment:^105 Oxidation of primary alcohol in 315 with ABNO/PIDA led to the carboxylic acid, which was methylated, providing methyl ester 316. Further transformation led to daphnilongeranin A and calyciphylline A
		Other oxidation reactions used: UHP/TFAA epoxidation of olefin; m-CPBA oxidation of tertiary amine to N-oxide; ozonolysis; H2O2 oxidation of tertiary amine to N-oxide; and KHMDS/O2/P(EtO)3 α-hydroxylation of ketone
9	Disciformycin A (320) is a polyketide-derived macrolide glycoside isolated from the myxobacterium Pyxidicoccus fallax strain AndGT8. This compound exhibits antibacterial activity against Gram-positive bacteria
		Comment:^106 At the final stage of synthesis, the allylic alcohol in tetrol 319 was selectively oxidized with Bobbitt's salt without protection of the sugar hydroxy groups
		Other oxidation reactions used: MnO2 oxidation of allylic alcohol; DM oxidation of primary alcohol to aldehyde; Pinnick oxidation; and DDQ deprotection of PMB

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3.4 Oxidation by alcohol dehydrogenation

Alcohol oxidation via dehydrogenation is an important transformation in organic synthesis. It enables the conversion of primary and secondary alcohols into aldehydes and ketones, respectively, without the use of stoichiometric oxidants. This reaction typically employs transition metal catalysts that mediate the removal of a molecule of hydrogen from the hydroxy group and the carbon linked to it, releasing molecular hydrogen as the sole by-product, making the process highly atom-economical and environmentally attractive. The catalysts most often used for alcohol dehydrogenation are complexes of noble metals such as Ru, Ir, Pt, Pd, and Rh, although earth-abundant metals such as Mn, Fe, Co, Ni, and Cu have also been used. In addition, the carbonyl compounds formed in the reaction can be used for subsequent transformations before the catalyst returns the bonded hydrogen to liberate the product and regenerate the catalyst, which is a concept termed “hydrogen autotransfer” or “borrowing hydrogen”.¹⁰⁷ In the presence of a chiral ligand, the reaction proceeds in an enantioselective manner, which is often required in natural product synthesis.^107c The merits of mild conditions, high selectivity and reduced waste generation make alcohol dehydrogenation an attractive alternative to traditional stoichiometric oxidants in natural product synthesis. Significantly, owing to the discovery by Tu,¹⁰⁸ and Krische's innovative contribution,¹⁰⁹ the direct catalytic functionalization of carbinol C–H bonds (Scheme 30a) has become a redox-economical reaction.^108b,c,109 Particularly, Krische's elegant catalytic asymmetric version has rendered this methodology a powerful tool in the catalytic asymmetric total synthesis of natural products,^2g as highlighted by the selected examples shown below.

Scheme 30 Catalytic enantioselective hydrogen autotransfer reaction in the synthesis of leiodermatolide.

In the total synthesis of leiodermatolide A (324) by Krische's group,¹¹⁰ in the presence of an iridium-(S)-DM-SEGPHOS catalyst generated in situ, alcohol 321 underwent dehydrogenation to form the corresponding aldehyde (not shown), which was further reacted with the allenyliridium generated from the Ir–H complex with the conjugated enyne (322), providing 323 in 63% yield, 9 : 1 dr and 90% ee (Scheme 30b).

In the synthesis of neaumycin B (167) by Chen's group,¹⁰⁰ two homoallylic alcohol intermediates, 327 and 329, were obtained via transfer hydrogenative crotylation. On the one hand, (R)-SEGPHOS-Ir catalyzed the dehydrogenative coupling of alcohol 325 with but-3-en-2-yl acetate (326) provided homoallylic alcohol 327 in high diastereo- and enantio-selectivity. On the other hand, coupling of alcohol 328 and 326 using the (S)-SEGPHOS-Ir catalyst afforded fragment 329 (Scheme 31).

Scheme 31 Catalytic enantioselective hydrogen autotransfer reaction in the synthesis of neaumycin B.

In the total synthesis of the indolizidine alkaloid bipolamine I (333) by Pierce's group,¹¹¹ the resultant aldehyde (not shown) from the dehydrogenation of alcohol 330 was coupled with the allylruthenium intermediate formed from the acetylenic pyrrole (331), providing key intermediate 332 (Scheme 32).

Scheme 32 Catalytic hydrogen autotransfer reaction in the synthesis of (±)-bipolamine I.

In summary, hypervalent iodine reagents, Ley–Griffith oxidation, nitroxyl radicals, and alcohol dehydrogenation are common methods for alcohol oxidation in natural product total syntheses. Hypervalent iodine(V) reagents are mild, selective and metal-free reagents for the oxidation of alcohols to aldehydes or ketones with broad functional group tolerance, but require stoichiometric quantities, which generate waste. Ley–Griffith oxidation is efficient, high-yielding and compatible with a wide range of functional groups, but requires stringent anhydrous conditions, besides the high cost of the TPAP catalyst. Nitroxyl radicals are catalytic, selective for alcohols, and compatible with a wide range of functional groups. Additionally, when combined with environmentally friendly, inexpensive co-oxidants such as bleach and oxygen, hazardous waste is minimized, making nitroxyl radicals a more sustainable choice for alcohol oxidation, especially for large-scale reactions. Finally, alcohol dehydrogenation using transition metal catalysts is highly atom economical and environmentally attractive, though the requirement of higher temperatures and expensive transition metal catalysts limit its broad application to some degree. Together, these methods provide complementary tools for selective and efficient alcohol oxidation in natural product total syntheses.

4. Oxidation of aldehydes to carboxylic acids and esters

A number of methods have been developed for the oxidation of aldehydes to carboxylic acids and esters. Traditional methods employing reagents such as KMnO₄ and Cr(VI) (Jones oxidation) are inexpensive and reliable but suffer from poor selectivity and environmental concerns, leading to their reduced use. Hypervalent iodine reagents, such as PIDA and IBX, offer mild and versatile options but are limited by their cost and formation of stoichiometric waste. The Pinnick oxidation is often the method of choice for natural product synthesis owing to its high chemoselectivity, functional group compatibility and mild conditions. However, TEMPO-catalyzed oxidation is a more sustainable alternative as it utilizes inexpensive and green terminal oxidants, such as NaOCl or molecular oxygen. Apart from carboxylic acids, in the presence of a metal catalyst such as Pd, Cu, and Ag or stoichiometric iodine in combination with an alcohol, aldehydes can be converted to esters in one step under oxidative esterification conditions.

4.1 Pinnick oxidation

The Pinnick oxidation is a highly selective and mild method for oxidizing aldehydes to carboxylic acids.¹¹² In this reaction, inexpensive sodium chlorite (NaClO₂) is used as the oxidant. 2-Methyl-2-butene is often added to the reaction as a scavenger to prevent interference from the byproduct hypochlorous acid (HOCl) formed during the reaction. The advantages of the Pinnick oxidation include high chemoselectivity, and tolerance to a broad range of functional groups, such as double bonds, triple bonds and epoxides. The reaction is particularly effective for oxidizing α,β-unsaturated aldehydes, which are often problematic substrates with other oxidants.¹¹³ Owing to these merits, the Pinnick oxidation has found wide application in natural product synthesis, as illustrated below.

Irijimasides are 14-membered macrolide glycosides isolated from the marine cyanobacterium Okeania sp. collected from Irijima, Okinawa, Japan. In the first total synthesis of (−)-irijimaside A (336) by Umehara and co-workers,¹¹⁴ chemoselective oxidation of the primary alcohol in 334 with TEMPO/NCS and further Pinnick oxidation of the resultant aldehyde (not shown) provided carboxylic acid 335 in 58% yield over the two steps (Scheme 33).

Scheme 33 Pinnick oxidation in the synthesis of (−)-irijimaside A.

(−)-Zygadenine (339) is one of the most highly oxygenated members of the Veratrum alkaloids. In the first total synthesis of zygadenine by Luo's group,¹¹⁵ the aldehyde in the sensitive intermediate (337) underwent Pinnick oxidation smoothly, providing carboxylic acid 338 in excellent yield (Scheme 34).

Scheme 34 Pinnick oxidation in the synthesis of (−)-zygadenine.

Liangshanone (342) is a hexacyclic ent-kaurane diterpenoid alkaloid with a range of biological activities. In the first total synthesis of liangshanone by Qin and co-workers,¹¹⁶ Pinnick oxidation of aldehyde 340 provided carboxylic acid 341 in 95% yield without affecting the tertiary amine (Scheme 35).

Scheme 35 Pinnick oxidation in the synthesis of liangshanone.

In Aggarwal's synthesis of 10-deoxymethynolide (345),¹¹⁷ Dess–Martin oxidation of alcohol 343 followed by Pinnick oxidation provided carboxylic acid 344 in 80% yield over two steps without affecting the enone and the silyl group (Scheme 36).

Scheme 36 Pinnick oxidation in the synthesis of 10-deoxymethynolide.

Arbophyllidine (349) is an unusual pentacyclic monoterpenoid indole alkaloid isolated from the bark of Malayan Kopsia arborea. This compound displayed growth inhibitory activity against HT-29 human cancer cells. In the first asymmetric total synthesis of arbophyllidine by Zhai and co-workers,¹¹⁸ IBX oxidation of the primary alcohol in 346 followed by Pinnick oxidation of the resultant aldehyde 347 led to lactone 348 instead of the corresponding carboxylic acid (Scheme 37). The unusual lactonization is likely facilitated by the carbocation generated at C16 from free chlorine in the reaction medium, as suggested by their DFT calculation.

Scheme 37 Pinnick oxidation in the synthesis of arbophyllidine.

4.2 Nitroxyl radical-catalyzed oxidation

In the nitroxyl radical-catalyzed oxidation of primary alcohols, the aldehydes formed can be further oxidized to carboxylic acids in the presence of a suitable co-oxidant such as PIDA, TCCA and O₂. This one-pot operation provides direct selective and efficient access to carboxylic acids from primary alcohols. For example, in the synthesis of piperaborenine B (352),¹¹⁹ exhaustive oxidation of both the aldehyde and alcohol in 350 under the Ma oxidation conditions⁹² provided the dicarboxylic acid (351), which was converted to piperaborenine B by sequential reactions with oxalyl chloride and dihydropyridinone (Scheme 38).

Scheme 38 TEMPO-catalyzed oxidation of alcohol/aldehyde to carboxylic acid in the synthesis of piperaborenine B.

In the synthesis of tetrachlorovancomycin (355) as a new vancomycin analogue,¹²⁰ oxidation of the primary alcohol in 353 with TEMPO/PhI(OAc)₂ (2.5 eq.) provided the corresponding carboxylic acid (354) in excellent yield without affecting the electron-rich biaryl moiety (Scheme 39).

Scheme 39 TEMPO-catalyzed oxidation of alcohol to carboxylic acid in the synthesis of tetrachlorovancomycin.

In the synthesis of (−)-isoscopariusin A (358), an immunosuppressive meroditerpenoid natural product isolated from the aerial parts of Isodon scoparius, oxidation of the primary alcohol in 356 with ABNO/PhI(OAc)₂ (2.4 eq.) provided carboxylic acid 357 in 89% yield (Scheme 40).¹²¹

Scheme 40 ABNO-catalyzed oxidation of alcohol to carboxylic acid in the synthesis of (−)-isoscopariusin A.

4.3 Oxidative esterification

Oxidative esterification of aldehydes enables the conversion of an aldehyde in conjunction with an alcohol directly to an ester without the need to isolate the carboxylic acid.¹²² The transformation involves reacting the aldehyde with an alcohol to form a hemiacetal, which is then oxidized by a suitable catalyst or oxidant to form the ester. For example, in the synthesis of (−)-demethoxychippiine (361),¹²³ an aldehyde (359) was converted to a methyl ester (360) using an excess of iodine and KOH (Scheme 41). Ester intermediate 360 was transformed into (−)-demethoxychippiine and other members of post-iboga indole alkaloids.

Scheme 41 Oxidative esterification in the synthesis of (−)-demethoxychippiine.

Apart from aldehydes, lactols can also undergo oxidative esterification to form lactones. For instance, in a unified synthesis of cephalotaxus diterpenoids by Zhao's group,¹²⁴ the advanced lactol intermediate 362 was oxidized to lactone 363 using silver carbonate supported on Celite. Subsequent hydrogenation of the carbonyl group in 363 led to a mixture of cephanolide E (364) and its 13-epimer (365) in a ratio of 1 : 4.2, which was separated by silica gel chromatography (Scheme 42).

Scheme 42 Ag₂CO₃ oxidation of lactol to lactone in the synthesis of cephanolide E and its 13-epimer.

In summary, aldehydes can be oxidized to carboxylic acids via the Pinnick oxidation and nitroxyl radical-catalyzed oxidation. The Pinnick oxidation uses sodium chlorite under mild acidic conditions, offering broad functional group tolerance and efficiency for sensitive or sterically hindered substrates. Nitroxyl radical-catalyzed oxidation, often in conjunction with a base metal catalyst and benign co-oxidants such as oxygen, provides a selective, cost-efficient and greener method to convert aldehydes to carboxylic acids. Additionally, the reaction is often carried out under cascade or one-pot conditions, along with the previous step of alcohol oxidation to the aldehyde, making it a highly efficient operation to access carboxylic acids in natural product syntheses. Despite being less often employed and less atom economical, the direct conversion of aldehydes to esters through classical methods by using iodine and silver oxide remain a valuable methodology in certain structural settings.

5. Oxidation of alkenes

Alkene oxidations are a cornerstone for the synthesis of natural products, since they enable the conversion of carbon–carbon double bonds into oxygenated motifs such as epoxides, diols, carbonyls, and alcohols widely present in natural products. In addition, the oxygenated functionalities resulting from alkene oxidations often bridge the next stage of transformation in the synthesis. Modern alkene oxidation chemistry emphasizes not only chemo- and regio-selectivity, but also enantioselectivity, atom-economy, sustainability, and electrochemical and photo oxidations. This section will exemplify key alkene oxidation reactions, including epoxidation, dihydroxylation, carbonylation (Wacker oxidation) and hydroxylation, in recent studies on the synthesis of natural products.

5.1 Epoxidation of alkenes

Epoxidation converts an alkene to an epoxide, which is widely present in natural products. Additionally, epoxides often serve as intermediate motifs for further transformations, notably via stereoselective ring-opening with diverse nucleophiles. Methods for alkene epoxidations involve the use of peroxyacids, peroxides (oxiranes, Oxone, H₂O₂), Shi and Mn(salen) catalysts for unfunctionalized alkenes, and Sharpless asymmetric epoxidations for allylic alcohols. With an emphasis on sustainability, greener oxidants (H₂O₂, oxone, and molecular oxygen) and electrochemical methods have been applied in epoxidation reactions.

5.1.1 Epoxidation using peroxide reagents. Peroxy reagents, such as organic peracids [m-chloroperbenzoic acid (m-CPBA) and trifluoroperacetic acid], alkyl peroxides [t-butyl hydroperoxide (TBHP) and dimethyldioxirane (DMDO)], inorganic peroxides [urea-hydrogen peroxide complex (UHP)], and [potassium peroxymonosulfate (Oxone®)], are often used for alkene epoxidation due to their low cost. Selected examples on the application of peroxy reagents in alkene epoxidations are highlighted below.
5.1.1.1 Peroxyacids. As a classical oxidant, m-CPBA¹²⁵ remains one of the most used oxidants for alkene epoxidation in natural product synthesis, owing to its easy accessibility and low-cost. However, due to its thermal instability, potential explosion hazard and poor atom-economy, m-CPBA is mostly limited to small-scale laboratory use.

In Dong's first total synthesis of phainanoid A (370),¹²⁶ they attempted VO-catalyzed, OH-directed epoxidation of the olefin in 366, which resulted in epoxide 367 with undesired stereochemistry. Alternative m-CPBA epoxidation of TMS-protected alcohol 368 enabled epoxidation from the less hindered Re-face, providing the desired epoxide 369 in 65% yield as a single diastereomer (Scheme 43).

Scheme 43 m-CPBA epoxidation of olefin in the synthesis of phainanoid A.

Cyclopamine (373) is a teratogenic steroidal alkaloid inhibiting the Hedgehog signalling pathway. In the total synthesis of cyclopamine by Gao's group,¹²⁷ selective m-CPBA epoxidation of the more electron-rich tetrasubstituted C13–C17 double bond in 371 from the less hindered α-face was achieved by careful control of the reaction time and temperature (−15 °C), providing the desired mono-epoxide 372 in 60% yield (Scheme 44).

Scheme 44 m-CPBA epoxidation of olefin in the synthesis of cyclopamine.

In the total synthesis of (−)-sinulochmodin C (186) by Zhang's group,⁷³ epoxidation of the double bond in 374 with m-CPBA occurred preferentially from the less hindered bottom face, providing the desired α-epoxide 375 in 87% yield (Scheme 45).

Scheme 45 m-CPBA epoxidation of olefin in the synthesis of (−)-sinulochmodin C.

5.1.1.2 Urea hydrogen peroxide (UHP). Urea hydrogen peroxide [CO(NH₂)₂·H₂O₂, UHP] is a safe and convenient alternative to anhydrous hydrogen peroxide, with the advantages of controlled release of H₂O₂, water-free reaction conditions, environmental friendliness and cost-effectiveness. As a result, UHP has been widely used for alkene epoxidation, often in combination with a promoter such as carboxylic anhydrides, nitriles, or metal catalysts.¹²⁸ Examples of the use of UHP in alkene epoxidation for natural product synthesis are highlighted below.

