Metal-Catalyzed C–H Bond Oxidation in the Total Synthesis of Natural and Unnatural Products

Abstract

C–H bond oxidation is a powerful means for oxygen incorporation in organic molecules. Its use results in fast structural diversification and in a new way of thinking about retrosynthetic disconnections. In this review, we present the application of five metal-catalyzed methodologies for C(sp ³)–H oxidation in the total synthesis of natural and unnatural products, covering the period of 2004–2022.

1 Introduction

2 Copper-Mediated Hydroxylation of Methylenes β to Imines

3 Palladium Acetoxylation of Methyl Groups β to Oximes

4 Palladium-Mediated Allylic C–H Bond Oxidation of Terminal Olefins

5 Iron- and Manganese-Mediated Aliphatic Oxidation

6 Miscellaneous

7 Conclusion

Key words

C–H bond oxidation - catalysis - total synthesis - natural products - transition metals

Biographical Sketches

Victor Camargo Stork Santana received his B.S. degree in chemistry at the University of Campinas in 2019. In 2020, he began his Ph.D. studies at the same university under the supervision of Prof. Emilio C. de Lucca Jr. His research interests involve total synthesis of natural products and the development of transition metal catalysts.

Milena Cristina Vieira Fernandes received her degree in chemistry from the University of Campinas in 2021. In the following year she started her Ph.D. at the same university under the guidance of Prof. Emilio C. de Lucca Jr. Her research interest focusses on the development of transition metal catalytic systems.

Isadora Cappuccelli received her Bachelor's degree in Chemistry from the University of Campinas in 2022. During her tenure at the de Lucca research group, she worked on synthesizing natural products using metal-catalyzed C–H bond oxidation. Her research interest focuses on using emerging science's interdisciplinarity to discover and synthesize powerful drugs.

Ana Carolina Gonzales Richieri started their undergraduate studies at the University of Campinas in 2018. In 2020, they began their undergrad research on the total synthesis of natural products using C–H bond functionalization as a key step under the guidance of Prof. Emilio C. de Lucca Jr.

Emilio C. de Lucca Jr. was born in São Roque, Brazil in 1986 and completed his degree in chemistry at the University of São Paulo in 2008. After earning his M.Sc. (2011) and his Ph.D. (2015) under the guidance of Prof. Luiz C. Dias at University of Campinas, he joined the group of Prof. M.-Christina White at the University of Illinois at Urbana-Champaign as a postdoctoral fellow. Following a second postdoc with Prof. Carlos Roque D. Correia at the University of Campinas, he began his independent career as an Assistant Professor at the University of Campinas in 2018. In 2022, he was appointed for the Science of Synthesis Early Career Advisory Board.

1

Introduction

The addition of a new oxygenated functionality in a molecule has a potential to cause changes in its chemical, physical, and, in some cases, action in biological systems.[1]

In Nature, oxygen incorporation into organic molecules may take place through oxygenases, enzymes that oxidize a substrate by transferring oxygen from molecular oxygen. While monooxygenases add one oxygen atom of O₂ to a substrate (and the other atom is reduced to water), in dioxygenases both oxygen atoms are transferred to one or two substrates. These enzymes are very effective in selectively oxidizing a wide range of significant products (Scheme [1]).

Scheme 1 Oxygen incorporation by oxygenases

P450 Monooxygenases can provide 20-hydroxyeicosatetraenoic acid (1) and 11,12-epoxyeicosatrienoic acid (2) by oxidation of arachidonic acid. 7α-Hydroxycholesterol (3), which is the first intermediate in the synthesis of bile acids, also can be obtained by these enzymes (Scheme [1]A).[2]

In the case of dioxygenases, hydroperoxide-fatty acid 4 can be obtained from oxidation of arachidonic acid by lipoxygenases in the degradation of lipids. Prolyl hydroxylase is responsible for delivering 4-hydroxyproline 5, an important constituent of collagen. cis-Dihydrodiol 6 is obtained as a degradation of naphthalene by Pseudomonas (Scheme [1]B).[3]

In the laboratory, the incorporation of oxygen atoms into an organic molecule can be achieved through functional group manipulation.[4] Using powerful approaches, several total syntheses of natural products have been performed (Scheme [2]).

Scheme 2 Oxygen incorporation in the total synthesis of natural products

In the total synthesis of Taxol^® (9), a well-known antitumor agent used worldwide, Holton and co-workers performed an OsO₄-mediated dihydroxylation[5] on olefin 7 obtaining intermediate 8 in 80% yield.[6]

In a total synthesis of the endogenous steroid (±)-progesterone (12), Johnson and colleagues performed an ozonolysis[7] to oxidize the double bond of compound 10, delivering triketone 11 in 88% yield.[8]

Oxygen incorporation can also be achieved by epoxidations and S_N2 reactions.[9] These two transformations were applied in the total synthesis of (+)-pancratistatin, by Hudlicky and co-workers.[10] The VO(acac)₂/tert-butyl hydroperoxide (TBHP) treatment of intermediate 13 oxidize the β-face of its double bond and furnished compound 14 in 53% yield. The stereospecific opening of epoxide 14 in the presence of water and sodium benzoate delivered (+)-pancratistatin (15) in 51% yield.

Oxidations are extremely important reactions in organic chemistry and prevalent in the total synthesis of natural and unnatural products.[11] However, many of the available methods may suffer from a lack of chemoselectivity, leading to the use of protecting groups, which makes the syntheses longer with the generation of more residues.[12]

On the other hand, C–H bond oxidations, when used in a late-stage scenario may obviate unnecessary functional group manipulations and, more importantly, functionalize positions where traditional methods cannot, offering a complementary approach.[13]

The oxygenation of organic molecules by C–H bond oxidation has been known for a long time.[14] Breslow disclosed sequences of reactions (photolysis, dehydration, ozonolysis, and hydrolysis) that globally provided a formal selective C–H bond oxidation of an unactivated methylene in compound 16 to furnish ketone 17 (Scheme [3]A).[14a] Shilov reported the first example of a C–H functionalization of methane by a transition metal complex using platinum (Scheme [3]B). Barton demonstrated a Fenton-type system for C–H bond oxidation in adamantane (18) that delivered alcohols 19 and 20 and ketone 21 (Scheme [3]C).