In the asymmetric total syntheses of 8,9-seco-ent-kaurane diterpenoids by Ding's group,¹²⁹ chemo- and stereo-selective epoxidation of the more electron-rich trisubstituted alkene in (−)-shikoccin (376) was achieved by using UHP in combination with trifluoroacetic anhydride (TFAA), providing (−)-epoxyshikoccin (377) without affecting the exocyclic olefin. Further methylation on the hydroxy group provided (+)-O-methylepoxyshikoccin (378) (Scheme 46).

Scheme 46 UHP epoxidation of olefin in the synthesis of (−)-epoxyshikoccin.

In Li's synthesis of daphniphyllum alkaloids,¹⁰⁵ selective epoxidation of the exocyclic double bond in 379 with UHP and TFAA at −20 °C provided epoxide 380. Subsequently, base-promoted double bond migration-δ-alkoxy elimination cascade of the epoxide provided hydroxy dienone 381, which was transformed to calyciphylline A (318) (Scheme 47).

Scheme 47 UHP epoxidation of olefin in the synthesis of calyciphylline A.

In the synthesis of (−)-zygadenine (339) by Luo's group,¹¹⁵ regio- and diastereo-selective epoxidation of the C15–C16 olefin in 382 was achieved by using UHP-TFAA at 0 °C, providing epoxide 383. Subsequent cleavage of both the epoxide and carbonate by Ti-mediated radical reduction provided tetraol 384 in 57% yield over the two steps (Scheme 48).

Scheme 48 UHP epoxidation of olefin in the synthesis of (−)-zygadenine.

5.1.1.3 Sharpless asymmetric epoxidation. The Sharpless asymmetric epoxidation of prochiral allylic alcohols¹³⁰ is one of the most used methods for alkene epoxidation and has been applied in the synthesis of numerous natural products.¹³¹ This epoxidation method continues to be a powerful tool in natural product synthesis, as illustrated in the examples below.

Xiamycin A (387) was isolated from Streptomyces sp. GT2002/1503, an endophyte from the mangrove plant Bruguiera gymnorrhiza. This indole alkaloid displayed anti-HIV activities and can form rare N–N atropisomers (dixiamycins) by dimerization at the indole nitrogen. In the total synthesis of xiamycin A by Bisai's group,¹³² Sharpless asymmetric epoxidation of allylic alcohol 385 provided epoxide 386 in excellent yield and ee (Scheme 49).

Scheme 49 Sharpless asymmetric epoxidation in the synthesis of xiamycin A.

In Fürstner's total synthesis of mycinolide IV (391),¹³³ Sharpless asymmetric epoxidation of allylic alcohol 388 using cumene hydroperoxide as the terminal oxidant provided epoxide 389 in 87% ee. Further transformations led to enyne fragment 390 for mycinolide IV synthesis (Scheme 50).

Scheme 50 Sharpless asymmetric epoxidation in the synthesis of mycinolide IV.

Mannopeptimycins (MPPs) are cyclic peptides isolated from Streptomyces hygroscopicus LL-AC98. These compounds displayed promising activities against clinically important resistant Gram-positive pathogens such as Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococci (VRE). In the total synthesis of mannopeptimycin β (398) by Li's group,¹³⁴ Sharpless asymmetric epoxidation of two allylic alcohols (392 and 395) provided the corresponding epoxides (393 and 396), which were transformed to L- and D-β-hydroxyenduracididine (394 and 397) in suitably protected forms for the assembly of mannopeptimycin β, respectively (Scheme 51).

Scheme 51 Sharpless asymmetric epoxidation in the synthesis of mannopeptimycin.

Angucyclinones are a large family of aromatic polyketide natural products with a wide range of biological activities. In the total synthesis of angucyclinones by Kaliappan's group,¹³⁵ Sharpless asymmetric epoxidation of geraniol (399) provided epoxide 400, which was transformed to 4-hydroxy-8-O-methyltetrangomycin (401) and 4-keto-8-O-methyltetrangomycin (402) (Scheme 52).

Scheme 52 Sharpless asymmetric epoxidation in the synthesis of 4-hydroxy-8-O-methyltetrangomycin and 4-keto-8-O-methyltetrangomycin.

5.1.1.4 Other epoxidation methods. In addition to the aforementioned methods, there are several other methods/regents for the epoxidation of alkenes.

Dimethyldioxirane (DMDO) is an inexpensive yet versatile oxidant for the epoxidation of olefins. In 2014, Huang's group developed a DMDO-epoxidation-triggered double cyclization strategy enabling the four-step total synthesis of (−)-chaetominine.¹³⁶ Through further elaboration of this strategy, in 2025, this group disclosed the first enantioselective synthesis of both the proposed (405) and revised (407) structures of aspera chaetominine B, which was completed in five steps from the readily available D-tryptophan (Scheme 53).¹³⁷

Scheme 53 DMDO epoxidation of indole in the synthesis of aspera chaetominine B.

The Shi epoxidation¹³⁸ is an organocatalytic method for the asymmetric epoxidation of unfunctionalized olefins, which complements the Sharpless asymmetric epoxidation of allylic alcohols. This reaction uses a fructose-derived chiral ketone as the catalyst and potassium peroxymonosulfate (Oxone®) as the stoichiometric oxidant, which reacts with the chiral ketone to in situ form a chiral dioxirane intermediate for stereoselective epoxidation. This reaction is particularly effective for creating chiral epoxides from trans-disubstituted and trisubstituted alkenes with high enantioselectivity. For example, in the synthesis of the anti-cancer compound pladienolide B (411) by Krische's group,¹³⁹ diastereoselective Shi epoxidation of the double bond in 408 provided epoxide 409. Subsequent hydroboration of the alkyne led to fragment 410 for the synthesis of pladienolide B (Scheme 54).

Scheme 54 Shi epoxidation of olefin in the synthesis of pladienolide B.

V and Ti complexes have been used for substrate-controlled epoxidation of chiral allylic alcohols without a chiral ligand. For example, in a unified total synthesis of phomactins,⁶¹ hydroxy group-directed selective epoxidation of one or both C1–C14 and C3–C4 allylic alcohols in tetraene 412 was achieved by using VO(OEt)₃ and tert-butylhydroperoxide (TBHP) at lower temperatures, while VO(acac)₂ at ambient temperature failed. On the one hand, OH-directed epoxidation at −78 °C selectively epoxidized the more electro-rich C3–C4 double bond, providing syn-epoxide 413, which was transformed to phomactins R (414), P (415) and K (416) through elegantly planned sequential and selective oxidations. On the other hand, upon increasing the reaction temperature to 0 °C, both C3–C4 and C1–C14 olefins were epoxidized, affording bisepoxide (417), which was converted to phomactin A (136) and phomactin T (418) (Scheme 55).

Scheme 55 VO(OEt)₃-catalyzed epoxidation of allylic alcohol in the synthesis of phomactins.

Salarin C (421) is a cytotoxic nitrogenous marine macrolide featuring two epoxide groups. This natural product displayed high activities against a chronic myelogenous leukemia (CML) cell line (K562) with an IC₅₀ of 5 nM. In the first total synthesis of salarin C by Britton's group,¹⁴⁰ stereoselective installation of the crucial C12–C13 epoxide in the heavily functionalized intermediate 419 was a challenge, as the allylic alcohol is kinetically mismatched for typical Sharpless epoxidation conditions. Consequently, the chiral C14–OH-directed epoxidation was explored. Investigation of VO(acac)₂ and Ti(OⁱPr)₄ in combination with TBHP under a range of conditions identified the best conditions that provided the desired epoxide 420 in excellent yield and threo-selectivity (Scheme 56).

Scheme 56 Ti(OⁱPr)₄-catalyzed epoxidation of allylic alcohol in the synthesis of salarin C.

With the increasing awareness and emphasis on sustainability, enzymatic epoxidation of alkenes has attracted substantial attention¹⁴¹ and has been applied in natural product synthesis. In a very recent example of the chemoenzymatic synthesis of the antibacterial and anti-tumour natural product alchivemycin A (425) by Lei's group,¹⁴² consecutive selective epoxidation of the highly functionalized advanced intermediate 422 by using flavin adenine dinucleotide (FAD)-dependent monooxygenases AvmO3 and AvmO2 provided bisepoxide 424 in excellent yield. Final Baeyer–Villiger type oxidation of the tetramic acid ring by using an engineered AvmO1 (AvmO1-Y282R) converted it into the 2H-tetrahydro-4,6-dioxo-1,2-oxazine (TDO) ring, completing the efficient chemoenzymatic synthesis of alchivemycin A (Scheme 57).

Scheme 57 Enzymatic epoxidation of olefin in the synthesis of alchivemycin A.

In summary, the epoxidation of alkenes is a fundamental transformation in natural product syntheses, enabling access to versatile epoxides. Peroxyacids such as m-CPBA are widely used for direct epoxidation, offering simplicity but are limited in terms of stereochemical control and the generation of stoichiometric by-products. Peroxides such as H₂O₂, Oxone® and DMDO provide greener alternatives with good selectivity but lack of stereochemical control. The Sharpless asymmetric epoxidation provides a method for the highly enantioselective epoxidation of allylic alcohols with broad functional group compatibility. The Shi epoxidation, which complements the Sharpless asymmetric epoxidation, allows the highly enantioselective epoxidation of unfunctionalized alkenes under mild, environmentally friendly conditions using a fructose-derived catalyst with Oxone® as the oxidant. Finally, enzymatic epoxidation offers exceptional regio- and stereo-selectivity under aqueous, mild conditions, representing the most sustainable approach despite the need to screen and optimize an effective enzyme for each class of substrates. Overall, these methods provide a selection of tools for alkene epoxidation in natural product syntheses.

5.2 Dihydroxylation of alkenes

Dihydroxylation of alkenes enables the introduction of vicinal syn-diols, which are widely present in natural products. Three of the most often used methods for the dihydroxylation of alkene are Upjohn dihydroxylation, Sharpless asymmetric dihydroxylation (AD), and ruthenium-catalyzed dihydroxylation. The Upjohn dihydroxylation employs catalytic OsO₄ with a stoichiometric oxidant such as N-methylmorpholine N-oxide (NMO) or t-butyl hydroperoxide.⁵² Despite its effectiveness in the cis-dihydroxylation of a wide range of alkenes, the reaction results in racemic products unless controlled by the substrate. The Sharpless asymmetric dihydroxylation (AD), an improved method of the Upjohn method, uses OsO₄ or its less toxic precursor K₂OsO₂(OH)₄ as the catalyst, potassium ferricyanide as a co-oxidant and chiral cinchona alkaloid-derived ligands [(DHQ)₂-PHAL and (DHQD)₂-PHAL], enabling the enantioselective dihydroxylation of a wide range of alkenes.¹⁴³ Sharpless AD has been used in numerous syntheses of natural products and pharmaceutical molecules.^144,145 Due to the cost and toxicity of the osmium catalyst, ruthenium catalysts such as RuCl₃ or RuO₄ have also been used as alternatives for alkene dihydroxylation in conjunction with NaIO₄ as a co-oxidant.¹⁴⁶ The reaction is generally less selective and more prone to over-oxidation by cleavage of the diol to carbonyl compounds. To overcome this drawback, an improved protocol was developed by the addition of CeCl₃ as an additive, which not only suppresses diol cleavage but also broadens the scope of the reaction and reduces the catalyst loading.¹⁴⁷ Same as the Upjohn dihydroxylation, the reaction produces racemic diols unless controlled by the substrate. Applications of these dihydroxylation methods in natural product synthesis are illustrated below.

5.2.1 The Upjohn dihydroxylation. Tagetitoxin is a phytotoxin produced by Pseudomonas syringae pv. Tagetis. It inhibits RNA synthesis directed by chloroplast RNA polymerase. In the total synthesis and structural revisiting of tagetitoxin by Baran's group,¹⁴⁸ conditions for the OsO₄-catalyzed selective dihydroxylation of cyclopentene in the presence of an amidoacrylate side chain (426) were extensively screened. It was found that N-Boc protection of methyl 2-acetamidoacrylate greatly improved the selectivity for cyclopentene dihydroxylation, while the addition of citric acid as an additive was critical for the rate of the reaction. Under the optimized conditions, the required diol 427 was obtained as a single diastereomer in 81% yield after acidic workup, which concomitantly removed the N-Boc protection. This work achieved the synthesis of both (+)-tagetitoxin (428) and (−)-tagetitoxin (429) (Scheme 58), allowing the confirmation of (+)-tagetitoxin as the natural isomer through an RNA polymerase inhibition assay.¹⁴⁸

Scheme 58 Upjohn dihydroxylation in the synthesis of (+)-tagetitoxin and (−)-tagetitoxin.

In the synthesis of tetrodotoxin (129) and 9-epitetrodotoxin (432) by Qi's group,⁵⁹ substrate-controlled Upjohn dihydroxylation of olefin 430 and subsequent 1,2-diol protection provided acetonide 431 in excellent diastereoselectivity (Scheme 59).

Scheme 59 Upjohn dihydroxylation in the synthesis of tetrodotoxin and 9-epitetrodotoxin.

Cotylenin A (436) was initially isolated as a plant growth regulator, but later found to be able to induce the differentiation of murine and human myeloid leukemia cells and apoptosis in a wide range of human cancer cell lines by combined treatment with interferon-α. In the total synthesis of cotylenin A by Nakada's group,¹⁴⁹ methylenation of the ketone in 433 provided exo-alkene 434, which was selectively dihydroxylated from the less hindered α-face under Upjohn conditions, providing diol 435 without affecting the other two more hindered olefins (Scheme 60).

Scheme 60 Upjohn dihydroxylation in the synthesis cotylenin A.

5.2.2 Sharpless asymmetric dihydroxylation. FD-594 (439) is a complex polycyclic xanthone-type natural product with inhibitory activities against P388 and HeLa tumour cells. In Gao's total synthesis of FD-594,¹⁵⁰ Sharpless asymmetric dihydroxylation of the C6–C7 olefin in 437 with OsO₄ and chiral ligand (DHQ)₂PHAL afforded the desired diol 438 in excellent yield as a single diastereomer (Scheme 61).

Scheme 61 Sharpless asymmetric dihydroxylation in the synthesis of FD-594.

In the total synthesis of pre-schisanartanin C (298) by Yang's group,¹⁰¹ final-step regioselective Sharpless asymmetric dihydroxylation of the more reactive C23–C24 double bond in 440 with AD-mix-α and concomitant δ-lactonization of the C24-hydroxy group completed the synthesis of pre-schisanartanin C (Scheme 62).

Scheme 62 Sharpless asymmetric dihydroxylation in the synthesis of pre-schisanartanin C.

α-Amanitin (443) is a highly potent toxin isolated as the major product of the death cap mushroom (Amanita phalloides). This compound is a potent inhibitor of RNA polymerase II, which interrupts the basic transcription processes of eukaryotes, leading to apoptosis in their cells. This unique mechanism makes this toxin an ideal payload for antibody–drug conjugates (ADCs). In its recent total synthesis by Müller's group,¹⁵¹ Sharpless asymmetric dihydroxylation of olefin 441 with AD-mix-β provided the required diol 442 in excellent ee (Scheme 63).

Scheme 63 Sharpless asymmetric dihydroxylation in the synthesis of α-amanitin.

5.2.3 Ru-catalyzed alkene dihydroxylation. In Burton's total synthesis of sealutomicin C (175),⁷¹ ruthenium-catalyzed dihydroxylation of the double bond in 444 proceeded from the less hindered α-face, providing diol 445 in 88% yield as a single diastereomer (Scheme 64).

Scheme 64 RuCl₃-catalyzed dihydroxylation in the synthesis of sealutomicin C.

In summary, the Upjohn, Sharpless asymmetric and ruthenium-catalyzed dihydroxylations are the most often used methods for alkene dihydroxylation to produce vicinal diols in natural product syntheses. The Upjohn dihydroxylation provides efficient cis-dihydroxylation under mild conditions, though it lacks stereochemical control. The Sharpless asymmetric dihydroxylation enables highly enantioselective dihydroxylation of prochiral alkenes with excellent selectivity and functional group tolerance. Ruthenium-catalyzed dihydroxylation is more effective for less reactive alkenes with a trade-off in terms of selectivity and over-oxidation.

5.3 Catalytic oxidation of alkenes using molecular oxygen

In the presence of a suitable metal catalyst, alkenes can undergo oxidation with molecular oxygen to form either carbonyl compounds or alcohols. Among the alkene oxidation reactions, the Wacker oxidation converts terminal alkenes into aldehydes or ketones, whereas Mukaiyama hydration and Schenck Ene reaction enable the conversion of alkenes to alcohols. These reactions utilize molecular oxygen as a green oxidant, and hence provide a route for the more sustainable transformation of alkenes. Thus, they are increasingly applied in natural product synthesis, as exemplified below.

5.3.1 Conversion of alkenes to carbonyl compounds. The Wacker oxidation allows the conversion of terminal alkenes to aldehydes or methyl ketones via anti-Markovnikov or the Markovnikov addition of water, using palladium-based catalysts and oxygen as the oxidant. This reaction has been widely applied in the synthesis of natural products.¹⁵² Nevertheless, considering the high cost of palladium catalysts, less expensive metals such as iron and cobalt have also been explored for Wacker-type oxidation of alkenes,¹⁵³ although their applications are less general than Pd catalysts.

In the first total synthesis of (±)-cryptotrione (270) by Peng and co-workers,⁹⁵ at the final stage of their synthesis, the catechol dimethyl ether in the precursor (446) was demethylated with EtSNa generated in situ. The resulting catechol intermediate was oxidized with MnO₂, leading to p-quinone methide 447. Final Wacker oxidation of the terminal alkene installed the required methyl ketone in cryptotrione (Scheme 65).

Scheme 65 Wacker oxidation in the synthesis of (±)-cryptotrione.

(−)-Sinoracutine (452) is a member of the hasubanan alkaloids with a 6/6/5/5 tetracyclic structure. This compound was isolated from Sinomenium acutum and displays potent antioxidant activity, indicating its potential in the treatment of neurodegenerative diseases. Wacker oxidation was applied twice in Zhu's total synthesis of (−)-sinoracutine.¹⁵⁴ The first Wacker oxidation converted terminal olefin 448 to the corresponding methyl ketone (not shown), which then underwent base-promoted aldol condensation and subsequent aromatization, providing β-naphthol 449. Further transformations led to terminal olefin 450, which underwent a second Wacker oxidation to form the required methyl ketone 451 in 78% yield (Scheme 66).

Scheme 66 Wacker oxidation in the synthesis of (−)-sinoracutine.

At a late stage in the synthesis of (−)-lucidumone (219) by Li's group,⁷⁷ they attempted the conversion of the terminal alkene in 453 to methyl ketone 454 under the standard Wacker oxidation conditions, resulting in the formation of the anti-Markovnikov aldehyde (not shown), likely caused by the steric effect from the bulky cage moiety. Alternatively, iron-catalyzed Wacker-type oxidation of the alkene¹⁵⁵ provided the required methyl ketone 454 in 65% yield. Final demethylation of hydroquinone dimethyl ether furnished the synthesis of (−)-lucidumone (Scheme 67).

Scheme 67 Wacker oxidation in the synthesis of (−)-lucidumone.

5.3.2 Conversion of alkenes to alcohols. In the presence of a suitable metal catalyst, alkenes can undergo hydration to form an alcohol. Among the methods for alkene hydration, the Mukaiyama hydration and Schenck ene reaction are the two commonly used methods owing to their mild conditions, versatility and functional group tolerance. The Mukaiyama hydration is a metal (Co or Mn complexes)-catalyzed radical hydration reaction using a hydrosilane and molecular oxygen.¹⁵⁶ This reaction converts alkenes to Markovnikov alcohols under mild conditions and is especially useful in complex structural settings. On the other hand, the Schenck ene reaction¹⁵⁷ is a photooxidation reaction involving singlet oxygen reacting with alkenes via an ene mechanism to form allylic hydroperoxides, which are subsequently reduced to allylic alcohols. Tetraphenylporphyrin (TPP) is often used as the photosensitizer to generate singlet oxygen. These alkene hydration methods provide valuable strategies in natural product synthesis, as highlighted in the examples below.

In Yang's total synthesis of principinol B (178),⁷² Mukaiyama hydration of the exocyclic olefin in 455 provided the Markovnikov alcohol 456, which underwent S_N2 substitution at the preformed mesylate, leading to the pentacyclic compound 457 in 71% yield. Final reduction of the epoxide to alkene and TBS deprotection completed the synthesis of principinol B (Scheme 68).

Scheme 68 Mukaiyama hydration of olefin in the synthesis of principinol B.

In the first asymmetric total synthesis of (+)-davisinol (273) by Ding's group,⁹⁶ radical transannular cyclisation between C9–C10 of the two olefins in 458 to introduce a C11-alcohol and concurrently form tricyclo[4.3.1.0^3,7]decane skeleton 459 was explored. After screening a range of conditions, it was found that in the presence of Co(acac)₂, tetramethyldisiloxane (TMDS) and molecular oxygen, a hydrogen atom transfer (HAT) redox radical cascade was successfully achieved, providing 459 in 83% yield as a single isomer. This elegant single-step operation formed two highly strained rings and three contiguous stereogenic centers (Scheme 69).

Scheme 69 Co(acac)₂-catalyzed radical transannular cyclization–hydration of olefin in the synthesis of (+)-davisinol.

(−)-Garryine (462) is a veatchine-type C20-diterpenoid alkaloid isolated from the species of Garrya. In Qin's first asymmetric total synthesis of (−)-garryine,¹⁵⁸ Schenck ene reaction of the endocyclic olefin in 460 under the standard conditions (TPP, O₂, and hν then Me₃P) provided the allylic alcohol 461 in 73% yield as a single diastereomer (Scheme 70).

Scheme 70 Schenck ene reaction in the synthesis of (−)-garryine.

(−)-Daphenylline (465) and (−)-himalensine (466) are two C-30 alkaloids isolated from the Daphniphyllum genus. In their total synthesis by Qiu's group,¹⁵⁹ attempts to introduce the required 1,3-diene in 464via allylic C–H oxidation or bromination of the alkene in 463 using several conventional protocols were unsuccessful. Alternatively, allylic transpositional oxidation by Schenck ene reaction proceeded smoothly, providing the allylic alcohol (not shown), which, without isolation, was dehydrated using HCl in ethyl acetate, leading to the desired diene 464 in 81% yield (Scheme 71).

Scheme 71 Schenck ene reaction in the synthesis of (−)-daphenylline and (−)-himalensine.

In summary, the catalytic oxidation of alkenes with O₂ provides a sustainable route to carbonyl compounds and alcohols. The Wacker oxidation uses PdCl₂/CuCl₂ catalysts to convert terminal alkenes into ketones or aldehydes with good selectivity. In addition, owing to the use of water as the oxygen source and O₂ as the terminal oxidant, this reaction is sustainable and industrially significant. The Mukaiyama hydration employs cobalt or manganese catalysts with molecular oxygen to hydrate alkenes directly, forming alcohols under mild, functional group-tolerant conditions. The Schenck ene reaction converts an alkene to an alcohol via a photochemical process with singlet oxygen. These methods provide a route for the more sustainable transformation of alkenes, and hence are increasingly applied in natural product syntheses.

6. Oxidation of sp³ C–H bonds

In recent years, oxidation of sp³ C–H bonds has emerged as a revolutionary strategy in natural product synthesis, fundamentally changing retrosynthetic logic by allowing the direct oxygenation of non-activated sp³ C–H bonds. This strategy circumvents the need for lengthy functional group manipulations, reduces the use of protecting groups, and enables late-stage functionalization and diversification, thereby significantly streamlining synthetic routes. In addition, this approach expands the choice of starting materials, especially those from natural sources, making the synthesis more sustainable. The most common methods for sp³ C–H oxidation employ transition-metal catalysts or enzymes to achieve selective sp³ C–H bond cleavage and oxygen insertion. In addition, photo- and electro-chemical methods have emerged as valuable tools for the oxidation of sp³ C–H bonds. Owing to its high efficiency, conciseness and environmental friendliness, sp³ C–H oxidation is being increasingly applied in the synthesis of natural products.¹⁶⁰

6.1 Transition metal-catalyzed oxidation of sp³ C–H bonds

Transition metal (Pd, Mn, Cu, Ni, Co, Fe, etc.) catalysts in combination with an oxidant, such as oxygen, peroxides or hypervalent iodine, are often used in sp³ C–H bond oxidations. Mechanistically, oxidation often proceeds through sp³ C–H activation/functionalization, wherein the metal coordinates to the sp³ C–H bond, leading to a metal–carbon species, which is converted to an oxygenated functionality, most often a hydroxy group. The site and stereo-selectivity of the reaction are controlled either by the inherent reactivity of the sp³ C–H bonds or a directing group. In the directing group approach, a functional group already present or temporarily installed on the substrate coordinates to the metal, directing the catalyst in close proximity to a specific sp³ C–H bond for the oxidation. In the absence of a directing group, the selectivity of the reaction is governed by the intrinsic electronic or steric differences among the sp³ C–H bonds in the molecule, often favouring oxidation at the most electron-rich or least sterically hindered position. The latter approach, despite its conciseness in avoiding installation of a directing group, often results in a trade-off in selectivity, especially in molecules containing multiple sp³ C–H bonds. The applications of transition metal-catalyzed sp³ C–H oxidation in natural product synthesis have been reviewed previously.^160d Accordingly, selected recent examples are highlighted below.

Phainanoid A (370) is a member of the cyclodammarane-type triterpenoids isolated from Phyllanthus hainanensis Merr., a shrub only found in Hainan Island of China. This compound possesses a unique [4.3.1]propellane architecture embedded in its core and a highly oxygenated 5,5-oxaspirolactone moiety on its side chain. In the total synthesis of this challenging natural product by Dong's group,¹²⁶ ketone 467 served as a substrate for Baran's modified Schönecker C–H oxidation to introduce a C7 alcohol in 469. The pyridyl directing group was installed via imine formation of the ketone with 2-(aminomethyl)pyridine. The crude imine 468 was used for the directed C7–H oxidation using Cu(NO₃)₂ as the catalyst and hydrogen peroxide as the oxidant, leading to the C7-β-alcohol (469) in 76% yield with the desired equatorial selectivity (Scheme 72).

Scheme 72 Directed sp³ C–H oxidation in the synthesis of phainanoid A.

This pyridyl-directed sp³ C–H oxidation was also applied to a divergent synthesis of (−)-veratramine (474) and (−)-cyclopamine (373), two representative members of the isosteroidal alkaloids.¹⁶¹ In Qin's synthetic route, 3-acetyl dehydro-epi-androsterone (471) was subjected to Baran's C–H oxidation protocol¹⁶² to introduce the required C12-β-OH via (imino)pyridine intermediate 472. The hydroxy compound 473 was prepared in impressive 80% yield in >40-gram scale for the synthesis of both (−)-veratramine and (−)-cyclopamine (Scheme 73).

Scheme 73 Directed sp³ C–H oxidation in the synthesis of (−)-veratramine and (−)-cyclopamine.

Apart from the pyridyl group, oxime has also been used as a directing group in Pd-catalyzed C–H oxidation in conjunction with PhI(OAc)₂ as the oxidant, resulting in acetoxylation of a suitably positioned sp³ C–H bond.¹⁶³ For example, in the synthesis of an ent-beyerane metabolite (478) by de Lucca's group,¹⁶⁴ the ketone (475) was converted to oxime 476, which directed Pd-catalyzed oxidation of the C17 methyl group, providing the C17 acetoxylated compound 477 in 52% yield (Scheme 74).

Scheme 74 Directed sp³ C–H oxidation in the synthesis of an ent-beyerane metabolite.

In another example, in the first total syntheses of the antiviral natural products xiamycins D (481) and E (482) by Dethe’ group,¹⁶⁵ an oxime (479) was used to direct the selective oxidation of the equatorial methyl group with Pd(OAc)₂/PIDA in AcOH/acetonitrile, providing the desired acetate 480 in 64% yield (Scheme 75).

Scheme 75 Directed sp³ C–H oxidation in the synthesis of xiamycins D and E.

While directed sp³ C–H oxidations provide high regio- and stereo-selectivity, oxidation without a directing group is advantageous in that it saves two steps in installation and removal of the directing group. However, there is often a trade-off in selectivity. Nevertheless, some excellent developments such as the White–Chen catalyst¹⁶⁶ have enabled selective sp³ C–H oxidations with impressive applications in natural product synthesis. A recent example is illustrated in Kalesse's asymmetric total synthesis of (−)-illisimonin A (484), a sesquiterpenoid isolated from the fruits of Illicium simonsii.¹⁶⁷ In the final step of the synthesis, oxidation of the C4–H in precursor 483 using an (±)-Fe(PDP) catalyst [prepared by mixing equal amounts of (–)-Fe(S,S)PDP and (+)-Fe(R,R)PDP] and concomitant lactonization completed the synthesis of (−)-illisimonin A (Scheme 76).

Scheme 76 Non-directed sp³ C–H oxidation in the synthesis of (−)-illisimonin A.

(–)-Deoxoapodine (489) is a member of the aspidosperma alkaloids first isolated from Tabernae armeniaca. In the concise total synthesis of (–)-deoxoapodine by Tokuyama's group,¹⁶⁸ a later-stage oxidative transannular Mannich reaction on intermediate 485 using Fe(S,S) PDP, H₂O₂ and AcOH, via hemiaminal 486 from the oxidation of C19–H, provided hexacyclic compound 488 in 35% yield. Final methoxy carbonylation at C3 completed the synthesis of (–)-deoxoapodine (Scheme 77).

Scheme 77 Non-directed sp³ C–H oxidation in the synthesis of (–)-deoxoapodine.

6.2 Enzymatic oxidation of sp³ C–H bonds

Enzymatic oxidation of sp³ C–H bonds is a crucial transformation in nature, enabling the biosynthesis of diverse oxygenated natural products that are essential for biological processes.^2d These reactions are primarily catalyzed by metalloenzymes such as cytochrome P450s and non-heme iron oxygenases, which achieve remarkable site- and stereo-selectivity in the oxidation of unactivated sp³ C–H bonds, often in complex structural settings. Harnessing and engineering these enzymes have provided powerful tools for the synthesis and late-stage diversification of complex natural products,¹⁶⁹ as highlighted in the recent examples below.

In the chemo-enzymatic first total synthesis of four trans–syn-fused drimane meroterpenoids by Renata and co-workers, enzymatic C–H hydroxylation was employed to install the prerequisite C3 hydroxy group of the starting material 9-epi-sclareolide (490) and its 8-epi-δ-lactone analogue (494).¹⁷⁰ Screening a collection of P450_BM3 variants identified the KSA15 variant, which selectively oxidized the C3–β-H in 490, providing the required 3-β-hydroxy compound 491 in 67% yield. On the other hand, the MERO1 L75A variant was found to be more effective for the C3–β-H oxidation of 494, leading to the corresponding 3-β-hydroxy compound 495. Subsequent chemical transformations of the two hydroxylated intermediates led to the synthesis of four trans–syn-fused drimane meroterpenoids, i.e. polysin (492), N-acetyl-polyveoline (493), chrodrimanin C (494), and verruculide A (495) (Scheme 78).

Scheme 78 Enzymatic C–H hydroxylation in the synthesis of drimane meroterpenoids.

In another work on the synthesis of nimbolide (500) by Li's group,¹⁷¹ screening an enzyme library of P450 monooxygenases and α-ketoglutarate (αKG)-dependent dioxygenases (AndA) against six labdane substrates led to the identification of 9,11-dehydrosclareolide (498) as a privileged substrate for selective C–H hydroxylation. Further directed evolution of AndA identified a mutant, AndA I69Y N120C L175A, which exhibited a better performance for C6 α-hydroxylation with 100% selectivity, 85% conversion and 76% yield, providing the required 6-α-hydroxy compound (499). Further chemical transformations led to the synthesis of the anti-cancer natural product nimbolide (Scheme 79).

Scheme 79 Enzymatic C–H hydroxylation in the synthesis of nimbolide.

The cyclopiane diterpenes are a family of natural products featuring a 6-5-5-5 tetracyclic carbon skeleton containing 6–9 stereogenic centres, rendering them challenging targets for total synthesis. While chemical routes are generally lengthy, enzymatic or chemoenzymatic routes can be more concise and efficient, as demonstrated by the recent work by Xu's group.¹⁷² In their approach, a pivotal compound, deoxyconidiogenol (501), which contains a 6-5-5-5-fused tetracyclic cyclopiane core, was produced by an engineered E. coli strain XT02015 expressed with the corresponding terpene cyclase using prenol/isoprenol as the substrates. The crucial hydroxy group in deoxyconidiogenol served as the starting point for chemical transformations that led to A and B ring-modified cyclopiane diterpenes, i.e. conidiogenone B (502), conidiogenone (503), conidiogenol (504) and conidiogenone G (505) (Scheme 80).

Scheme 80 Enzymatic synthesis of deoxyconidiogenol for the divergent synthesis of cyclopiane diterpenes.

Further efforts to access ring D-functionalized cyclopianes by late-stage non-directed chemical sp³ C–H oxidation via acetyl conidiogenone were unsuccessful due to the inert reactivity and poor selectivity of different types of C–H bonds within this molecule. Alternatively, a docking study and screening a library of P450-BM3 variants found that BM3-A3 combined with a phosphite dehydrogenase variant, Rnd6, for NADPH regeneration was effective in hydroxylating C12-β-H of conidiogenone (503), providing conidiogenone H (506) in 80% isolated yield on a gram scale. The C12-β-hydroxy group in 506 served as a pivotal functionality, enabling divergence to five other cyclopiane diterpenes (507–511) via chemical transformations (Scheme 81).¹⁷²

Scheme 81 Enzymatic hydroxylation of conidiogenone for the divergent synthesis of cyclopiane diterpenes.

6.3 Photo- and electro-chemical oxidation of sp³ C–H bonds

Photochemical sp³ C–H oxidations involve the use of hydrogen-atom transfer (HAT) catalysts, photoexcited oxidants, or radical intermediates, enabling the activation of sp³ C–H bonds, which are then oxidized by an oxidant.¹⁷³ On the other hand, electrochemical oxidation enables the oxidation of sp³ C–H bonds via direct anodic oxidation or mediated routes, avoiding stoichiometric oxidants and harsh conditions.¹⁷⁴ Compared to the well-studied sp² C–H oxidation, oxidation of sp³ C–H bonds by photo- and electro-chemical means is more challenging due to their inertness and selectivity. Nevertheless, the examples highlighted below have shown their potential in natural product synthesis.