Selenium-mediated oxidations of activated allylic C–H bonds (i.e., Riley oxidation) have been substantially reviewed.[15] A representative example of this transformation was reported by Trost and Tang in the enantioselective total synthesis of the opiate (–)-morphine (24) (Scheme [4]). At the end of the synthesis, the treatment of intermediate 22 with SeO₂ in dioxane afforded the corresponding allylic alcohol, which was oxidized in one-pot with Dess–Martin periodinane to furnish enone 23 in 58% yield after two steps.[16] The use of selenium and chromium reagents for oxidizing allylic positions in total synthesis will not be covered by this review.

Scheme 3 Some examples of C–H bond oxidations

Scheme 4 Allylic oxidation in the total synthesis of (–)-morphine (24)

The dioxiranes dimethyldioxirane (DMDO) and methyl(trifluoromethyl)dioxirane (TFDO) are efficient reagents for the oxidation of unactivated C–H bonds.[17] The Baran group reported a two-phase total synthesis of Taxol^® (9), where DMDO selectively oxidized the C1 tertiary C–H bond and epoxidized the Δ^5,6-olefin in intermediate 25. The Δ^11,12-olefin remained intact, and 26 was obtained in 49% yield as a single diastereomer (Scheme [5]).[18] The use of organic oxidants in total synthesis was recently reviewed and will not be covered here.[19]

Scheme 5 Key C–H oxidation by DMDO in the total synthesis of Taxol^® (9)

The ubiquity of carbon and hydrogen in organic molecules and chemoselectivity issues through functional group intolerance impose site- and chemoselectivity challenges in the oxidation of C–H bonds in complex molecules. As a result, there is a limited number of examples of total syntheses using aliphatic C–H bond oxidations.[20]

This review will cover metal-catalyzed C(sp ³)–H bond oxidations in the total synthesis of natural products. The main focus of our contribution is the use of methodologies exploring copper (Cu), palladium (Pd), iron (Fe), and manganese (Mn) in total synthesis. To the best of our knowledge, these are the transition metal methodologies applied in the synthesis of natural and unnatural products.

By considering C–H bonds as functional groups, new transformations can be accommodated, and the logic of retrosynthetic analysis can be transformed.

2

Copper-Mediated Hydroxylation of Methylenes β to Imines

In 2003, the Schönecker group disclosed a copper-catalyzed diastereoselective intramolecular hydroxylation of methylenes (Scheme [6]).[21] The use of pyridylmethylimino and pyridylethylimino as directing groups, Cu(OTf)₂ as catalyst, benzoin as catalyst regenerator, benzene and dichloromethane as solvents, and O₂ as terminal oxidant introduce a hydroxy group β to a ketone in a stereo- and regioselective fashion.

Schönecker’s four-step protocol to convert imine 27 into the oxidized product 29 featured serious difficulties, low yields, and long reaction times. The Baran group updated and improved the original oxidation protocol.[22a]

The new protocol for this oxidation involved the use of the imine 28 in the presence of Cu(MeCN)₄PF₆ (1.3 equiv.) and sodium ascorbate (2 equiv.) in MeOH/acetone at 50 °C delivering the desired product in 90% yield in only 1.5 h. Five different imine groups were investigated, and the best results were obtained using (4-methylpyridin-2-yl)methanamine.

Scheme 6 Conditions of intramolecular C–H hydroxylation catalyzed by copper, developed by the Schönecker and Baran groups

Garcia-Bosch and co-workers investigated the mechanism for the copper-mediated hydroxylation of methylenes β to imines (Scheme [7]).[22b] The catalytic cycle initiates with the formation of intermediate 31 through the complexation of copper, the imine, and O₂. The reaction with O₂ leads to the formation of Cu(II) species 32, which reacts with H₂O₂ (generated by disproportionation and oxidation of the solvent). This step furnishes intermediate 33, which undergoes homolytic O–O cleavage to generate the HO^• radical responsible for the C–H bond cleavage. The carbon-centered radical formed in intermediate 35 is rebonded in an intramolecular C–O bond formation.

2.1

C12 Oxidation

2.1.1

Total synthesis of (–)-Cyclopamine and Analogue

(–)-Cyclopamine (40) is the first known inhibitor of hedgehog proteins (Hh), proteins in a signaling pathway related with cell differentiation in embryonic cells.[23] In 2009, the Giannis group completed the total synthesis of (–)-cyclo­pamine (40) (Scheme [8]).[24]

Scheme 7 Mechanism of oxidation using a copper complex and molecular oxygen for intramolecular hydroxylation

Scheme 8 C–H oxidation in the total synthesis of (–)-cyclopamine (40)

The methylene oxidation of imine 38 catalyzed by Cu(MeCN)₄PF₆ and O₂ as terminal oxidant delivered keto alcohol 39 in 48% yield as a single diastereomer together with 9% of recovered starting material. This oxidation was crucial to make a Wagner–Meerwein-type rearrangement between the C and D rings possible. The total synthesis of (–)-cyclopamine (40) was completed in 20 steps with 1.5 % overall yield. Under acidic conditions cyclopamine, a very pH sensitive molecule, can be converted into toxic veratramine (41).

In continuation of their studies, Giannis, Heretsch, and co-workers also synthesized a carbacyclopamine analogue 43 (Scheme [9]).[25] The authors investigated a more acid stable molecule, focused on eliminating the allylic ether oxygen in the E ring, responsible for acid decomposition of cyclopamine. This allylic ether was substituted by an all-carbon­ E ring and a pyridine F ring, instead of a piperidine ring. In the oxidation step, the intermediate 42 was treated with Cu(MeCN)₄PF₆ and O₂ and the alcohol 29 was obtained in 46% yield as a single isomer. During the workup of oxidation, the A ring alcohol was regenerated.

Scheme 9 C–H oxidation in the total synthesis of carbacyclopamine analogue 43

2.1.2

Total Synthesis of (+)-Cephalostatin 1

(+)-Cephalostatin 1 (46) is a natural product first isolated in 1988 that can be synthetically lethal with the p16 tumor suppressor gene. The synthetic lethality for cancer is the ability to select their targets, inhibiting a genetic alteration on tumor cells, killing them while the healthy cells are still alive.[26] This characteristic is required for the most modern anticancer therapy.

In 2010, Shair and co-workers disconnected (+)-cephalostatin 1[27] into two steroidal fragments, right and left side in relation to pyrazine ring (Scheme [10]).[28] The right-side part was hydroxylated at the C12 position using Schönecker’s conditions. Treating compound 44 with Cu(OTf)₂, benzoin, triethylamine, and O₂ afforded product 45 in 25% yield as the only diastereomer. Compound 45 was, after some steps, converted into (+)-cephalostatin 1 (46).

Scheme 10 C–H oxidation in the total synthesis of (+)-cephalostatin 1 (46)

2.1.3

Total Synthesis of Polyoxypregnanes

To prove the efficiency of their protocol, the Baran group synthesized the natural polyoxypregnanes, found in Asclepiadaceae plants, (–)-pergularin (49), (+)-utendin (50), and (+)-tomentogenin (51), from imine 47. The presence of a Δ⁶-i-diene in this intermediate was used as an unprecedent synthetic strategy to mask the A-ring functionality, avoiding the use of protecting groups. The imine 47 was submitted to Baran’s conditions to afford compound 48 in 40% yield (Scheme [11]).[22a]

Scheme 11 Synthesis of (–)-pergularin (49), (+)-utendin (50), and (+)-tomentogenin (51)

2.1.4

Total Synthesis of 7-Oxygenated 12α-Hydroxy Steroid Derivatives

7-Oxygenated steroids have been studied on various biological mechanisms, among them: higher absorption of cholesterol, antidiabetic activity, less post-traumatic stress disorder symptoms, lower alcohol consumption, and weight loss.[29] Therefore, the synthesis of this type of molecule is necessary to enable a more extensive study of biochemical properties of these compounds and to facilitate the identification of new compounds.

Yoshimoto and co-workers used Schönecker’s conditions to oxidize the C12 position of intermediate 52, affording alcohol 53 in 48% yield. After some steps, including a correction of the stereochemistry at C12, 12α-hydroxy dehydroepiandrosterone (DHEA) (54) and 7-oxygenated 12-hydroxy steroid 55 were obtained (Scheme [12]).[29]

Scheme 12 Synthesis of 7-oxygenated 12α-hydroxy steroid 55

2.1.5

Total Synthesis of (+)-Ritterazine B

(+)-Ritterazine B (56) is a natural product found on Riterella­ tokioka, a marine invertebrate animal of the subphylum­ Tunicata, found in Japan and isolated in 1995 by Fusetani and co-workers.[30] This molecule is part of a powerful class of antitumoral compounds, being cited as ‘among the most potent growth inhibitor ever tested’ by the National Cancer Institute (NCI).[31]

In 2021, Reisman and co-workers synthesized (+)-ritterazine B (56) (Scheme [13]).[31] The known imine 27 was oxidized under Baran’s protocol for C12 oxidation, using Cu(NO₃)₂·3H₂O and H₂O₂, to afford compound 29 in 84% yield.

Scheme 13 C–H oxidation in the total synthesis of (+)-ritterazine B (56)

When compared to the Shair’s total synthesis of (+)-cephalostatin 1 (46) (Schönecker’s conditions, Scheme [10]), the C–H oxidation step in the total synthesis of (+)-ritterazine B (56) used Baran’s protocol delivering the desired product in higher yields, which showcases the advantages associated with the improved protocol.

2.2

C7 Oxidation

2.2.1

Total Synthesis of (±)-Walsucochin B

In 2008, Yue and co-workers[32] isolated the nortriterpenoids walsucochins A and B from Walsura cochinchinensis (Baill) (family Meliaceae). These compounds possess biological activities against Alzheimer and Parkinson diseases.[33]

In 2020, Gong Xu and co-workers used Baran’s protocol for the oxidation of the C7 position (Scheme [14]).[33] The oxidation of imine 57 using Cu(NO₃)₂·3H₂O and H₂O₂ delivered compound 58 in 69% yield after two steps from the ketone, as a single isomer. The choice of H₂O₂ as oxidant by the authors was based on the increase of yield reported by Garcia-Bosch and co-workers in the mechanistic investigation study.[22b] Compound 58 was, after some steps, converted into (±)-walsucochin B (59).

2.2.2

Total Synthesis of (±)-Phainanoid A

(+)-Phainanoid A belongs to a recently discovered class of dammarane-type triterpenoids, isolated from Phyllanthus hainanensis Merr., present in China that showed potent immunosuppressive activities in vitro against T and B lymphocytes.[34]

Scheme 14 C–H oxidation in the total synthesis of (±)-walsucochin B (59)

In 2021, inspired by its structure biological activities, the Dong group reported the total synthesis of (±)-phainanoid A (62), applying Baran’s protocol to oxidize the C7 position of compound 60 (Scheme [15]).[35] Treatment of imine 60 with Cu(NO)₃·3H₂O and H₂O₂ afforded diastereoselectively pure alcohol 61 in 76% yield after two steps from the ketone.

Scheme 15 C–H oxidation in the total synthesis of (±)-phainanoid A (62)

2.3

C3 Oxidation

2.3.1

Total Synthesis of ent-3β-Acetoxy-trachyloban-19-al

ent-3β-Acetoxy-trachyloban-19-al (64) is a trachylobane diterpene isolated from Jungermannia exsertifolia by Scher and co-workers.[36] The Magauer group synthesized compound 64 using Cu(NO₃)₂·3H₂O and H₂O₂ with intermediate 63.[37] After acetylation of the corresponding alcohol, compound 64 was obtained in 32% yield after two steps (Scheme [16]).

Scheme 16 C–H oxidation in the total synthesis of ent-3β-acetoxy-trachyloban-19-al (64)

To the best of our knowledge, compound 63 is the first example where an imine prepared from an aldehyde was used in a copper-mediated hydroxylation of a methylene β to an imine.