6.3.1 Photochemical sp³ C–H oxidation. Benzylic and allylic hydrogens generally have lower dissociation energies compared to most aliphatic C–H bonds, which is attributed to the resonance stabilization of the resulting radicals. Considering these different reactivities, photochemical sp³ C–H oxidation is often applied to benzylic and allylic hydrogens to achieve useful selectivity.

In Zhu's total synthesis of (+)-stephadiamine (514),¹⁷⁵ an alkaloid isolated from the vine Stephania japonica, photocatalytic aerobic oxidation of the benzylic C–H in 512 using {[Ir(dF(CF₃)ppy)₂(5,5′-dCF₃bpy)]}PF₆ as the photocatalyst and blue LED light provided ketone intermediate 513 in high selectivity and yield (Scheme 82).

Scheme 82 Photochemical sp³ C–H oxidation in the synthesis of (+)-stephadiamine.

In the synthesis of ceforalide C (516) by Sarpong's group,¹⁷⁶ selective oxidation of the less hindered C7 benzylic hydrogens in ceforalide D (515) was achieved by using [Ru(bpy)₃]Cl₂ as the photocatalyst and 2-iodosobenzoic acid (IBA) as the oxidant (Scheme 83). Considering that there are four types of benzylic hydrogens and a secondary alcohol in this molecule, the selectivity was remarkable.

Scheme 83 Photochemical sp³ C–H oxidation in the synthesis of ceforalide C.

(+)-Heilonine (519) is a member of Veratrum steroidal alkaloids isolated from Fritillaria ussuriensis Maxim. cultivated in the Hei-Long-Jiang Province in China. In a convergent total synthesis of (+)-heilonine by Dai's group,¹⁷⁷ stereoselective photooxidation of the allylic C6-β-hydrogen in enone 517 using Na₂-Eosin Y catalyst and visible light provided the C6-β-hydroxylated compound 518 in 45% yield (Scheme 84).

Scheme 84 Photochemical sp³ C–H oxidation in the synthesis of (+)-heilonine.

6.3.2 Electrochemical sp³ C–H oxidation. The reactivity of sp³ C–H bonds in electrochemical oxidation is primarily determined either by their bond dissociation energy (BDE) (in radical pathways) or oxidation potential (in direct electron transfer pathways). Based on these principles, the sp³ C–H bonds adjacent to π systems or heteroatoms are the most reactive to oxidation. For example, in the recent first total synthesis of dragocins A, B and C (50–52) by Baran's group,¹⁷⁸ formation of the critical 9-membered cyclic ether at the benzylic position in 520 was achieved by diastereoselective oxidative electrochemical cyclization. Under anodic oxidation conditions, precursor 520 was selectively oxidized at the benzylic position, providing the desired cyclic ether 521 in 44% yield (Scheme 85). The selectivity was remarkable considering the presence of multiple reactive C–H bonds and a pyrrolidine moiety within the molecule.

Scheme 85 Electrochemical sp³ C–H oxidation in the synthesis of dragocins.

In another example, in Lu's divergent total synthesis of bipolarolides A (526) and B (86),¹⁷⁹ two members of the ophiobolin family of sesterterpenes possessing intricate cage-like structures, the crucial cyclic allylic ether was installed by electrochemical oxidation, while the conventional method for C–O bond formation using Suárez oxidation conditions [PhI(OAc)₂, I₂, and hν] failed. Electrochemical oxidative etherification of 522 at the C12 allylic axial-H mediated by the more reactive secondary alcohol afforded cyclic ether 523, which was then transformed to bipolarolide A (524). Under similar conditions, etherification of sidechain-elongated compound 525 led to cyclic ether 526, which was converted to bipolarolide B (86) in a one-pot operation via allylic oxidation and ester reduction (Scheme 86). The authors found that the addition of amide 527 was crucial for the electrochemical oxidation as it effectively suppressed competing decomposition pathways, likely functioning as a sacrificial agent under high-voltage conditions that protected both the substrate and the products.

Scheme 86 Electrochemical sp³ C–H oxidation in the synthesis of bipolarolides A and B.

In summary, oxidation of sp³ C–H bonds is a powerful strategy for functionalizing otherwise inert sites in organic molecules, significantly shortening and streamlining natural product syntheses. Transition-metal catalysts enable oxidation of sp³ C–H bonds to alcohols or carbonyl compounds but often require a directing group or a carefully designed catalyst for effective site and stereochemical control. Enzymatic sp³ C–H oxidation offers remarkable regio- and stereo-selectivity under mild aqueous conditions, making it highly attractive in natural product synthesis despite the need to screen and optimize the enzyme for a particular type of substrate. Photo- and electro-chemical methods utilize light and electrons as green energy inputs, eliminating stoichiometric oxidants, and thus facilitating sustainable sp³ C–H oxidation. Overall, sp³ C–H oxidation is still in its infancy, and hence more efficient and broadly applicable methods still need to be developed.

7. Addendum

7.1. Concise total synthesis of ambiguine P

Ambiguine P (528) belongs to the hapalindole-type natural products. In 2025, Li, Yang and co-workers reported a remarkably concise six-step synthesis of this challenging target from 2,2-dimethylcycloheptanone (Scheme 87).¹⁸⁰ Their synthetic strategy was inspired by the biosynthesis of this indole family and highlighted by a newly developed Cope/Prins/Friedel–Crafts cascade reaction. In this seven-reaction, six-step total synthesis, four reactions are oxidative transformations. Among them, three steps involve dehydration reactions: (1) C3-chlorination of tricyclic indole derivative 530 with t-BuOCl/i-Pr₂NEt, followed by DBU-promoted elimination of HCl and tautomerization to afford dehydrogenated product 531; (2) DDQ-mediated dehydrogenation at C10–C11 of pentacyclic intermediate 534 delivered from the key Cope/Prins/Friedel–Crafts cascade reaction to afford compound 535 as an inseparable mixture; and (3) once again, t-BuOCl/i-Pr₂NEt-initiated chlorination–HCl elimination–tautomerization of 535 to afford triene 537, which was subjected to in situ hydroxylation of 537 at C15 under Rawal conditions¹⁸¹ [KHMDS, P(OMe)₃, and O₂], producing the desired ambiguine P (528) in 43% yield, along with its C15-epimer in 19% yield. Notably, more than 100 mg of ambiguine P was prepared through this route.

Scheme 87 Concise total synthesis of ambiguine P by Yang/Li and co-workers.

7.2. Total synthesis and late-stage C–H oxidations of ent-trachylobane natural products

It is now recognized that a sophisticated two-phase strategy for terpene biosynthesis is adopted in nature, involving a cyclase phase to build the skeletons and oxidase phase to functionalize them.^2d,182,183 By mimicking this approach, the efficient total synthesis of several terpenes has been achieved, with the most well-known one being Baran's two-phase synthesis of Taxol.¹⁸⁴ For the “oxidase phase”, chemical C–H oxidation constitutes a highly desirable yet challenging tactic. In 2022, Magauer and co-workers reported the total synthesis of ent-trachylobane natural products,¹⁸⁵ in which late-stage C–H oxidations were employed to synthesize ent-3β-acetoxy-trachyloban-19-al (538) and 11-oxo-ent-trachyloban-19-oate (539) (Scheme 88). After preparing ample amounts of ent-trachylobanes 540 and 541, they first attempted the undirected C–H oxidation. Among the reported protocols tried, Curci's methyl (trifluoromethyl)dioxirane (TFDO),¹⁸⁶ Baran's electrochemical conditions, and Ru(TMP)(CO) (542) gave C-11 selective oxidation products 543, 544, and 539, respectively. Next, alcohol 545 was employed for exploring directed oxidation. Employing the Suárez oxidation protocol, the reaction of 545 afforded C-20 iodide 546 in 28% yield as the sole product. Alternatively, by converting alcohol 545 to imine 547, and exposing the latter to copper(II) nitrate trihydrate and hydrogen peroxide, followed by acetylation, terpene 538 was obtained in 32% yield.

Scheme 88 Oxidase phase C–H oxidations of ent-trachylobanes 540, 541, and 545: A. undirected C–H oxidations and B. directed C–H oxidations.

7.3. Total syntheses of naturally occurring antiviral indolosesquiterpene alkaloids xiamycins C–F

Indolosesquiterpene alkaloids including xiamycins and oridamycins are a class of architecturally complex natural products possessing important biological activities such as antimicrobial, antiviral, antitumor, immunomodulatory, and enzyme inhibitory activities, and are promising inhibitors against nsp10 of SARS-CoV-25 pathogenicity. In 2022, Bisai and co-workers reported the concise total syntheses of the naturally occurring antiviral indolosesquiterpene alkaloids xiamycin C (548a), D (548b), E (548c) and F (548d) via late-stage oxidative δ-Csp³–H functionalization of an advanced pentacyclic enone intermediate.¹⁸⁷ The synthesis started from a naturally occurring diterpenoid, dehydroabietic acid methyl ester, which was converted to deoxyxiamycin A methyl ester in four steps. N-Tosylation followed by benzylic oxidation using CrO₃ in acetic acid (Jones oxidation) furnished ketone 549 in 70% yield over 2 steps. After attempting several oxidative conditions for the ketone (550) to enone (551) transformation, three protocols including a two-step protocol and two one-pot methods, Saegusa–Ito oxidation and oxidation with SeO₂, were established for this desaturation reaction. After extensive experimentation, regioselective Csp³–H functionalization of 551 was achieved by treating 551 with NBS in the presence of catalytic sulfuric acid in acetic anhydride to afford product 552 in 86% yield. DBU-promoted elimination followed by allylic oxidation with SeO₂ provided bis-enone 554 in 82% yield. The latter was converted into xiamycin D (548b) in four steps. Selective oxidation of the benzylic alcohol in xiamycin D (548b) with MnO₂ furnished xiamycin E (548c) in 79% yield. Saponification of xiamycin E (548c) yielded xiamycin F (548d) in 72% yield. The latter was converted to xiamycin C (548a) by diastereoselective reduction with NaBH₄ (Scheme 89).

Scheme 89 Total syntheses of the naturally occurring antiviral indolosesquiterpene alkaloids, xiamycins C–F by Bisai and co-workers.

7.4. Total synthesis of (+)-oridamycins A and B

Continuing synthetic efforts by Bisai and co-workers on indolosesquiterpene alkaloids allowed them to report, in 2024, the collective total synthesis of (+)-oridamycins A and B and xiamycin A (555a) and xiamycin A methyl ester (555b) by a unified strategy.¹⁸⁸ Oxidation reactions were extensively employed in the second half of their synthesis. Firstly, Sharpless asymmetric epoxidation was employed not only to build the initial chiral centers, but also laid the foundation for the key TiCl₄-mediated epoxy-ene-aryl double cyclization to afford the common intermediate (+)-558. Oxidative cleavage of the vinyl moiety in 558 afforded dihydroxy aldehyde (559) in 78% yield. The latter was subjected to Wolff–Kishner reduction and chemoselective oxidation of the primary alcohol with TEMPO/PIDA, which provided the β-hydroxy aldehyde (560) in 64% yield over 2 steps. Pinnick oxidation of the aldehyde group in 560 furnished the corresponding carboxylic acid, which was detosylated to afford xiamycin A (555a) in 90% yield over 2 steps (Scheme 90).

Scheme 90 Total synthesis of xiamycin A by Bisai and co-workers.

On the other hand, Pinnick oxidation of aldehyde (559) followed by esterification afforded N-tosyl oridamycin B methyl ester (561). Selective deoxygenation reaction of the primary alcohol in 561 by the Barton–McCombie protocol, N-detosylation, and saponification completed the total synthesis of oridamycin A (562a) (Scheme 91).

Scheme 91 Total synthesis of oridamycin A by Bisai and co-workers.

7.5. Concise enantioselective total syntheses of rearranged ent-trachylobane diterpenoids (–)-wallichanols A and B

Wallichanol A (563) and wallichanol B (564) are two rearranged ent-trachylobane diterpenoids isolated from the medicinal herb Euphorbia wallichii, which has long been used in Tibetan folk medicine to treat edema and various skin ailments, including abscesses, eruptions, and anthrax infections. In 2025, Dethe and coworkers disclosed the first enantioselective total syntheses¹⁸⁹ of these two natural products, and structurally related sanguinolane (565), isolated from Stillingia sanguinolenta. Five oxidation reactions were employed in the total syntheses, with four carried out at the later stage of the total syntheses. Aerobic oxidation of the α-carbon adjacent to the carbonyl group in compound 566 based on literature precedents¹⁹⁰ proved to be non-trivial. After systematic screening of several reaction parameters, the optimal conditions were defined, involving the use of NaH and POEt₃ in DMF under an O₂ atmosphere at −20 °C for 5 h. Under these conditions, the oxidized product 567 was obtained in 60% isolated yield (84% brsm). The Dess–Martin oxidation was used twice, one for the oxidation of wallichanol A (563) to sanguinolane (565), and the other for the transformation of the common intermediate 568 into ketone 569. The latter was subjected to another aerobic oxidation of the ketone α-carbon, which was efficiently achieved using KOtBu in tBuOH under an oxygen atmosphere and proceeded with concomitant deacetylation to afford 570. The last required oxidation involved the challenging chemoselective mono-oxidation of the carbinol at C2 of triol 571. After unsuccessful attempts with several oxidants such as PDC, PCC, and DMP, the combination of p-toluenesulfonic acid and Bobbitt's salt (4-AcNH-TEMP=O⁺ BF4⁻),^191–193 an oxoammonium salt, proved effective, affording the desired selective oxidation product (–)-wallichanol B (564) in 87% yield (Scheme 92).

Scheme 92 Concise enantioselective total syntheses of the rearranged ent-trachylobane diterpenoids, (–)-wallichanols A and B by Dethe and co-workers.

7.6. Total synthesis of a bis(cyclotryptamine) alkaloid bearing the elusive piperidinoindoline scaffold

In their synthetic efforts towards bis(cyclotryptamine) alkaloids, Garcia-Garibay and Garg proposed that the product they obtained was a natural product, named “psychotriadine (572)”.¹⁹⁴ Its synthesis features a stereospecific solid-state photodecarbonylation reaction to introduce the key vicinal quaternary stereocenters. In an attempt to perform oxidative cleavage of the p-methoxybenzyl (PMB) moieties from N,N′-diPMB-protected bis-pyrrolidin-2-one ketone using ceric ammonium nitrate (CAN), imides 575 and 576, intermediates of PMB cleavage by CAN, were isolated in low yields. The unanticipated isolation of crystalline products allowed them to realize the key photodecarbonylation reaction of 576 to afford 578 after N-deprotection. In a late-stage, 579 was subjected to Ley–Griffith oxidation, affording compound 572 in 74% yield. This compound was found to spectroscopically match that of a previously unidentified compound during the isolation of dehydrobhesine (573)¹⁹⁵ and was named “psychotriadine” (Scheme 93).

Scheme 93 Total synthesis of a bis(cyclotryptamine) alkaloid by Garcia-Garibay/Garg and co-workers.

7.7. Total synthesis of (+)-shearilicine

In 2023, Newhouse and co-workers reported the first total synthesis of the indole diterpenoid shearilicine, which was realized in 11 steps.¹⁹⁶ In their synthesis route, the isopropylidene moiety in 584 needed to be excised. Although oxidative cleavage of the C=C bond is a routine transformation realizable by several methods such as ozonolysis, C(sp³)–C(sp²) bond cleavage is rare. They found that Kwon's hydrodealkenylative C(sp³)–C(sp²) bond fragmentation method using ozone, an iron salt, and a hydrogen atom donor¹⁹⁷ was well-suited to achieve the desired transformation. Using this protocol, enantioenriched 585 was obtained in 53% yield. The highly oxidized terminal ring was constructed at a late-stage. When subjecting carbazole 586 to Sharpless dihydroxylation at low temperature with an extended reaction time, the furan diol product 587 underwent a tandem Achmatowicz rearrangement, affording the desired diol 588 in 40% yield with a dr of 3 : 1. Treatment of 588 with TsOH and CuSO₄ led to shearilicine (580) (Scheme 94).

Scheme 94 First total synthesis of shearilicine by Newhouse and co-workers.