3

Palladium Acetoxylation of Methyl Groups β to Oximes

The palladium-mediated acetoxylation of methyl C–H bonds β to oximes (acting as directing groups) was first reported by Baldwin and co-workers in 1985 (Scheme [17]).[38] Under Baldwin’s conditions, the palladium source was used in stoichiometric quantities and compounds 65–67 were obtained in good yields.

Scheme 17 Baldwin’s conditions for C–H oxidation directed by oximes

When Na₂PdCl₄ reacts with oxime 68, the cyclopalladium dimer 69 is formed, which is then cleaved by the addition of pyridine. The oxidation of pyridine complex 70 with Pb(OAc)₄ and reduction with NaBH₄ furnishes the acetoxylated compound 71 (Scheme [18]).

Scheme 18 Mechanism of Baldwin’s process

In 2004, the Sanford group performed this reaction catalytically on palladium using PhI(OAc)₂ as terminal oxidant.[39] In the Sanford work, O-alkyl- or O-acetyloximes act as directing groups and compounds 72 and 73 were obtained in good yields (Scheme [19]). Pyridines can also be used as directing groups and compound 74 was obtained in moderate yield.

Scheme 19 The Sanford group’s conditions for C–H oxidation directed by O-methyloxime

While imines, which are used as directing groups in copper-mediated hydroxylations of methylenes, are hydrolyzed during the work up of the oxidation reaction, oximes are more stable, and the addition of a removal step is necessary.

The proposed catalytic cycle for this transformation is depicted in Scheme [20]. In the first step, chelate-directed C–H activation of the substrate 76 takes place on palladium salt 75, generating intermediate 77. Then, palladium is oxidized by PhI(OAc)₂ to give the Pd(IV) intermediate 78. In the final step, reductive elimination occurs, promoted either by an intramolecular acetate elimination or by an attack of an acetate from the solution in an S_N2-like reaction, to afford the acetoxylated product 79 and regenerate 75.[40]

The steric dependence on Pd causes high selectivity for primary carbons, which is very useful in the total synthesis of natural products.

3.1

Total Synthesis of Rostratone

Scheme 20 Proposed mechanism for the acetoxylation of C–H bonds β to an oxime

Isolated in 1993 from the plant Nolana rostrata, (+)-rostratone[41] is a terpenoid[42] that was first synthesized in 2004 by the Cuerva group. In this synthesis, intermediate 80 was treated under Baldwin’s conditions to deliver compound 81 in 76% yield, and, after some steps, rostratone (82) was obtained (Scheme [21]).[43]

Scheme 21 C–H oxidation in the total synthesis of rostratone (82)

3.2

Total Synthesis of (–)-Jiadifenolide

(–)-Jiadifenolide (86)[44] was first isolated in 2009 by Fukuyama and co-workers, from the flowering plant Illicium jiadifengpi.[45] This compound belongs to a class of natural products with promising neurotrophic properties and significantly potentiating neutrite outgrowth with a low dose that is a possible candidate for a therapeutic strategy focused on controlling the loss of nerve function in Alzheimer’s disease patients.[45]

In 2014, Sorensen and co-workers synthesized (–)-jiadifenolide­ (86) using Sanford’s methodology (Scheme [22]).[46] The acetoxylation of compound 83 using Pd(OAc)₂ and PhI(OAc)₂ furnished compound 85 in 22% yield; 85 and diastereomer 84 were obtained in 1:1 ratio. The authors also observed a small amount of oxidation in both methyl groups.

Scheme 22 C–H oxidation in the total synthesis of (–)-jiadifenolide (86)

The lack of diastereoselectivity in this process was attributed to the high temperature of the reaction and the conformational flexibility of the six-membered ring. This hypothesis was tested by the execution of another method of oxidation at room temperature, which resulted in a preference for the undesired diastereomer 84.

Scheme 23 C–H oxidation in the total synthesis of (±)-paspaline (89)

3.3

Total Synthesis of (±)-Paspaline

Paspaline (89)[47] was isolated in 1966 from Claviceps paspali, a fungus that affects grass, by Acklin and Fehr.[48] Its derivatives exhibited potent activity as potassium channel antagonists, which means that these compounds may be useful for glaucoma treatment.[49] Another derivative (JBIR-03) has shown anti-MRSA (methicillin-resistant Staphylococcus aureus) and antifungal activity against Valsa ceratosperma, a fungus that causes a disease of apple, Valsa canker.[50]

Sharpe and Johnson completed the total synthesis of paspaline using Sanford’s methodology (Scheme [23]).[51] The reaction between O-benzyloxime 87, Pd(OAc)₂, and PhI(OAc)₂ delivered compound 88 in 79% yield. The lowest energy conformation of the compound has the C–N π bond and the equatorial methyl group aligned, giving this reaction very high diastereoselectivity.

3.4

Total Synthesis of Indolosesquiterpenoid (Oridamycin B)

First isolated in 2010, oridamycin compounds are known for their antibiotic action. (+)-Oridamycin B is a pentacyclic natural product obtained from Streptomyces sp. strain KS84, a water mold that infects freshwater fish, and ova and is the first indolosesquiterpene to be isolated from a prokaryote.[52]

Scheme 24 C–H oxidation in the total synthesis of (±)-oridamycin B (92)

In 2015, the Li group completed the total synthesis of (±)-oridamycin B (92), using Sanford’s methodology (Scheme [24]).[53] The treatment of compound 90 with Pd(OAc)₂ and PhI(OAc)₂ delivered compound 91 in 82% yield. It is interesting to highlight that the reaction has a good yield despite the methyl group being in the β position to two carbonyl groups.

In 2017, Trotta also used this methodology for the total synthesis of (±)-oridamycin B (92).[54] The treatment of Boc-protected compound 93 with Pd(OAc)₂ and PhI(OAc)₂ delivered compound 94 in 69% yield (Scheme [25]).

Scheme 25 C–H oxidation in the total synthesis of (±)-oridamycin B (92) by Trotta

3.5

Total Synthesis of (–)-Septedine

(–)-Septedine (97) is a diterpenoid alkaloid,[55] a group of molecules that have been used for many functions, from medicine to poisons.[56] It was first isolated in 1995 by Usmanova­ and co-workers from the roots of Aconitum septentrionale, a flowering plant.[55] This molecule was first synthesized in 2018 by the Li group using Sanford’s protocol (Scheme [26]).[57] Compound 95 was treated with Pd(OAc)₂ and PhI(OAc)₂ resulting in compound 96 in 42% yield as the only isomer together with 33% of recovered starting material. Epoxide opening side products were also observed in a small amount. Since this methodology does not tolerate olefins, the presence of the epoxide on compound 95, obtained by olefin epoxidation with meta-chloroperbenzoic acid (mCPBA), was mandatory.

Scheme 26 C–H oxidation in the total synthesis of (–)-septedine (97)

3.6

Total Synthesis of (+)-Xiamycins D and E

First isolated in 2016 by Oh and co-workers, (+)-xiamycins D (101) and E (100) are indolosesquiterpenoids isolated from Streptomyces sp. strain #HK18, a saltern-derived actinomycete. Xiamycin D showed a significant inhibitory activity against replication of porcine epidemic diarrhea virus[58] (PEDV, a disease that affects pigs causing diarrhea and dehydration)[59] and thus is a potential antivirus against PEDV and similar viruses.[58]

In 2021, Dethe and Shukla accomplished the first total synthesis of xiamycins D and E using Sanford’s methodology through the reaction between compound 98, Pd(OAc)₂, and PhI(OAc)₂ to deliver compound 99 in 64% yield (Scheme [27]).[60]

Scheme 27 C–H oxidation in the total synthesis of (+)-xiamycins D (101) and E (100)

3.7

Total Synthesis of (–)-15-Hydroxylongiborneol

In 2016, Bahadoor, Harris, and co-workers reported the isolation of the natural product (–)-15-hydroxylongiborneol (106), a secondary metabolite from Fusarium graminearum.[61]

Compound 106 was recently synthesized by Sennari, Sarpong, and Lusi using Sanford’s methodology (Scheme [28]).[62]

Oxime 102 was acetoxylated in the presence of Pd(OAc)₂ and PhI(OAc)₂ to deliver compounds 103 and 104 in 41% yield and 2:1 dr as an inseparable mixture. This mixture afforded, after some steps, compounds (–)-14-hydroxylongiborneol (105) and (–)-15-hydroxylongiborneol (106).

3.8

Synthesis of 17-Hydroxy-16-oxo-ent-beyeran-19-oic Acid

The diterpenoid 17-hydroxy-16-oxo-ent-beyeran-19-oic acid (109) was isolated as a secondary metabolite of the biotransformation of isosteviol by Penicillium chrysogenum.[63] This molecule was previously synthesized by Avent, Hanson­, and de Oliveira and exhibited inhibitory effects on Epstein–Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate in Raji cells.[64]

De Lucca and co-workers applied Sanford’s protocol to synthesize this diterpenoid (Scheme [29]).[65] The oxime 107 was treated with Pd(OAc)₂ and PhI(OAc)₂, furnishing the acetoxylated product 108 in 52% yield together with 26% of recovered starting material.

Scheme 28 C–H oxidation in the total synthesis of (–)-14-hydroxylongiborneol (105) and (–)-15-hydroxylongiborneol (106)

Scheme 29 C–H oxidation in the total synthesis of 17-hydroxy-16-oxo-ent-beyeran-19-oic-acid (109)

4

Palladium-Mediated Allylic C–H Bond Oxidation of Terminal Olefins

Since 2004, the White group has been involved in the development of allylic C–H bond oxidations of terminal olefins using Pd(II)/bis-sulfoxide (White catalyst), benzoquinone as oxidant, and a nucleophile (Scheme [30]).[66] Intra- and intermolecular examples were developed, among them, lactonizations were applied in the total synthesis of natural products. Compounds 110 and 111 show examples of two different nucleophiles applied in an intermolecular context to generate linear and branched products, respectively.

Scheme 30 Representative examples using the White catalyst for the oxidation of allylic C–H bonds

Scheme 31 Proposed mechanism of allylic oxidation catalyzed by the White catalyst

Compounds 112 and 113 represent examples of lactonizations in good selectivities. Furthermore, enantioselective reactions have also been explored (vide product 114), using a chiral Lewis acid that increases the π acidity of the metal ligand and transfers chirality to the metal center.

According to the White group,[66b] the catalytic cycle initiates with the coordination of palladium to the olefin on 115, increasing the acidity of the allylic hydrogen which is removed by the acetate anion to generate 116. After benzoquinone (BQ) coordination to Pd, nucleophilic attack occurs in the allylic system of 117, promoting the formation of the product and releasing a Pd(0) species 118, which is reoxidized to Pd(II) by BQ (Scheme [31]).

The bis-sulfoxide ligand is responsible and effective for C–H bond cleavage, during the first step of the catalytic cycle (i.e., the formation of π-allyl-palladium complex 116). BQ, instead, acts as a ligand to activate 117 toward the nucleophilic functionalization. Furthermore, when using chiral Lewis acids, the enantioinduction occurs during functionalization, highlighting the importance of the interaction of BQ and the Lewis acid.

4.1

Total Synthesis of (–)-6-Deoxyerythronolide B

The polyketide (–)-6-deoxyerythronolide (121) was isolated by Martin and Rosenbrook while studying the synthesis of erythronolide B by the bacteria Saccharopolyspora erythraea.[67] This molecule is an important biosynthetic precursor to erythromycins, bearing ten chirality centers embedded in a 14-membered macrolactone. It has gained the attention of chemists over the years, resulting in total syntheses by several research groups.[68]

In 2009, Stang and White used a late-stage allylic C–H bond macrolactonization in their total synthesis of (–)-6-deoxyerythronolide and were able to construct compound 120 in 56% yield as the only isomer by the treatment of intermediate 119 with the White catalyst and BQ (Scheme [32]).[69]

Scheme 32 C–H oxidation in the total synthesis of (–)-6-deoxyerythronolide B (121)

4.2

Total Synthesis of Macrolactone of Migrastatin

Migrastatin (125) is a natural product first isolated from Streptomyces sp. MK929-43F1 by Imoto and co-workers and is a metastasis suppressor.[70] [71] Iqbal and Gade synthesized the macrolactone of migrastatin (124) using an allylic C–H bond oxidation approach.