7.8. Unified total synthesis of the brevianamide alkaloids enabled by chemical investigations into their biosynthesis

In 2022, Lawrence and co-workers reported the full details of their synthetic efforts to gain insight into the chemical feasibility of a proposed network of biosynthetic pathways towards the brevianamide family alkaloids, which resulted in the total synthesis of all known bicyclo[2.2.2]diazaoctane brevianamides.¹⁹⁸ Dehydroproline 595, a component for the synthesis of their proposed (bio)synthetic intermediate (+)-dehydrodeoxybrevianamide E (596), was prepared in practical quantities from proline methyl ester using N-chlorosuccinimide as the oxidant (Scheme 95). Diastereoselective tandem oxidation–cyclization of 596 turned out to be challenging. A variety of oxidants (e.g. peroxy acids, singlet oxygen, dioxiranes, oxaziridines, and m-CBPA) were attempted for this transformation. However, they all led to the formation of two diastereomers, 597 and 598, in low diastereoselectivities. Noteworthy is that use of Davis chiral oxaziridine resulted in a relatively clean reaction but with no diastereoselectivity. The best result was obtained when using m-CBPA as the oxidant, which afforded dehydrobrevianamide E (597) and 598 in 57% combined yield with a modest dr of 63 : 37. Brief exposure of dehydrobrevianamide E (597) to LiOH in water at room temperature produced the natural (+)-enantiomers of brevianamide A (589) and B (590) with the bicyclo[2.2.2]diazaoctane ring system formed in a combined 63% yield. As an alternative to oxidation with m-CPBA, treating (+)-dehydrodeoxybrevianamide E (596) with N-chlorosuccinimide and aqueous trifluoroacetic acid resulted in the direct formation of oxindoles 599 and 600 in excellent yield and with a diastereoselectivity of 69 : 31. Exposing the major diastereomer oxindole 599 to LiOH led to the [4 + 2] adduct (+)-brevianamide Y (591) in 32% combined yield as the major diastereomer.

Scheme 95 Unified total synthesis of the brevianamide alkaloids by Lawrence and co-workers.

7.9. Enantioselective total synthesis of taiwaniadducts I, J, and L

Taiwaniaquinoids are a class of tetraterpenoids isolated from the endemic evergreen species Taiwania cryptomerioides, which exhibited impressive biological activities. In 2025, Bisai and co-workers disclosed the enantioselective total synthesis of taiwaniadducts I, J, and L.¹⁹⁹ For the structurally most complex taiwaniaquinoid, taiwaniadduct J (601), bioinspired Diels–Alder cycloaddition and [2 + 2] cycloaddition were employed to construct its skeleton and multiple quaternary centers. In the asymmetric synthesis of trans-ozic acid methyl ester (diene), five oxidation reactions were used. (1) Site-selective allylic oxidation of commercially available 2E,6E-farnesyl acetate (604) afforded allylic alcohol 605 in 52% yield based on recovered starting materials (brsm) (Scheme 96). (2) Sharpless catalytic asymmetric epoxidation of 605 afforded epoxy alcohol 606 in 95% yield with 94% ee. (3) Dess–Martin periodinane (DMP) oxidation of 606 followed by (4) Pinnick oxidation and methylation of the resultant carboxylic acid gave 608 in 77% yield over 3 steps. In addition to the four consecutive oxidation reactions, the primary alcohol in 610 was oxidized with DMP to afford the corresponding aldehyde. This set the stage for three sequential Wittig reactions to afford the desired diene component 612. For the asymmetric synthesis of abeo-abietane diterpenoid 619 as the dienophile component, enantiopure epoxy-ether diene 613 was converted, in five steps, to compound 614. Following the protocol reported by Li,^200,201614 was converted to diazoketone 615via benzylic oxidation with CrO₃/3,5-dimethylpyrazole. In the subsequent five-step transformations, three oxidation reactions were employed, including DMP oxidation, Bayer–Villiger oxidation of aldehyde 616, and ceric(IV) ammonium nitrate (CAN)-mediated oxidative dearomatization to produce p-benzoquinone derivative 619 (Scheme 96). After the key Diels–Alder reaction, the resulting inseparable mixture was subjected, one again, to DMP oxidation, which facilitated the separation of two regioisomeric adducts 622 and 623. Demethylation of 622 and 623 and light-promoted [2 + 2]-cycloaddition of compound 622 completed the first total syntheses of taiwaniadducts I, L and J respectively (Scheme 97).

Scheme 96 Syntheses of the two segments 612 (A) and 619 (B) for the total synthesis of taiwaniadducts I, J, and L.

Scheme 97 Completion of the enantioselective total synthesis of taiwaniadducts I, J, and L by Bisai and co-workers.

7.10. Unified total syntheses of benzenoid cephalotane-type norditerpenoids: cephanolides and ceforalides

Cephanolides and ceforalides are benzenoid cephalotane-type norditerpenoids isolated by Yue's group from Cephalotaxus sinensis²⁰² and the seeds of Cephalotaxus fortunei var. alpine,²⁰³ respectively. In 2022, Sarpong and co-workers developed a unified strategy for the total syntheses of all of the known cephanolides and five recently isolated ceforalides 624–629 in 8–13 steps from commercially available hydroxyindanone.¹⁷⁶ Although the authors did not mention the concept of two-phase synthesis, their approach is likely to be the case. The key pentacyclic core 630 was efficiently prepared in four steps from hydroxyindanone. For the elaboration of 630, they first developed an efficient and highly regioselective method for direct alkene difunctionalization that relies on borocupration. Under the optimized conditions, 630 was converted into the desired methyl boronic ester in 83% yield as a single isomer. Subjecting 630 to tandem methyl-boration–oxidation led to methyl alcohol 631 in 77% yield as a single isomer. DMP oxidation of 631 and reduction of the resulting ketone yielded the desired endo-oriented alcohol, which was subjected to Suaŕez oxidation²⁰⁴ and one-pot cleavage of TMS to afford hexacyclic compound 633 in excellent yield (99%) over two steps. Although compound 634, obtained via Barton–McCombie's deoxygenation protocol, could be converted to cephanolide A by treating with malonoyl peroxide (635) and subsequent hydrolysis, the authors were not satisfied with the yield (39%) and selectivity (6 : 1) and developed a stepwise approach consisting of C–H thianthrenation with TFTO (636), under photocatalytic borylation of 637 to yield boronic ester 633, and one-pot oxidation of the resulting Bpin moiety gave rise to 624 in 92% yield. In this second phase, 4/5 or 4/6 steps involve oxidative transformations (Scheme 98).

Scheme 98 Total synthesis of the benzenoid cephalotane-type norditerpenoid, cephanolide A by Sarpong and co-workers.

In the synthesis of ceforalides, several oxidation reactions have been employed. The Jones oxidation of common intermediate 631 under acidic conditions resulted in concomitant alcohol oxidation and desilylation, affording ketoalcohol 639 in 50% yield, which was converted into ceforalide D (626) in three steps. Chemoselective selective benzylic oxidation in the presence of the free secondary alcohol group in 626 was achieved using a photoredox-catalysis strategy with hypervalent iodine²⁰⁵ to afford ceforalide C (625) in 49% yield. For the synthesis of ceforalide F (627) from 626, two consecutive oxidative transformations were used: photoirradiation of 626 with Pb(OAc)₄, I₂, and CaCO₃ gave 634 in 97% yield, and C7 benzylic oxidation of the latter using PCC gave ceforalide F (627). The three-step transformation of compound 637 to ceforalide G (628) also involved two oxidation reactions: (1) photoredox oxygenation of intermediate 638 using a compact fluorescent light (CFL) instead of blue light-emitting diodes (LEDs) (400 nm) afforded alcohol 640 selectively and (2) oxidation of the Bpin moiety with NaBO₃·4H₂O afforded ceforalide G (628) in 42% yield over 2 steps. Lastly, phenyliodine(III) diacetate (PIDA)-mediated oxidative dearomatization of 624 selectively gave rise to 629 in 78% yield as a single constitutional isomer (Scheme 99).

Scheme 99 Total syntheses of the benzenoid cephalotane-type norditerpenoids, ceforalides C, D, F, G, H by Sarpong and co-workers.

8. Summary and outlook

In summary, oxidation reactions are a class of indispensable transformations in organic synthesis, particularly in the total synthesis of biologically active natural products. As can be seen from the twenty cases surveyed, oxidation reactions often serve as key steps in a total synthesis, and the percentage of the oxidation steps can exceed 40% of all the synthetic steps of a total synthesis. Because about 50% of the US FDA approved drugs are developed from/or inspired by natural products, the abovementioned conclusion could also reflect the situation in the pharmaceutical industry. Thus, it is our expectation that synthetic chemists, in particular those in the field of total synthesis of natural products, and medicinal chemists will find the information summarized in this review helpful for their research. Additionally, because both the total synthesis of natural products and the synthesis of structurally complex medicinal agents can rely heavily on oxidation reactions, this constitutes the major driving force for the development of oxidation chemistry. According to the highlighted total syntheses, on one hand, we witness how novel oxidation reactions, protocols, and reagents such as Mukaiyama hydration, oxidative cyclization/cycloaddition, and C–H oxidation can facilitate total syntheses. On the other hand, we have to admit that the chemistry of oxidation is underdeveloped. Actually, most oxidation protocols involve stoichiometric reactions, and the safety of oxidants remain a concern, even for the widely used IBX.²⁰⁶ All these highlighted issues will prompt organic chemists to develop safer, catalytic oxidation reactions featuring high selectivity, versatility, and high redox economy.²⁰⁷

Author contributions

JFZ, AC and PQH wrote the paper. YJG was responsible for the artwork and references.

Conflicts of interest

The authors declare no other competing interests.

Data availability

The data supporting this article have been included as part of the article.

Acknowledgements

We are grateful to the National Natural Science Foundation of China for the financial support (grant numbers: 22571269 and 22571267).