The oxidation step optimization was performed using different solvents, additives, and temperatures, and the intermediate 122 was treated with the White catalyst, BQ, and Cr(salen)Cl in dioxane at 45 °C to deliver compound 123 in 40% yield (Scheme [33]).[72]

Scheme 33 C–H oxidation in the synthesis of migrastatin macrolide core 124

4.3

Total Synthesis of (–)-Castanospermine

(–)-Castanospermine (128) is a tetrahydroxyindolizidine alkaloid isolated from Castanospermum australae seeds.[73] In cells, castanospermine and analogues act as an in vitro inhibitor of some types of viruses, such as human immunodeficiency virus (HIV), influenza virus, and Sars-Cov-2.[74] It was also found to have antifungal properties. Frequently used in the isomeric form in medical studies,[75] some groups were concerned about the isolated isomers properties. While (+)-castanospermine synthesis was performed by several groups,[76] the enantiomer (–)-castanospermine (128) has only been synthesized once.[77]

The Jarosz group performed the total synthesis of (–)-castanospermine (128) employing the White catalyst on the allylic C–H oxidation step (Scheme [34]).[78] In the optimized conditions, the White catalyst was used with intermediate 126 in the presence of BQ and Yb(OTf)₃ as additive affording compound 127 in 71% yield, which could be elaborated to (–)-castanospermine (128) after some steps.

Scheme 34 C–H oxidation in total synthesis of (–)-castanospermine (128)

The carbamate acts as an intramolecular O-nucleophile. This strategy was previously reported by the White group, using N-Boc amines as substrates.[66j] The oxophilic Lewis acid additive, Yb(OTf)₃, probably promotes the reaction by increasing the susceptibility of π-allyl-Pd(BQ) species to undergo S_N2-type cyclization.

4.4

Total Synthesis of (±)-Hippolachnin A

(+)-Hippolachnin A is a natural product isolated from the marine sponge Hippospongia lachne and found to have antifungal properties against several fungi. Hippolachnin A was also evaluated to be a potential agent in the treatment of Cryptococcus neoformans infections.[79]

Scheme 35 C–H oxidation in the collaborative total synthesis of (±)-hippolachnin A (131)

Having accomplished the total synthesis of (+)-hippolachnin A independently, the Wood and Brown groups decided to work in collaboration[80] to obtain an optimal route towards (±)-hippolachnin A (131). The collaborative route constituted of the early stages of the Brown synthesis and the endgame of the Wood route. The intermediate 129 was treated with the White catalyst, Cr(salen)Cl, and BQ delivering compound 130 in 70% yield (Scheme [35]).[81]

5

Iron- and Manganese-Mediated Aliphatic Oxidation

Since 2007, the White group has also developed catalysts, such as Fe(PDP) (White–Chen catalyst, Fe-132), Fe(CF₃-PDP) (White–Gormisky catalyst, Fe-133), and Mn(CF₃-PDP) (White–Gormisky–Zhao catalyst, Mn-133) (Figure [1]) which selectively hydroxylate remote C–H bonds on tertiary and secondary carbons with synthetically useful yields, using acetic or chloroacetic acid as the additive, and H₂O₂ as terminal oxidant.[82]

Figure 1 Iron and manganese catalysts developed by White group; M = Fe, Mn

The selectivity of the Fe(PDP) system relies on three factors: electronics, sterics, and stereoelectronics (Scheme [36]). For the electronic factor, since the catalyst is electrophilic, oxidation occurs preferentially at the most electron-rich C–H bond and this is generally the most remote site from electron-withdrawing groups (Scheme [36]A). For example, using Fe(PDP), AcOH, and H₂O₂ in MeCN gave compound 135 in 43% yield in a 5:1 remote/proximal ratio together with 35% of recovered starting material.

Moreover, locations with less steric demand are preferentially oxidized (Scheme [36]B). Compound 137 was obtained in 50% yield in a ratio of 11:1 favoring the oxidation in the C1 position. The C–H bond in C8 position is blocked by the acetate methyl group.

Positions activated by stereoelectronic effects (e.g., hyperconjugation, relief of 1,3-diaxial interactions, and torsional strain)[83] are also preferentially oxidized (Scheme [36]C). The lactone 139 was obtained in 80% yield, with oxidation carried out in a position activated by hyperconjugation of the lone pairs of the oxygen atom in the C ring.[82c]

In the absence of acetic acid, a carboxylic acid in the substrate can act as a directing group and favors the formation of five-membered lactones; the acid may overcome the effects mentioned above.[82e] For example, when the methyl ester 140 is used in the presence of AcOH, the lactone 141 is obtained in 27% yield and the methyl ketone 142 in 41% yield. On the other hand, the use of the acid 143 as starting material provided the lactone 141 as the only product in 70% yield (Scheme [36]D).

Scheme 36 Factors that affect the selectivity of oxidations catalyzed by Fe(PDP)

There are substrates where steric and electronic factors strongly diverge to favor distinct locations and, in these cases, Fe(PDP) was not selective. In these substrates, Fe(CF₃-PDP) provided useful site selectivities of 146 based on its ability to overcome electronic influences of the substrate in favor of steric influences (Scheme [36]E).[82f]

The White group also developed protocols for oxidations involving Fe(PDP) and Fe(CF₃-PDP), which tolerate nitrogen-containing molecules.[82g] [i] The scope of these protocols includes pyridines (Scheme [37]A), primary, secondary, and tertiary amines (Scheme [37]B), amides (Scheme [37]C), and imides. It is also possible to oxidize peptides remotely or in C–H bonds α to the nitrogen of proline.[82h]

Scheme 37 Other protocols used with PDP catalysts

Mn(CF₃-PDP) in combination with chloroacetic acid proved to be useful for the chemoselective oxidation of methylenes in aromatic group containing molecules (Scheme [37]D).[82j]

Scheme 38 Mechanism of Mn(CF₃-PDP) C–H oxidation mediated by a carboxylic acid

Scheme [38] shows the oxidation mechanism promoted by Mn(CF₃-PDP).[84] The in situ formation of the catalytically active species occurs through the complexation of acid and peroxide affording the intermediate 157 (Scheme [38]A). Metal oxo species react with the substrate, through the homolytic cleavage of the substrate C–H bond, generating a radical with a half life of 1.10^–10 s, and then rapid reaction with the ^•OH radical occurs resulting in retention of the configuration (Scheme [38]B).[85] In substrates with secondary carbons there is a second oxidation round.

5.1

Total Synthesis of (+)-Pseudoanisatin

(+)-Pseudoanisatin (162) is an Illicium sesquiterpene isolated from the Japanese star anise.[86] While (–)-jiadifenolide (86), which also belongs to the Illicium sesquiterpene family, promotes neurite outgrowth at low concentrations, (+)-pseudoanisatin is a potential insecticide.[87]

In 2016, the Maimone group synthesized (+)-pseudoanisatin (162) as an entry to this family of oxidized natural products. The intermediate 158 was treated with Fe(mepp) as catalyst, TBHP as terminal oxidant, and Tl(OTf) as additive, and lactones 159, 160, and 161 were obtained in 20%, 11%, and 6% yield, respectively (Scheme [39]).[88] According to the authors, the use of Tl(OTf) resulted in a boost of 5–10% in the observed yields.

Scheme 39 C–H oxidation in the total synthesis of (+)-pseudoanisatin (162)

5.2

Total Synthesis of (±)-Scaparvins

The scaparvins belong to the clerodane diterpene family, a class that possesses antifeedant, antitumor, antifungal, and antibiotic properties, and were isolated by Lou and co-workers.[89]

The Snyder group used a C–H bond oxidation in their total synthesis of scaparvins B–D (166–168). Treatment of compound 163 with Fe(PDP) and H₂O₂ generated lactone 165 in 43% yield (Scheme [40]). Besides the oxidation of the tertiary C–H bond, this condition also provided the epoxidation of the double bond and compound 164 was obtained in 28% yield. Epoxide 164 was converted into olefin 165 in 71% yield by treatment with Cp₂TiCl₂ and zinc.[90] The authors also accomplished the total synthesis of (±)-scaparvin B (167) and (±)-scaparvin D (168) from (±)-scaparvin C (166).

Scheme 40 C–H oxidation in the total synthesis of (±)-scaparvins C (166), B (167), and D (168)

5.3

Total Synthesis of Illicium Sesquiterpenes

In their studies on the total synthesis of Illicium natural products, the Maimone group used Fe(mep) and H₂O₂ in the synthesis of 14-deoxydebenzoyldunnianin (173) to oxidize the C4 position of the intermediate 169 affording lactone 170 in 22% yield (Scheme [41]).[91] Under these conditions, the removal of the silyl protecting group was observed, but compound 171 was easily converted into compound 170. The formation of epoxide 172 was also observed through successive oxidations.

Scheme 41 C–H oxidation in the total synthesis of 14-deoxydebenzoyldunnianin (173)

Scheme 42 The use of Fe(mep) in the total synthesis of natural products

Scheme 43 Syntheses of sesquiterpenes 179 and 180 from the intermediate 159

Although 14-deoxydebenzoyldunnianin is not a natural product, other natural products were accessed in this study using Fe(mep)- and Fe(mepp)-mediated C–H bond oxidations (Schemes 42 and 43). Lactones 175 and 176 were obtained using 174 as starting material, Fe(mep), and TBHP in MeCN (Scheme [42]). Compound 175 was used in the formal syntheses of sesquiterpenes 177 and 178.

The intermediate 159 obtained in the entry work of these family of compounds (Scheme [39]), was also used in the formal synthesis of compound 179 and in the total synthesis of product 180 (Scheme [43]).

5.4

Total Synthesis of (±)-Illisimonin A

(–)-Illisimonin A was isolated from Illicium simonsii. Similarly to (–)-jiadifenolide (86), this molecule possesses neuroprotective effects, more specifically against oxygen-glucose deprivation-induced cell injury in SH-SY5Y cells.[92] In their total synthesis of (±)-illisimonin A (182), Rychnovsky and Burns performed a late-stage oxidation of the carboxylic acid 181 using (±)-Fe(PDP) and H₂O₂ in MeCN and hexafluoroisopropanol (HFIP), which afforded the natural product in 48% yield (Scheme [44]).[93]

Scheme 44 C–H oxidation in the total synthesis of (±)-illisimonin A (182)

The use of HFIP increases substrate solubility and deactivates the C14 position through hydrogen bonding donation, preventing the hyperconjugation between the oxygen lone pair and C14–H bond (n_O→σ*_C–H).

Scheme 45 (A) Conversion of mitrephorone B (183) into mitrephorone A (184) and (B) conversion of compound 185 into mitrephorone A (184)

5.5

Total Synthesis of Mitrephorone A

The ent-trachylobane natural products mitrephorones A, B, and C have moderate antimicrobial and anticancer activities, and were isolated from Mitrephora glabra by Oberlies and co-workers.[94] The Magauer group used Fe(PDP) to convert mitrephorone B (183) into mitrephorone A (184) in 60% yield using (R,R)-Fe(PDP) and 30% with (S,S)-Fe(PDP) (Scheme [45]A). As an investigation of reaction pathways in the oxidation of compound 183, the same catalyst was also used to convert intermediate 185 into mitrephorone A (184) in a modest 13% yield (Scheme [45]B).[95]

Scheme 46 Proposed mechanisms for oxidation of mitrephorone B (183)

One of the mechanistic proposals involves a radical translocation, with Fe(PDP) oxidizing the enol double bond of mitrephorone B (183), affording intermediate 186. The radical translocation occurs, which generates, after oxidation, the C9-oxidized intermediate 188. Then, an oxidative ring closure on intermediate 188 yields mitrephorone A (Scheme [46]A). The other mechanistic proposal initiates with direct C5 oxidation to furnish intermediate 189. After hydrogen abstraction to deliver radical 190 and oxidative ring-closure, mitrephorone A is obtained (Scheme [46]B).