References

1. Organic Named Reactions, Reagents and Rules, ed. P.-Q. Huang, Chemical Industry press, Beijing, 2nd edn, 2019. ISBN: 9787122344038.
2. For selected reviews, see: (a) Y. Qiu and S. Gao, Trends in Applying C–H Oxidation to the Total Synthesis of Natural Products, Nat. Prod. Rep., 2016, 33, 562–581; (b) M. C. White and J. Zhao, Aliphatic C–H Oxidations for Late-Stage Functionalization, J. Am. Chem. Soc., 2018, 140, 13988–14009; (c) I. Bakanas, R. F. Lusi, S. Wiesler, J. H. Cooke and R. Sarpong, Strategic Application of C–H Oxidation in Natural Product Total Synthesis, Nat. Rev. Chem., 2023, 7, 783–799; (d) M. Kourgiantaki, G. G. Bagkavou, C. I. Stathakis and A. L. Zografos, Selective Preparative ‘Oxidase Phase’ in Sesquiterpenoids: the Radical Approach, Org. Chem. Front., 2023, 10, 2095–2114; (e) M. C. Carson and M. C. Kozlowski, Recent Advances in Oxidative Phenol Coupling for the Total Synthesis of Natural Products, Nat. Prod. Rep., 2024, 41, 208–227; (f) E. Bicer and M. Yilmaz, Recent Advances in Manganese(III)-Assisted Radical Cyclization for the Synthesis of Natural Products: A Comprehensive Review, Molecules, 2024, 29, 2264; (g) J. Wu, K. L. Verboom and M. J. Krische, Catalytic Enantioselective C-C Coupling of Alcohols for Polyketide Total Synthesis beyond Chiral Auxiliaries and Premetalated Reagents, Chem. Rev., 2024, 124, 13715–13735; (h) Y. Wang and X. Qi, Total Syntheses of Highly Oxidized Natural Products, Chin. J. Chem., 2025, 43, 650–714; (i) T. H. El-Assaad, J. Zhu, A. Sebastian, D. V. McGrath, I. Neogi and K. N. Parida, Dioxiranes: A Half-century Journey, Org. Chem. Front., 2022, 9, 5675–5725.
3. (a) W. Ou and P.-Q. Huang, Direct Reductive Transformation of Amides: From Methodology Development to Applications in Total Synthesis, Acc. Chem. Res., 2025, 58, 2332–2349; (b) R. A. Shenvi, D. P. O'Malley and P. S. Baran, Chemoselectivity: The Mother of Invention in Total Synthesis, Acc. Chem. Res., 2009, 42, 530–541.
4. (a) Y. Gao and D.-W. Ma, In Pursuit of Synthetic Efficiency: Convergent Approaches, Acc. Chem. Res., 2021, 54, 569–582; (b) P.-Q. Huang, Z.-J. Yao and R. P. Hsung, Efficiency in Natural Product Total Synthesis, John Wiley & Sons, 2018; (c) T. Newhouse, P. S. Baran and R. W. Hoffmann, The Economies of Synthesis, Chem. Soc. Rev., 2009, 38, 3010–3021; (d) P. A. Wender, V. A. Verma, T. J. Paxton and T. H. Pillow, Function-oriented Synthesis, Step Economy, and Drug Design, Acc. Chem. Res., 2008, 41, 40–49.
5. (a) C. J. Li and B. M. Trost, Green Shemistry for Shemical Synthesis, Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 13197–13202; (b) P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, New York, 1998. ISBN: 9780198506980.
6. V. A. P. Ruf, L. J. Sprenger, K. Volynskiy, V. M. Kandler, N. Nasiri and E. M. Carreira, Enantioselective Total Synthesis of (−)-Novofumigatonin, J. Am. Chem. Soc., 2025, 147, 31456–31462.
7. J. A. R. Salvador, M. L. Sae Melo and A. S. Campos Neves, Copper-catalysed Allylic Oxidation of Δ⁵-Steroids by t-Butyl Hydroperoxide, Tetrahedron Lett., 1997, 38, 119–122.
8. X. Wan, J. Lin, J. Bai, J. Li, K. Wang, z. Cao, M. Li, X. Bao and X. Wan, Interception of RCONCl₂: late-stage hydrolysis and esterification of primary amides., Org. Chem. Front., 2024, 11, 183–193.
9. D. H. R. Barton, D. J. Lester and S. V. Ley, Dehydrogenation of Steroidal Ketones Using Benzeneseleninic Anhydride, J. Chem. Soc., Chem. Commun., 1978, 3, 130–131.
10. K. Tanemura, T. Suzuki and T. Horaguchi, 2,3-Dichloro-5,6-dicyano-p-benzoquinone as A Mild and Efficient Catalyst for the Deprotection of Acetals, J. Chem. Soc., Chem. Commun., 1992, 14, 979–980.
11. Q.-B. Zhuang, J.-R. Tian, K. Lu, X.-M. Zhang, F.-M. Zhang, Y.-Q. Tu, R. Fan, Z.-H. Li and Y.-D. Zhang, Catalytic Asymmetric Polycyclization of Tertiary Enamides with Silyl Enol Ethers: Total Synthesis of (–)-Cephalocyclidin A, J. Am. Chem. Soc., 2023, 145, 26550–26556.
12. G. R. Jones and Y. Landais, The Oxidation of the Carbon-Silicon Bond, Tetrahedron, 1996, 52, 7599–7662.
13. Y. Zhang, Y. Chen, M. Song, B. Tan, Y. Jiang, C. Yan, Y. Jiang, X. Hu, C. Zhang, W. Chen and J. Xu, Total Syntheses of Calyciphylline A-type Alkaloids (−)-10-Deoxydaphnipaxianine A, (+)-Daphlongamine E, and (+)-Calyciphylline R via Late-stage Divinyl Carbinol Rearrangements, J. Am. Chem. Soc., 2022, 144, 16042–16051.
14. M. Shibuya, M. Tomizawa, I. Suzuki and Y. Iwabuchi, 2-Azaadamantane N-Oxyl (AZADO) and 1-Me-AZADO: Highly Efficient Organocatalysts for Oxidation of Alcohols, J. Am. Chem. Soc., 2006, 128, 8412–8413.
15. S. V. Ley, J. Norman, W. P. Griffith and S. P. Marsden, Tetrapropylammonium Perruthenate, Pr₄N⁺RuO₄⁻, TPAP: A Catalytic Oxidant for Organic Synthesis, Synthesis, 1994, 639–666.
16. M. Shibuya, M. Tomizawa and Y. Iwabuchi, Oxidative Rearrangement of Tertiary Allylic Alcohols Employing Oxoammonium Salts, J. Org. Chem., 2008, 73, 4750–4752.
17. Y.-Y. Chen, W.-Q. Chen, J.-T. Zhang and J. Xu, Total Synthesis of Laurane and Guaiane Sesquiterpenoids via Oxidative Nazarov Reaction, Chin. J. Chem., 2024, 42, 1267–1274.
18. X.-D. Li, J.-C. Su, B.-Z. Jiang, Y.-L. Li, Y.-Q. Guo and P. Zhang, Janthinoid A, an Unprecedented Tri-nor-meroterpenoid with Highly Modified Bridged 4a,1-(Epoxymethano) Phenanthrene Scaffold, Produced by the Endophyte of Penicillium janthinellum TE-43, Org. Chem. Front., 2021, 8, 6196–6202.
19. F. Tang, Z.-C. Zhang, Z.-L. Song, Y.-H. Li, Z.-H. Zhou, J.-J. Chen and Z. Yang, Asymmetric Total Synthesis of Janthinoid A, J. Am. Chem. Soc., 2025, 147, 4731–4735.
20. E. J. Corey and J. Zhang, Highly Effective Transition Structure Designed Catalyst for the Enantio- and Position-Selective Dihydroxylation of Polyisoprenoids, Org. Lett., 2001, 3, 3211–3214.
21. Y. D. Boyko, C. J. Huck, S. Ning, A. S. Shved, C. Yang, T. Chu, E. J. Tonogai, P. J. Hergenrother and D. Sarlah, Synthetic Studies on Selective, Proapoptotic Isomalabaricane Triterpenoids Aided by Computational Techniques, J. Am. Chem. Soc., 2021, 143, 2138–2155.
22. A. Citterio, R. Sebastiano, M. Nicolini and R. Santi, Synthesis of γ-Lactones by Iron(III) Perchlorate Oxidation of Malonic Esters in the Presence of Olefins, Synlett, 1990, 42–43.
23. W. Zi, Z. Zuo and D. Ma, Intramolecular Dearomative Oxidative Coupling of Indoles: A Unified Strategy for the Total Synthesis of Indoline Alkaloids, Acc. Chem. Res., 2015, 48, 702–711.
24. Q. Guo, Y. Yang, H. Zhang, D. Wang, B. Li, D. Jiang, X. Tu, X. Gao, C. Zhang, Y. Qin, L. Gao, W. Wang and Z. Song, Total Syntheses of Bryostatins 1, 7, 9 and 9-N₃, Angew. Chem., Int. Ed., 2025, 64, e202423465.
25. L. Guo and P.-Q. Huang, The Diverted and Scalable Enantioselective Total Syntheses of Three Bryostatin Congeners and An Analogue, Sci. China:Chem., 2025, 68, 4541–4543.
26. P. A. Wender, C. T. Hardman, S. Ho, M. S. Jeffreys, J. K. Maclaren, R. V. Quiroz, S. M. Ryckbosch, A. J. Shimizu, J. L. Sloane and M. C. Stevens, Scalable Synthesis of Bryostatin 1 and Analogs, Adjuvant Leads against Latent HIV, Science, 2017, 358, 218–223.
27. S. G. Hentges and K. B. Sharpless, Asymmetric Induction in the Reaction of Osmium-Tetroxide with Olefins, J. Am. Chem. Soc., 1980, 102, 4263–4265.
28. Z.-Q. Wang, J.-J. Wang, P. Wang, N. Song, X.-W. Liu and M. Li, Modular Synthesis and Cytotoxicity Evaluation of Dragocins A-C and Their Analogues: Discovery of a Potential Anticancer Agent, Chin. J. Chem., 2025, 43, 1107–1113.
29. H. Zhou, X. Liao, W. Yin, J. Ma and J. M. Cook, General Approach for the Synthesis of 12-Methoxy-Substituted Sarpagine Indole Alkaloids Including (−)-12-Methoxy-N_b-Methylvoachalotine, (+)-12-Methoxy N_a-methylvellosimine, (+)-12-Methoxyaffinisine, and (−)-Fuchsiaefoline, J. Org. Chem., 2006, 71, 251–259.
30. Z. Wang, L. Zhu, F. Yin, Z. Su, Z. Li and C. Li, Silver-Catalyzed Decarboxylative Chlorination of Aliphatic Carboxylic Acids, J. Am. Chem. Soc., 2012, 134, 4258–4263.
31. C.-P. Xu, Z.-H. Xiao, B.-Q. Zhuo, Y.-H. Wang and P.-Q. Huang, Efficient and Chemoselective Alkylation of Amines/Amino Acids Using Alcohols as Alkylating Reagents Under Mild Conditions, Chem. Commun., 2010, 46, 7834–7836.
32. K. Zhao, Y. Cheng and Y. Jia, Twenty-step Total Synthesis of (+)-Phorbol, CCS Chem., 2025, 7, 375–380.
33. S. Kawamura, H. Chu, J. Felding and P. S. Baran, Nineteen-step Total Synthesis of (+)-Phorbol, Nature, 2016, 532, 90–93.
34. S. Magar, R. C. Desai and P. L. Fuchs, Synthesis of Phorbol C-Ring Analogs: A Biomimetic Model Study on the Phorbol to 12-Hydroxydaphnetoxin Conversion, J. Org. Chem., 1992, 57, 5360–5369.
35. T. Mukaiyama, J. Matsuo and M. Yanagisawa, A New and Efficient Method for Oxidation of Various Alcohols by Using N-tert-Butyl Phenylsulfinimidoyl Chloride, Chem. Lett., 2000, 29, 1072–1073.
36. (a) K. Tamao, M. Akita, T. Iwahara, R. Kanatani, J. Yoshida and M. Kumada, Oxidative Cleavage of Silicon-Carbon Bonds in Organosilicon Fluorides to Alcohols, Tetrahedron, 1983, 39, 983–990; (b) I. Fleming, R. Henning and H. Plaut, The Phenyldimethylsilyl Group as A Masked Form of the Hydroxy Group, J. Chem. Soc., Chem. Commun., 1984, 29–31; (c) W. Bernhard, I. Fleming and D. Waterson, Diastereoselectivity in the Alkylation of Enolates Having An Adjacent Silkyl Group, J. Chem. Soc., Chem. Commun., 1984, 28–29.
37. T. Mukaiyama, J. Matsuo and H. Kitagawa, A New and One-Pot Synthesis of α,β-Unsaturated Ketones by Dehydrogenation of Various Ketones with N-tert-Butyl Phenylsulfinimidoyl Chloride, Chem. Lett., 2000, 29, 1250–1251.
38. K. Nagaraju, D. S. Ni and D. Ma, Total Synthesis of Kopsinitarine E, Angew. Chem., Int. Ed., 2020, 59, 22039–22042.
39. F. A. Davis, Recent Applications of N-sulfonyloxaziridines (Davis oxaziridines) in Organic Synthesis, Tetrahedron, 2018, 74, 3198–3214.
40. B. Li, C. Tan, T. Ma and Y. Jia, Bioinspired Total Synthesis of Bipolarolides A and B, Angew. Chem., Int. Ed., 2024, 63, e202319306.
41. X.-H. Zhao, Q. Zhang, J.-Y. Du, X.-Y. Lu, Y.-X. Cao, Y.-H. Deng and C.-A. Fan, Total Synthesis of (±)-Lycojaponicumin D and Lycodoline-Type Lycopodium, Alkaloids, J. Am. Chem. Soc., 2017, 139, 7095–7103.
42. X.-H. Zhao, Q.-Y. Yang, M.-Y. Ma, L.-L. Meng, J.-R. Xu, X.-T. An, P.-X. Xie, Z.-W. Zhang, Y.-H. Shang and C.-A. Fan, The Bridgehead Enone Directed Total Synthesis of Bipolarolide B and Bipoladien B, CCS Chem., 2026, 8, 1540–1550.
43. Y. Ito, T. Hirao and T. Saegusa, Synthesis of α,β-Unsaturated Carbonyl Compounds by Palladium(II)-Catalyzed Dehydrosilylation of Silyl Enol Ethers, J. Org. Chem., 1978, 43, 1011–1013.
44. (a) Y. Shvo and H. I. Arisha, Regioselective Catalytic Dehydrogenation of Aldehydes and Ketones, J. Org. Chem., 1998, 63, 5640–5642; (b) D. Huang, Y. Zhao and T. R. Newhouse, Synthesis of Cyclic Enones by Allyl-Palladium-Catalyzed α,β Dehydrogenation, Org. Lett., 2018, 20, 684–687; (c) K. C. Nicolaou, Y.-L. Zhong and P. S. Baran, A New Method for the One-Step Synthesis of α,β-Unsaturated Carbonyl Systems from Saturated Alcohols and Carbonyl Compounds, J. Am. Chem. Soc., 2000, 122, 7596–7597.
45. H. C. Brown and P. J. Geoghegan, Jr., Solvomercuration-demercuration. I. Oxymercuration-demercuration of Representative Olefins in An Aqueous System. Mild Procedure for the Markovnikov Hydration of the Carbon-Carbon Double Bond, J. Org. Chem., 1970, 35, 1844–1850.
46. (a) N. Rabjohn, Selenium Dioxide Oxidation, Org. React., 1976, 24, 261–415; (b) A. Nakamura and M. Nakada, Allylic Oxidations in Natural Product Synthesis, Synthesis, 2013, 1421–1451.
47. A. J. Mancuso, S.-H. Huang and D. Swern, Oxidation of Long-chain and Related Alcohols to Carbonyls by Dimethyl Sulfoxide “Activated” by Oxalyl Chloride, J. Org. Chem., 1978, 43, 2480–2482.
48. A. I. Kim and S. D. Rychnovsky, Unified Strategy for the Synthesis of (−)-Elisapterosin B and (−)-Colombiasin A, Angew. Chem., Int. Ed., 2003, 42, 1267–1270.
49. C.-H. Liu, H. Gong, Y. Sheng, W. Wang, Q. Xia and H. Ding, Divergent Total Syntheses of Elisapterane and Relevant Diterpenoids Assisted by In Silico Structure Reassignment, J. Am. Chem. Soc., 2025, 147, 33136–33152.
50. K. Gao, J. Hu and H. Ding, Tetracyclic Diterpenoid Synthesis Facilitated by ODI-Cascade Approaches to Bicyclo[3.2.1]octane Skeletons, Acc. Chem. Res., 2021, 54, 875–889.
51. J. D. Albright and L. Goldman, Dimethyl Sulfoxide-Acid Anhydride Mixtures for the Oxidation of Alcohols, J. Am. Chem. Soc., 1967, 89, 2416–2423.
52. M. Schroeder, Osmium Tetraoxide cis-Hydroxylation of Unsaturated Substrates, Chem. Rev., 1980, 80, 187–213.
53. M. Kirihara, Y. Ochiai, S. Takizawa, H. Takahata and H. Nemoto, Aerobic Oxidation of α-Hydroxycarbonyls Catalysed by Trichlorooxyvanadium: Efficient Synthesis of α-Dicarbonyl Compounds, Chem. Commun., 1999, 1387–1388.
54. K. Yamakawa, T. Satoh, N. Ohba, R. Sakaguchi, S. Takita and N. Tamura, Studies on the Terpenoids and Related Alicyclic Compounds—XXII: Stereochemical Study on the Angular Hydroxylation of Polycyclic Ketones Using Benzeneseleninic Anhydride, Tetrahedron, 1981, 37, 473–479.
55. Z. Peralta-Neel and K. A. Woerpel, Hydroperoxidations of Alkenes Using Cobalt Picolinate Catalysts, Org. Lett., 2021, 23, 5002–5006.
56. J. L. F. Silva and B. Olofsson, Hypervalent Lodine Reagents in the Total Synthesis of Natural Products, Nat. Prod. Rep., 2011, 28, 1722–1754.
57. M. M. Heravi, T. Momeni, V. Zadsirjan and L. Mohammadi, Applications of the Dess-Martin Oxidation in Total Synthesis of Natural Products, Curr. Org. Synth., 2021, 18, 125–196.
58. N. Zhang, C. Wang, H. Xu, M. Zheng, H. Jiang, K. Chen and Z. Ma, Asymmetric Total Synthesis of Alstrostine G Utilizing a Catalytic Asymmetric Desymmetrization Strategy, Angew. Chem., Int. Ed., 2024, 63, e202407127.
59. P. Chen, J. Wang, S. Zhang, Y. Wang, Y. Sun, S. Bai, Q. Wu and X. Cheng, Peng Cao and X. Qi, Total Syntheses of Tetrodotoxin and 9-epi-Tetrodotoxin, Nat. Commun., 2014, 15, 679.
60. Y. Zhang, L. Chen and Y. Jia, Total Synthesis of Pallamolides A-E, Angew. Chem., Int. Ed., 2024, 63, e202319127.
61. P. R. Leger, Y. Kuroda, S. Chang, J. Jurczyk and R. Sarpong, C–C Bond Cleavage Approach to Complex Terpenoids: Development of a Unified Total Synthesis of the Phomactins, J. Am. Chem. Soc., 2020, 142, 15536–15547.
62. R. J. Linderman and D. M. Graves, Oxidation of Fluoroalkyl-substituted Carbinols by the Dess-Martin reagent, J. Org. Chem., 1989, 54, 661–668.
63. N. Diddi and D. E. Ward, Total Synthesis of Dolabriferol C by a Highly Stereoselective One–Pot Coupling of a meso-3,7-Diketone with Two Chiral Aldehydes, Angew. Chem., Int. Ed., 2021, 60, 26777–26782.
64. Z. Sun, S. Jin, J. Song, L. Niu, F. Zhang, H. Gong, X. Shu, Y. Wang and X.-D. Hu, Enantioselective Total Synthesis of (–)-Cephalotanin B, Angew. Chem., Int. Ed., 2023, 62, e202312599.
65. J. Lee, S. C. Davis, A. Sheu, J. W. Gu and T. R. Newhouse, A Convergent Approach to Phragmalin-Type Limonoids: Total Synthesis of Thaigranatin P, J. Am. Chem. Soc., 2025, 147, 36085–36089.
66. J. Ji, J. Chen, S. Qin, W. Li, J. Zhao, G. Li, H. Song, X.-Y. Liu and Y. Qin, Total Synthesis of Vilmoraconitine, J. Am. Chem. Soc., 2023, 145, 3903–3908.
67. X. Zheng, X. Guo, H. Wang, P.-P. Zhou and X. Chen, Total Synthesis of (±)-Rubriflordilactone A, J. Am. Chem. Soc., 2024, 146, 7198–7203.
68. J. L. Sutro and A. Fürstner, Total Synthesis of the Allenic Macrolide (+)-Archangiumide, J. Am. Chem. Soc., 2024, 146, 2345–2350.
69. J. Ding and A. B. Smith, III, Total Synthesis of the Reported Structure of Neaumycin B, J. Am. Chem. Soc., 2023, 145, 18240–18246.
70. S. J. Plamondon and J. L. Gleason, Total Synthesis of (−)-3-Oxoisotaxodione, Org. Lett., 2022, 24, 2305–2309.
71. S. M. Astle, S. Guggiari, J. R. Frost, H. B. Hepburn, D. J. Klauber, K. E. Christensen and J. W. Burton, Enantioselective Synthesis of Sealutomicin C, J. Am. Chem. Soc., 2024, 146, 17757–17764.
72. Q. Du, Z. Fan and M. Yang, Total Synthesis of Principinol B, Angew. Chem., Int. Ed., 2024, 63, e202400956.
73. Y.-P. Zhang, S. Du, Y. Ma, W. Zhan, W. Chen, X. Yang and H. Zhang, Structure-Unit-Based Total Synthesis of (-)-Sinulochmodin C, Angew. Chem., Int. Ed., 2024, 63, e202315481.
74. M. Liu, C. Wu, X. Xie, H. Li and X. She, Total Synthesis of the Euphorbia Diterpenoid Pepluacetal, Angew. Chem., Int. Ed., 2024, 63, e202400943.
75. H. Wang, Y. Liu, H. Zhang, B. Yang, H. He and S. Gao, Asymmetric Total Synthesis of Cephalotaxus Diterpenoids: Cephinoid P, Cephafortoid A, 14-epi-Cephafortoid A and Fortalpinoids M N, P, J. Am. Chem. Soc., 2023, 145, 16988–16994.
76. D. Isak, L. A. Schwartz, S. Schulthoff, G. Pérez-Moreno, C. Bosch-Navarrete, D. González-Pacanowska and A. Fürstner, Collective and Diverted Total Synthesis of the Strasseriolides: A Family of Macrolides Endowed with Potent Antiplasmodial and Antitrypanosomal Activity, Angew. Chem., Int. Ed., 2024, 63, e202408725.
77. X.-Z. Liao, R. Wang, X. Wang and G. Li, Enantioselective Total Synthesis of (-)-Lucidumone Enabled by Tandem Prins Cyclization/Cycloetherification Sequence, Nat. Commun., 2024, 15, 2647.
78. O. Vyhivskyi and O. Baudoin, Total Synthesis of the Diterpenes (+)-Randainin D and (+)-Barekoxide via Photoredox-Catalyzed Deoxygenative Allylation, J. Am. Chem. Soc., 2024, 146, 11486–11492.
79. B. C. Derstine, A. J. Cook, J. D. Collings, J. Gair, J. Saurí, E. E. Kwan and N. Z. Burns, Total Synthesis of (+)-Discorhabdin V, Angew. Chem., Int. Ed., 2024, 63, e202315284.
80. Y.-J. Cheng, L.-P. Zhao, L. Wang and Y. Tang, Catalytic [2 + 2 + 2] Tandem Cyclization with Alkyl Substituted Methylene Malonate Enabling Concise Total Synthesis of Four Malagasy Alkaloids, CCS Chem., 2023, 5, 124–132.
81. W. P. Griffith, S. V. Ley, G. P. Whitcombe and A. D. White, Preparation and Use of tetra-n-Butylammonium Perruthenate (TBAP reagent) and tetra-n-Propylammonium Perruthenate (TPAP reagent) as New Catalytic Oxidants for Alcohols, J. Chem. Soc., Chem. Commun., 1987, 1625–1627.
82. T. Watanabe, K. Oga, H. Matoba, M. Nagatomo and M. Inoue, Total Synthesis of Taxol Enabled by Intermolecular Radical Coupling and Pd-Catalyzed Cyclization, J. Am. Chem. Soc., 2023, 145, 25894–25902.
83. L. Betschart and K.-H. Altmann, Total Synthesis of Isoxeniolide A, Angew. Chem., Int. Ed., 2024, 63, e202315423.
84. Y. Zong, Z.-J. Xu, R.-X. Zhu, A.-H. Su, X.-Y. Liu, M.-Z. Zhu, J. Han, J.-Z. Zhang, Y.-L. Xu and H.-X. Lou, Enantioselective Total Syntheses of Manginoids A and C and Guignardones A and C, Angew. Chem., Int. Ed., 2021, 60, 15286–15290.
85. W. Zhang, Z. Zhang, J.-C. Tang, J.-T. Che, H.-Y. Zhang, J.-H. Chen and Z. Yang, Total Synthesis of (–)-Haperforin-G, J. Am. Chem. Soc., 2020, 142, 19487–19492.
86. T. Matsumura, T. Nishikawa and A. Nakazaki, Total Synthesis of 19-Nordigitoxigenin, An Antiaroside Y Aglycon, J. Org. Chem., 2023, 88, 15142–15150.
87. B. Chen, K. Long, L. Wang and Y. Chen, Convergent Total Syntheses of Brassicicenes C, F, H, J, and K, CCS Chem., 2026, 8, 1023–1032.
88. D. Leifert and A. Studer, Organic Synthesis Using Nitroxides, Chem. Rev., 2023, 123, 10302–10380.
89. A. De Mico, R. Margarita, L. Parlanti, A. Vescovi and G. Piancatelli, A Versatile and Highly Selective Hypervalent Lodine (III)/2,2,6,6-Tetramethyl-1-piperidinyloxyl-Mediated Oxidation of Alcohols to Carbonyl Compounds, J. Org. Chem., 1997, 62, 6974–6977.
90. M. Shibuya, M. Tomizawa, Y. Sasano and Y. Iwabuchi, An Expeditious Entry to 9-Azabicyclo[3.3.1]nonane N-Oxyl (ABNO): Another Highly Active Organocatalyst for Oxidation of Alcohols, J. Org. Chem., 2009, 74(12), 4619–4622.
91. J. M. Hoover and S. S. Stahl, Highly Practical Copper(I)/TEMPO Catalyst System for Chemoselective Aerobic Oxidation of Primary Alcohols, J. Am. Chem. Soc., 2011, 133, 16901–16910.
92. X. Jiang, J. Zhang and S. Ma, Iron Catalysis for Room Temperature Aerobic Oxidation of Alcohols to Carboxylic Acids, J. Am. Chem. Soc., 2016, 138, 8344–8347.
93. N. Merbouh, J. M. Bobbitt and C. Brückner, Preparation of Tetramethylpiperdine-1-oxoammonlum Salts and Their Use as Oxidants in Organic Chemistry. A Review, Org. Prep. Proced. Int., 2004, 36, 1–31.
94. W. Zhang, P.-C. Yu, C.-Y. Feng and C.-C. Li, Asymmetric Total Synthesis of Pedrolide, J. Am. Chem. Soc., 2024, 146, 2928–2932.
95. M.-Y. Lyu, Z. Zhong, V. K.-Y. Lo, H. N. C. Wong and X.-S. Peng, Total Synthesis of Cryptotrione, Angew. Chem., Int. Ed., 2020, 59, 19929–19933.
96. K. Yu, F. Yao, Q. Zeng, H. Xie and H. Ding, Asymmetric Total Syntheses of (+)-Davisinol and (+)-18 Benzoyldavisinol: A HAT-Initiated Transannular Redox Radical Approach, J. Am. Chem. Soc., 2021, 143, 10576–10581.
97. A. R. Wong, N. J. Fastuca, V. W. Mak, J. K. Kerkovius, S. M. Stevenson and S. E. Reisman, Total Syntheses of the C₁₉ Diterpenoid Alkaloids (−)-Talatisamine, (−)-Liljestrandisine, and (−)-Liljestrandinine by a Fragment Coupling Approach, ACS Cent. Sci., 2021, 7, 1311–1316.
98. J. E. Steves and S. S. Stahl, Copper(I)/ABNO-Catalyzed Aerobic Alcohol Oxidation: Alleviating Steric and Electronic Constraints of Cu/TEMPO Catalyst Systems, J. Am. Chem. Soc., 2013, 135, 15742–15745.
99. G. Xu, J. Wu, L. Li, Y. Lu and C. Li, Total Synthesis of (−)-Daphnezomines A and B, J. Am. Chem. Soc., 2020, 142, 15240–15245.
100. S. Zhang, S. Zhang, Y. Fan, X. Zhang, J. Chen, C. Jin, S. Chen, L. Wang, Q. Zhang and Y. Chen, Total Synthesis of the Proposed Structure of Neaumycin B, Angew. Chem., Int. Ed., 2023, 62, e202313186.
101. Y.-L. Jiang, H.-X. Yu, Y. Li and Z. Yang, Asymmetric Total Synthesis of Pre-schisanartanin C, J. Am. Chem. Soc., 2020, 142, 573–580.
102. Y. Watanabe, H. Morozumi, H. Mutoh, K. Hagiwara and M. Inoue, Total Synthesis of (–)-Batrachotoxin Enabled by a Pd/Ag-Promoted Suzuki–Miyaura Coupling Reaction, Angew. Chem., Int. Ed., 2023, 62, e202309688.
103. H. Takeuchi, S. Inuki, K. Nakagawa, T. Kawabe, A. Ichimura, S. Oishi and H. Ohno, Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso-Cyclization, Angew. Chem., Int. Ed., 2020, 59, 21210–21215.
104. H. Fujino, T. Fukuda, M. Nagatomo and M. Inoue, Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular Radical Addition to Aldehyde, J. Am. Chem. Soc., 2020, 142, 13227–13234.
105. W. Zhang, M. Lu, L. Ren, X. Zhang, S. Liu, M. Ba, P. Yang and A. Li, Total Synthesis of Four Classes of Daphniphyllum Alkaloids, J. Am. Chem. Soc., 2023, 145, 26569–26579.
106. P. Waser and K.-H. Altmann, an RCM–Based Total Synthesis of the Antibiotic Disciformycin B, Angew. Chem., Int. Ed., 2020, 59, 17393–17397.
107. (a) N. Joly, S. Gaillard, A. Poater and J.-L. Renaud, Hydrogen Autotransfer with Alcohols for Alkylations, Org. Chem. Front., 2024, 11, 7278–7317; (b) B. G. Reed-Berendt, D. E. Latham, M. B. Dambatta and L. C. Morrill, Borrowing Hydrogen for Organic Synthesis, ACS Cent. Sci., 2021, 7, 570–585; (c) A. Alexandridis and A. Quintard, Enantioselective Borrowing Hydrogen: A Modern Tool to Construct Enantioenriched Molecules, ChemCatChem, 2014, 16, e202400902.
108. (a) L. Shi, Y.-Q. Tu, M. Wang, F.-M. Zhang, C.-A. Fan, Y.-M. Zhao and W.-J. Xia, A Reaction for sp³−sp³ C−C Bond Formation via Cooperation of Lewis Acid-Promoted/Rh-Catalyzed C−H Bond Activation, J. Am. Chem. Soc., 2005, 127, 10836; (b) S.-Y. Zhang, F.-M. Zhang and Y.-Q. Tu, Direct sp³ α-C–H Activation and Functionalization of Alcohol and Ether, Chem. Soc. Rev., 2011, 40, 1937–1949; (c) P.-Q. Huang, Krische-Tu α-Alkylation of Alcohols, in Organic Naed Reactions, Reagents and Rules, 2nd ed, ed. P.-Q. Huang, Chemical Industry press, Beijing, 2019, pp. 63–69. ISBN: 9787122344038.
109. (a) J. F. Bower, I. S. Kim, R. L. Patman and M. J. Krische, Catalytic Carbonyl Addition through Transfer Hydrogenation: A Departure from Preformed Organometallic Reagents, Angew. Chem., Int. Ed., 2009, 48, 34–46; (b) J. M. Ketcham, I. Shin, T. P. Montgomery and M. J. Krische, Catalytic Enantioselective C−H Functionalization of Alcohols by Redox-Triggered Carbonyl Addition: Borrowing Hydrogen, Returning Carbon, Angew. Chem., Int. Ed., 2014, 53, 9142–9150.
110. Y.-M. Siu, J. Roane and M. J. Krische, Total Synthesis of Leiodermatolide A via Transfer Hydrogenative Allylation, Crotylation and Propargylation: Polyketide Construction beyond Discrete Allyl- or Allenylmetal Reagents, J. Am. Chem. Soc., 2021, 143, 10590–10595.
111. X. Qiu and J. G. Pierce, Total Synthesis of Bipolamine I, J. Am. Chem. Soc., 2022, 144, 12638–12641.
112. B. P. Mundy, M. G. Ellerd and F. G. Favaloro Jr., Pinnick Oxidation, in Name Reactions and Reagents in Organic Synthesis, John Wiley & Sons, Inc., Hoboken, New Jersey, 2005, pp. 518–519. ISBN 0-471-22854-0.
113. B. S. Bal, W. E. Childers and H. W. Pinnick, Oxidation of α,β-Unsaturated Aldehydes, Tetrahedron, 1981, 37, 2091–2096.
114. T. Suwa, M. Sasaki and A. Umehara, Total Synthesis of (–)-Irijimaside A Enabled by Ni/Zr-Mediated Reductive Ketone Coupling, Org. Lett., 2024, 26, 4377–4382.
115. Y. Guo, J.-T. Lu, R. Fang, Y. Jiao, J. Liu and T. Luo, Enantioselective Total Synthesis of (–)-Zygadenine, J. Am. Chem. Soc., 2023, 145, 20202–20207.
116. H.-X. Huang, F. Mi, C. Li, H. He, F.-P. Wang, X.-Y. Liu and Y. Qin, Total Synthesis of Liangshanone, Angew. Chem., Int. Ed., 2020, 59, 23609–23614.
117. K. J. Chambers, P. Sanghong, D. C. Martos, G. Casoni, R. C. Mykura, D. P. Hari, A. Noble and V. K. Aggarwal, Stereospecific Conversion of Boronic Esters into Enones using Methoxyallene: Application in the Total Synthesis of 10-Deoxymethynolide, Angew. Chem., Int. Ed., 2023, 62, e202312054.
118. H. Zhai, Z. Wang, K. Chen, T.-Y. Sun, J. Wei and Y.-D. Wu, Total Synthesis of Monoterpenoid Indole Alkaloid (–)-Arbophyllidine, Org. Chem. Front., 2022, 9, 2328.
119. Y. Liu, D. Ni and M. K. Brown, Boronic Ester Enabled [2 + 2]-Cycloadditions by Temporary Coordination: Synthesis of Artochamin J and Piperarborenine B, J. Am. Chem. Soc., 2022, 144, 18790–18796.
120. M. J. Moore, P. Qin, N. Yamasaki, X. Zeng, D. J. Keith, S. Jung, T. Fukazawa, K. Graham-O'Regan, Z.-C. Wu, S. Chatterjee and D. L. Boger, Tetrachlorovancomycin: Total Synthesis of a Designed Glycopeptide Antibiotic of Reduced Synthetic Complexity, J. Am. Chem. Soc., 2023, 145, 21132–21141.
121. B.-C. Yan, M. Zhou, J. Li, X.-N. Li, S.-J. He, J.-P. Zuo, H.-D. Sun, A. Li and P.-T. Puno, (–)-Isoscopariusin A, a Naturally Occurring Immunosuppressive Meroditerpenoid: Structure Elucidation and Scalable Chemical Synthesis, Angew. Chem., Int. Ed., 2021, 60, 12859–12867.
122. S. Yamada, D. Morizono and K. Yamamoto, Mild Oxidation of Aldehydes to the Corresponding Carboxylic Acids and Esters: Alkaline Iodine Oxidation Revisited, Tetrahedron Lett., 1992, 33, 4329–4332.
123. J. Zhou, D.-X. Tan and F.-S. Han, A Divergent Enantioselective Total Synthesis of Post–Iboga Indole Alkaloids, Angew. Chem., Int. Ed., 2020, 59, 18731–18740.
124. H. Shao, Z.-H. Ma, Y.-Y. Cheng, X.-F. Guo, Y.-K. Sun, W.-J. Liu and Y.-M. Zhao, Bioinspired Total Synthesis of Cephalotaxus Diterpenoids and Their Structural Analogues, Angew. Chem., Int. Ed., 2024, 63, e202402931.
125. H. Hussain, A. Al-Harrasi, I. R. Green, I. Ahmed, G. Abbas and N. U. Rehman, meta-Chloroperbenzoic acid (m-CPBA): a Versatile Reagent in Organic Synthesis, RSC Adv., 2014, 4, 12882–12917.
126. J. Xie, X. Liu, N. Zhang, S. Choi and G. Dong, Bidirectional Total Synthesis of Phainanoid A via Strategic Use of Ketones, J. Am. Chem. Soc., 2021, 143, 19311–19316.
127. H. Shao, W. Liu, M. Liu, H. He, Q.-L. Zhou, S.-F. Zhu and S. Gao, Asymmetric Synthesis of Cyclopamine, a Hedgehog (Hh) Signaling Pathway Inhibitor, J. Am. Chem. Soc., 2023, 145, 25086–25092.
128. M. S. Cooper, H. Heaney, A. J. Newbold and W. R. Sanderson, Oxidation Reactions Using Urea-Hydrogen Peroxide; A Safe Alternative to Anhydrous Hydrogen Peroxide, Synlett, 1990, 533–535.
129. B. Wang, Z. Liu, Z. Tong, B. Gao and H. Ding, Asymmetric Total Syntheses of 8, 9−Seco–ent–kaurane Diterpenoids Enabled by an Electrochemical ODI-[5 + 2] Cascade, Angew. Chem., Int. Ed., 2021, 60, 14892–14896.
130. T. Katsuki and K. B. Sharpless, The First Practical Method for Asymmetric Epoxidation, J. Am. Chem. Soc., 1980, 102, 5974–5976.
131. (a) S. K. Sartori, I. L. Miranda, M. A. N. Diaz and G. Diaz-Muñoz, Sharpless Asymmetric Epoxidation: Applications in the Synthesis of Bioactive Natural Products, Mini-Rev. Org. Chem., 2021, 18, 606–620; (b) M. M. Heravi, T. B. Lashaki and N. Poorahmad, Applications of Sharpless asymmetric epoxidation in total synthesis, Tetrahedron: Asymmetry, 2015, 26, 405–495.
132. R. Nandi, S. Niyogi, S. Kundu, V. R. Gavit, M. Munda, R. Murmu and A. Bisai, Total Synthesis of Atropisomeric Indolosesquiterpenoids via N–N bond Formation: Dixiamycins A and B, Chem. Sci., 2023, 14, 8047–8053.
133. B. Herlé, G. Späth, L. Schreyer and A. Fürstner, Total Synthesis of Mycinolide IV and Path–Scouting for Aldgamycin N, Angew. Chem., Int. Ed., 2021, 60, 7893–7899.
134. J. Wang, D. Lin, M. Liu, H. Liu, P. Blasco, Z. Sun, Y. C. Cheung, S. Chen and X. Li, Total Synthesis of Mannopeptimycin β via β-Hydroxyenduracididine Ligation, J. Am. Chem. Soc., 2021, 143, 12784–12790.
135. A. Singh and K. P. Kaliappan, Asymmetric Total Synthesis of 4-Hydroxy 8-O-methyltetrangomycin, 4-Hydroxytetrangomycin, and 4-Keto-8-O-methyltetrangomycin, J. Org. Chem., 2024, 89, 10965–10973.
136. Q.-L. Peng, S.-P. Luo, X.-E. Xia, L.-X. Liu and P.-Q. Huang, The Four-step Total Synthesis of (−)-Chaetominine, Chem. Commun., 2014, 50, 1986–1988.