5.6

Total Synthesis of (–)-Deoxoapodine

(–)-Deoxoapodine (195), first isolated from Tabernae armeniaca­, is a member of the aspidosperma alkaloid family and possesses antitumoral properties.[96] In their total synthesis of (–)-deoxoapodine, Tokuyama and co-workers carried out an oxidative transannular Mannich reaction on intermediate 191 using (S,S)-Fe(PDP), H₂O₂, and AcOH in t-AmOH affording compound 194 in 35% yield (Scheme [47]).

Scheme 47 C–H oxidation in the total synthesis of (–)-deoxoapodine (195)

Scheme 48 C–H oxidation in the total synthesis of 2α,17-dihydroxy-16-oxo-ent-beyeran-19-oic acid (198)

The oxidation of the C–H bond α to the tertiary nitrogen generates the hemiacetal 192 that is dehydrated under acidic conditions to the iminium 193, which is the electrophilic partner for the ring closure.[97]

5.7

Synthesis of 2α,17-Dihydroxy-16-oxo-ent-beyeran­-19-oic Acid

2α,17-Dihydroxy-16-oxo-ent-beyeran-19-oic acid (198) is a metabolite obtained from the incubation of steviol-16α,17-epoxide with Streptomyces griseus ATCC 10137.[98] In 2022, de Lucca and co-workers accomplished its first synthesis.[65] Treatment of intermediate 196 with Mn(CF₃-PDP), ClCH₂CO₂H, and H₂O₂ enabled the site- and diastereoselective oxidation of the C2 position, delivering alcohol 197 in 38% yield as the only product together with 18% of recovered starting material (Scheme [48]).

6

Miscellaneous

6.1

Total Synthesis of Gracilioether F

First isolated from Agelas gracilis, a marine sponge, the gracilioethers are polyketides with antimalarial activity.[99] Brown and Rasik used a C–H oxidation in the synthesis of (±)-gracilioether F (200).[100] In the final step of the synthesis, the catalytic system formed by Cu(OAc)₂ and H₂O₂ in MeCN converted the carboxylic acid 199 into the desired natural product in 15% yield together with 51% of recovered starting material (Scheme [49]). The use of Fe(PDP) provided gracilioether in 9% yield with 48% of rsm. The authors argue that the choice for a metal source without ancillary ligands, like Cu(OAc)₂, as an alternative to Fe(PDP) would favor the C–H oxidation due to less steric hindrance.

Scheme 49 C–H oxidation in the total synthesis of (±)-gracilioether F (200)

6.2

Total Synthesis of (±)-Avenaol

Avenaol (204) is a natural product and the first natural germination stimulant related to strigolactone structures, which was isolated by Yoneyama and co-workers.[101]

In the development of an oxidation methodology for an intermediate, Tsukano and co-workers evaluated the reaction between compound 201, Fe(PDP), acetic acid, and H₂O₂ in MeCN generating ketone 203 (through hydrolysis of hemiketal 202) in 65% yield (Scheme [50]), but it was necessary to use stoichiometric amounts of Fe(PDP).[102] Therefore, the optimized conditions used TFDO in CH₂Cl₂ at –78 °C to afford ketone 203 in 96% yield.

Scheme 50 Fe(PDP) in the development of the total synthesis of (±)-avenaol (204)

6.3

Total Synthesis of (–)-Taxuyunnanine D

On the route to the total synthesis of Taxol^® by the Baran group, the authors synthesized (–)-taxuyunnanine D (207). (+)-Taxadiene (205)[103] was converted into intermediate 206 using a palladium-catalyzed C5-selective allylic acetoxylation under the conditions reported by Åkermark and Bäckvall,[104] in 49% yield, which was, after some steps, turned into (–)-taxuyunnanine D (207) (Scheme [51]).[105]

Scheme 51 C–H oxidation in the total synthesis of (–)-taxuyunnanine D (207)

Experimental observations indicate that anisole probably facilitates the reoxidation of Pd(0) to Pd(II).

6.4

Total Synthesis of (–)-Maximiscin

First isolated in 2014 by Cichewicz, Moobery, and co-workers, (–)-maximiscin (210) is a fungus metabolite obtained from a crowdsourced Alaskan soil sample. Its complex structure is composed by three separate metabolic pathways: polyketide synthase (PKS), non-ribosomal peptide synthetase (NRPS), and shikimate pathway.[106] (–)-Maximiscin (210) was synthesized in 2020 by the Baran group (Scheme [52]).[107] The reaction between the amide 208 and Pd(OAc)₂, LiOAc, NaIO₄, and Ac₂O delivered compound 209 in 58% yield.

Scheme 52 C–H oxidation in the total synthesis of (–)-maximiscin (210)

One of the challenges associated with this transformation is the need for a six-membered palladacycle intermediate to afford the desired product. An extensive optimization of the reaction conditions using different directing groups, oxidants, palladium sources, bases, and reagent quantities was conducted. Chlorine at the C4 position of the pyridine ring led to the best yield and diastereomeric ratio. While PhI(OAc)₂ showed similar results to NaIO₄, NaIO₄ was preferred due to cost and ease of purification.

7

Conclusion

In the last 20 years, the metal-catalyzed oxidation of C–H bonds has arisen as a powerful means of introducing oxygen functionality in complex molecules. With very reliable rules (electronic, steric, and stereoelectronic effects) to predict selectivity, many challenges regarding site- and chemoselectivity have been overcome and several classes of natural products, such as, terpenes, alkaloids, polyketides, and steroids, have been synthesized.

Although wonderful advances have been made by the organic chemistry community over the last two decades, the overwhelming majority of applications in total synthesis rely on directing groups or non-directed transformations in activated positions, which we believe shows that we still have a conservative mindset when it comes to retrosynthetic disconnections.

We hope this review will encourage researchers to consider the oxidation of C–H bonds as a powerful option for their disconnections and stimulate further total syntheses.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We also thank Prof. M. Christina White (UIUC) for helpful discussions and Livia Diniz Denadai for early discussions on this review.

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For other total syntheses of hippolachnin A, see:
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For other total synthesis of (–)-mitrephorone A, see:
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Publikationsverlauf

Eingereicht: 30. April 2022

Angenommen nach Revision: 04. August 2022

Accepted Manuscript online:
04. August 2022

Artikel online veröffentlicht:
06. Oktober 2022