137. J.-F. Lü, J.-F. Wu, J.-L. Ye and P.-Q. Huang, Further Elaboration of the Stereodivergent Approach to Chaetominine-Type Alkaloids: Synthesis of the Reported Structures of Aspera chaetominines A and B and Revised Structure of Aspera chaetominine B., Beilstein J. Org. Chem., 2025, 21, 2072–2081.
138. Y. Zhu, Q. Wang, R. G. Cornwall and Y. Shi, Organocatalytic Asymmetric Epoxidation and Aziridination of Olefins and Their Synthetic Applications, Chem. Rev., 2014, 114, 8199–8256.
139. M. Yoo and M. J. Krische, Total Synthesis of the Spliceosome Modulator Pladienolide B via Asymmetric Alcohol-Mediated syn- and anti-Diastereoselective Carbonyl Crotylation, Angew. Chem., Int. Ed., 2021, 60, 13923–13928.
140. D. M. Wilson and R. Britton, Enantioselective Total Synthesis of the Marine Macrolides Salarins A and C, J. Am. Chem. Soc., 2024, 146, 8456–8463.
141. V. Petkevičius, C. Mügge and D. Tischle, Enzymatic Epoxidation Strategies for the Stereoselective Synthesis of Chiral Epoxides, Cell Rep. Phys. Sci., 2025, 6, 102794.
142. H. Dong, N. Guo, D. Hu, B. Hong, D. Liao, H. J. Zhu, Z. Y. Yan, H. M. Ge and X. Lei, Chemoenzymatic Total Synthesis of Alchivemycin A, Nat. Synth., 2024, 3, 1124–1133.
143. H. C. Kolb, M. S. VanNieuwenhze and K. B. Sharpless, Catalytic Asymmetric Dihydroxylation, Chem. Rev., 1994, 94, 2483–2547.
144. M. M. Heravi, V. Zadsirjan, M. Esfandyari and T. B. Lashaki, Applications of Sharpless Asymmetric Dihydroxylation in the Total Synthesis of Natural Products, Tetrahedron: Asymmetry, 2017, 28, 987–1043.
145. A. Mushtaq, A. F. Zahoor, S. M. Hussain, M. Irfan, R. Akhtar, A. Irfan, K. Kotwica-Mojzych and M. Mojzych, Sharpless Asymmetric Dihydroxylation: An Impressive Gadget for the Synthesis of Natural Products: A Review, Molecules, 2023, 28, 2722.
146. T. K. M. Shing, E. K. W. Tam, V. W. F. Tai, I. H. F. Chung and Q. Jiang, Ruthenium-catalyzed cis-Dihydroxylation of Alkenes, Chem. – Eur. J., 1996, 2, 50–57.
147. B. Plietker and M. Niggemann, RuCl₃/CeCl₃/NaIO₄: A New Bimetallic Oxidation System for the Mild and Efficient Dihydroxylation of Unreactive Olefins, J. Org. Chem., 2005, 70, 2402–2405.
148. C. He, H. Chu, T. P. Stratton, D. Kossler, K. J. Eberle, D. T. Flood and P. S. Baran, Total Synthesis of Tagetitoxin, J. Am. Chem. Soc., 2020, 142, 13683–13688.
149. M. Uwamori, R. Osada, R. Sugiyama, K. Nagatani and M. Nakada, Enantioselective Total Synthesis of Cotylenin A, J. Am. Chem. Soc., 2020, 142, 5556–5561.
150. T. Xie, C. Zheng, K. Chen, H. He and S. Gao, Asymmetric Total Synthesis of the Complex Polycyclic Xanthone FD–594, Angew. Chem., Int. Ed., 2020, 59, 4360–4364.
151. C. Lutz, W. Simon, S. Werner-Simon, A. Pahl and C. Müller, Total Synthesis of α- and β-Amanitin, Angew. Chem., Int. Ed., 2020, 59, 11390–11393.
152. S. N. Mhaldar, M. M. Gaikwad and S. G. Tilve, Wacker Oxidation: A Powerful Tool for Natural Product Synthesis, Asian J. Org. Chem., 2025, 14, e202500117.
153. R. A. Fernandes, A. K. Jha and P. Kumar, Recent Advances in Wacker Oxidation: From Conventional to Modern Variants and Applications, Catal. Sci. Technol., 2020, 10, 7448–7470.
154. G. Li, Q. Wang and J. Zhu, Unified Divergent Strategy towards the Total Synthesis of the Three Sub-classes of Hasubanan Alkaloids, Nat. Commun., 2021, 12, 36.
155. F. Puls, P. Linke, O. Kataeva and H.-J. Knölker, Iron-catalyzed Wacker Type Oxidation of Olefins at Room Temperature with 1,3-Diketones or Neocuproine as Ligands, Angew. Chem., Int. Ed., 2021, 60, 14083–14090.
156. S. Isayama and T. Mukaiyama, A New Method for Preparation of Alcohols from Olefins with Molecular Oxygen and Phenylsilane by the Use of Bis(acetylacetonato)cobalt(II), Chem. Lett., 1989, 18, 1071–1074.
157. P. Bayer, R. Pérez-Ruiz and A. J. von Wangelin, Stereoselective Photooxidations by the Schenck Ene Reaction, ChemPhotoChem, 2018, 2, 559–570.
158. C. Li, F. Lu, Y. Cai, C. Zhang, Y. Shao, Y. Zhang, X.-Y. Liu and Y. Qin, Catalytic Asymmetric Total Synthesis of (–)-Garryine via an Enantioselective Heck Reaction, J. Am. Chem. Soc., 2024, 146, 1081–1088.
159. B. Wang, B. Xu, W. Xun, Y. Guo, J. Zhang and F. G. Qiu, A General Strategy for the Construction of Calyciphylline A–Type Alkaloids: Divergent Total Syntheses of (–)-Daphenylline and (–)-Himalensine A, Angew. Chem., Int. Ed., 2021, 60, 9439–9443.
160. For selected reviews, see: (a) D. J. Abrams, P. A. Provencher and E. J. Sorensen, Recent Applications of C-H Functionalization in Complex Natural Product Synthesis, Chem. Soc. Rev., 2018, 47, 8925–8967; (b) J. Huang, M. Yang, C. Dai, Y. Zhou, H. Fang, L. Zhu, F. Yin and Z. Li, Novel Strategies in C-H Oxidations for Natural Product Diversification—A Remote Functionalization Application Summary, Front. Chem., 2021, 9, 737530; (c) V. C. S. Santana, M. C. V. Fernandes, I. Cappuccelli, A. C. G. Richieri and E. C. de Lucca Jr., Metal-Catalyzed C–H Bond Oxidation in the Total Synthesis of Natural and Unnatural Products, Synthesis, 2022, 5337–5359; (d) Y. Liu, T. You, H.-X. Wang, Z. Tang, C.-Y. Zhou and C.-M. Che, Iron- and Cobalt-catalyzed C(sp³)–H Bond Functionalization Reactions and Their Application in Organic Synthesis, Chem. Soc. Rev., 2020, 49, 5310–5358.
161. W. Hou, H. Lin, Y. Wu, C. Li, J. Chen, X.-Y. Liu and Y. Qin, Divergent and Gram-Scale Syntheses of (−)-Veratramine and (−)-Cyclopamine, Nat. Commun., 2024, 15, 5332.
162. Y. Y. See, A. T. Herrmann, Y. Aihara and P. S. Baran, Scalable C–H Oxidation with Copper: Synthesis of Polyoxypregnanes, J. Am. Chem. Soc., 2015, 137, 13776–13779.
163. C. Hui and J. Xu, Palladium-catalyzed sp³ C–H Oxidation Using Oxime as Directing Group—Applications in Total Synthesis, Tetrahedron Lett., 2016, 57, 2692–2696.
164. V. C. S. Santana, E. C. S. Rocha, J. C. S. Pavan, V. C. G. Heleno and E. C. de Lucca, Jr., Selective Oxidations in the Synthesis of Complex Natural ent-Kauranes and ent-Beyeranes, J. Org. Chem., 2022, 87, 10462–10466.
165. D. H. Dethe and M. Shukla, Enantioselective First Total Syntheses of the Antiviral Natural Products Xiamycins D and E, Chem. Commun., 2021, 57, 10644–10646.
166. M. S. Chen and M. C. White, A Predictably Selective Aliphatic C-H Oxidation Reaction for Complex Molecule Synthesis, Science, 2007, 318, 783–787.
167. C. Etling, G. Tedesco, A. Di Marco and M. Kalesse, Asymmetric Total Synthesis of Illisimonin A, J. Am. Chem. Soc., 2023, 145, 7021–7029.
168. K. Yoshida, K. Okada, H. Ueda and H. Tokuyama, A Concise Enantioselective Total Synthesis of (−)-Deoxoapodine, Angew. Chem., Int. Ed., 2020, 59, 23089–23093.
169. For selected reviews, see: (a) N. D. Fessner, P450 Monooxygenases Enable Rapid Late-Stage Diversification of Natural Products via C−H Bond Activation, ChemCatChem, 2019, 11, 2226–2242; (b) S. Chakrabarty, Y. Wang, J. C. Perkins and A. R. H. Narayan, Scalable Biocatalytic C–H Oxyfunctionalization Reactions, Chem. Soc. Rev., 2020, 49, 8137–8155; (c) S. Chakrabarty, E. O. Romero, J. B. Pyser, J. A. Yazarians and A. R. H. Narayan, Chemoenzymatic Total Synthesis of Natural Products, Acc. Chem. Res., 2021, 54, 1374–1384.
170. F. Li and H. Renata, A Chiral-Pool-Based Strategy to Access trans-syn-Fused Drimane Meroterpenoids: Chemoenzymatic Total Syntheses of Polysin, N-Acetyl-polyveoline and the Chrodrimanins, J. Am. Chem. Soc., 2021, 143, 18280–18286.
171. X. Liu, Y. Xu, L. Li and J. Li, Chemoenzymatic Oxidation of Labdane and Formal Synthesis of Nimbolide, J. Am. Chem. Soc., 2024, 146, 26243–26250.
172. T. Wang, J. Zou, K. Wang, Y. Liu, S. Zhang, Y. Kong and Z. Xu, Chemoenzymatic Synthesis of the Cyclopiane Family of Diterpenoid Natural Products, Angew. Chem., Int. Ed., 2025, 64, e20241909.
173. (a) M. Chao, Q. Zhang, G. Jin, G. Guo, X. Cheng and D. Shen, Photo-driven Aerobic C(sp³)-H Oxidation by Organic Photocatalysts: A Recent Review, Tetrahedron, 2015, 174, 134496; (b) N. Holmberg-Douglas and D. A. Nicewicz, Photoredox-Catalyzed C–H Functionalization Reactions, Chem. Rev., 2022, 122, 1925–2016.
174. (a) D. Ghosh, A. K. Samal, A. Parida, M. Ikbal, A. Jana, R. Jana, P. K. Sahu, S. Giri and S. Samanta, Progress in Electrochemically Empowered C–O Bond Formation: Unveiling the Pathway of Efficient Green Synthesis, Chem. – Asian J., 2024, 19, e202400116; (b) H. Wang, G. Zhang and K. Xu, Electrochemical C-H Hydroxylation and Alkoxylation Reactions, ChemSusChem, 2025, 18, e202402312; (c) M. Yan, Y. Kawamata and P. S. Baran, Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance, Chem. Rev., 2017, 117, 13230–13319.
175. B. Yang, G. Li, Q. Wang and J. Zhu, Enantioselective Total Synthesis of (+)-Stephadiamine, J. Am. Chem. Soc., 2023, 145, 5001–5006.
176. G. Sennari, K. E. Gardner, S. Wiesler, M. Haider, A. Eggert and R. Sarpong, Unified Total Syntheses of Benzenoid Cephalotane-Type Norditerpenoids: Cephanolides and Ceforalides, J. Am. Chem. Soc., 2022, 144, 19173–19185.
177. Y. Jin, S. Hok, J. Bacsa and M. Dai, Convergent and Efficient Total Synthesis of (+)-Heilonine Enabled by C-H Functionalizations, J. Am. Chem. Soc., 2024, 146, 1825–1831.
178. B. P. Smith, N. J. Truax, A. S. Pollatos, M. Meanwell, P. Bedekar, A. F. Garrido-Castro and P. S. Baran, Total Synthesis of Dragocins A C through Electrochemical Cyclization, Angew. Chem., Int. Ed., 2024, 63, e202401107.
179. Y. Liu, K. Sun, Q. Wei, J. Chen, S. Sun, Y. Li, Z. Feng, Y. Guo and Z. Lu, Enantioselective Total Synthesis of Bipolarolides A and B, J. Am. Chem. Soc., 2025, 147, 27219–27223.
180. Y. Fei, B. Fan, Z. Liu, M. Ba, Z. Cui, P. Yang and A. Li, Concise Total Synthesis of Ambiguine P., J. Am. Chem. Soc., 2025, 147, 18391–18396.
181. L. Hu and V. H. Rawal, Total Synthesis of the Chlorinated Pentacyclic Indole Alkaloid (+)-Ambiguine G., J. Am. Chem. Soc., 2021, 143, 10872–10875.
182. E. Davis and R. Croteau, Cyclization Enzymes in the Biosynthesis of Monoterpenes Sesquiterpenes and Diterpenes, in Topics in Current Chemistry, Vol. 209, ed. F. J. Leeper and J. C. Vederas, Springer-Verlag, Berlin/Heidelberg, 2000, pp. 53–95.
183. Y. Ishihara and P. S. Baran, Two-Phase Terpene Total Synthesis: Historical Perspective and Application to the Taxol® Problem, Synlett, 2010, 1733–1745.
184. Y. Kanda, H. Nakamura, S. Umemiya, R. K. Puthukanoori, V. R. M. Appala, G. K. Gaddamanugu, B. R. Paraselli and P. S. Baran, Two-Phase Synthesis of Taxol, J. Am. Chem. Soc., 2020, 142, 10526–10533.
185. L. A. Wein, K. Wurst and T. Magauer, Total Synthesis and Late-Stage C- H Oxidations of ent-Trachylobane Natural Products, Angew. Chem., Int. Ed., 2022, 61, e202113829.
186. P. Bovicelli, P. Lupattelli, E. Mincione, T. Prencipe and R. Curci, Oxidation of Natural Targets by Dioxiranes. 2. Direct hydroxylation at the Side Chain C-25 of Cholestane Derivatives and of Vitamin D₃ Windaus-Grundmann ketone, J. Org. Chem., 1992, 57, 5052–5054.
187. M. Munda, R. Nandi, V. R. Gavit, S. Kundu, S. Niyogi and A. Bisai, Total syntheses of Naturally Occurring Antiviral Indolosesquiterpene Alkaloids, Xiamycins C–F via Csp³-H Functionalization, Chem. Sci., 2022, 13, 11666–11671.
188. R. Murmu, S. Kundu, M. Majhi, S. Pal, A. Mondal and A. Bisai, Total Synthesis of (+)-Oridamycins A and B, Chem. Commun., 2024, 60, 9737–9740.
189. D. H. Dethe, N. Sharma and S. Juyal, Concise Enantioselective Total Syntheses of Rearranged ent-Trachylobane Diterpenoids (–)-Wallichanols A and B, Angew. Chem., Int. Ed., 2025, 64, e202505766.
190. A. K. Ganguly, T. R. Govindachari and P. A. Mohamed, Tetrahedron, 1966, 22, 3597–3599.
191. N. D. Kaetzel, K. M. Lambert and C. B. Kelly, Oxidation of Aldehydes to Nitriles with an Oxoammonium Salt: Preparation of Piperonylonitrile, Org. Synth., 2020, 97, 294–313.
192. N. E. Leadbeater and J. M. Bobbitt, TEMPO-Derived Oxoammonium Salts as Versatile Oxidizing Agents, Aldrichimica Acta, 2014, 47, 65–74.
193. J. M. Bobbitt, C. Brückner and N. Merbouh, Oxoammonium- and Nitroxide-Catalyzed Oxidations of Alcohols, Org. React., 2009, 74, 103–424.
194. J. J. Dotson, J. L. Bachman, M. A. Garcia-Garibay and N. K. Garg, Discovery and Total Synthesis of a Bis(cyclotryptamine) Alkaloid Bearing the Elusive Piperidinoindoline Scaffold, J. Am. Chem. Soc., 2020, 142, 11685–11690.
195. L. Verotta, T. Pilati, M. Tató, E. Elisabetsky, T. A. Amador and D. S. Nunes, Pyrrolidinoindoline Alkaloids from Psychotria colorata, J. Nat. Prod., 1998, 61, 392–396.
196. D. E. Kim, Y. Zhu, S. Harada, I. Aguilar, A. E. Cuomo, M. Wang and T. R. Newhouse, Total Synthesis of (+)-Shearilicine, J. Am. Chem. Soc., 2023, 145, 4394–4399.
197. A. J. Smaligo, M. Swain, J. C. Quintana, M. F. Tan, D. A. Kim and O. Kwon, Hydrodealkenylative C(sp3)-C(sp2) Bond Fragmentation, Science, 2019, 364, 681–685.
198. R. C. Godfrey, H. E. Jones, N. J. Green and A. L. Lawrence, Unified Total Synthesis of the Brevianamide Alkaloids Enabled by Chemical Investigations into Their Biosynthesis, Chem. Sci., 2022, 13, 1313–1322.
199. D. Jana, A. Khatua, S. Kundu, S. Noskar, Mo. Nandy and A. Bisai, Enantioselective Total Synthesis of Taiwaniadducts I, J, and L., JACS Au, 2025, 5, 1376–1381.
200. J. Deng, S. Zhou, W. Zhang, J. Li, R. Li and A. Li, Total Synthesis of Taiwaniadducts B, C, and D., J. Am. Chem. Soc., 2014, 136, 8185–8188.
201. J. Deng, R. Li, Y. Luo, J. Li, S. Zhou, Y. Li, J. Hu and A. Li, Divergent Total Synthesis of Taiwaniaquinones A and F and aiwaniaquinols B and D., Org. Lett., 2013, 15, 2022–2025.
202. Y.-Y. Fan, J.-B. Xu, H.-C. Liu, L.-S. Gan, J. Ding and J.-M. Yue, Cephanolides A - J, Cephalotane-Type Diterpenoids from Cephalotaxus sinensis, J. Nat. Prod., 2017, 80, 3159–3166.
203. Z.-P. Ge, B. Zhou, F. M. Zimbres, M. B. Cassera, J.-X. Zhao and J.-M. Yue, Cephalotane-Type Norditerpenoids from Cephalotaxus fortunei, var. alpina., Chin. J. Chem., 2022, 40, 1177–1184.
204. J. I. Concepcion, C. G. Francisco, R. Hernandez, J. A. Salazar and E. Suárez, Intramolecular Hydrogen Abstraction. Iodosobenzene Diacetate, an Efficient and Convenient Reagent for Alkoxy Radical Generation, Tetrahedron Lett., 1984, 25, 1953–1956.
205. G.-X. Li, C. A. Morales-Rivera, F. Gao, Y. Wang, G. He, P. Liu and G. Chen, A Unified Photoredox-Catalysis Strategy for C(sp³)-H Hydroxylation and Amidation Using Hypervalent Iodine, Chem. Sci., 2017, 8, 7180–7185.
206. L. McDermott, D. Aljovic, Z. G. Walters, F. Peng, R. Zhao, K. R. Campos and N. K. Garg, Safety Letter: Evaluation of the Popular Oxidant 2-Iodoxybenzoic Acid (IBX), Org. Lett., 2025, 27, 13165–13169.
207. N. Z. Burns, P. S. Baran and R. W. Hoffmann, Redox Economy in Organic Synthesis, Angew. Chem., Int. Ed., 2009, 48, 2854–2867.

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