Cobalt catalysis in organic synthesis: a powerful tool in the synthesis of natural products and pharmaceutically active compounds

Abstract

Cobalt-mediated catalysis has proven to be a potent and versatile method in the realm of present-day organic synthesis, facilitating the synthesis of biologically significant natural products and complex molecules. The field of natural product chemistry has always provided crucial advancements in the field of chemical science and pharmacology. Cobalt-mediated catalysis play a significant role towards the synthesis of biologically significant natural products, such as alkaloids, terpenoids, diterpenoids, polyketides, glycoside containing natural products, macrolides, as well as pharmaceutically active compounds such as nirmatrelvir, (S)-pazinaclone and MK-0371 etc. The present review focuses on the importance and applications of cobalt-mediated catalysis towards the synthesis of biologically significant natural products and pharmaceutical drugs, reported since 2018.

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1 Introduction

Transition metals play a central role in modern organic synthesis, offering highly selective and efficient transformations that facilitate functional group modification, strategic bond construction and complex molecule assembly.^1–3 The abundance of third row transition metals in nature makes them more compatible for natural product synthesis than fourth and fifth row transition metal series. Nevertheless, the remarkable efficiency with which nature constructs diverse molecular architecture using these metals, highlights an underlying potential for first row transition metal chemistry.^4,5 Among these, cobalt occupies a distinctive position as the earliest and lightest member of the group 9 transition metals. As a naturally abundant 3rd transition element, cobalt has found striking applications in organic synthesis, most notably in catalytic transformations.⁶

The historical importance of cobalt catalysis can be traced to the work of Roelen in 1938, who implemented the hydroformylation of alkenes with Co₂(CO)₈ catalyst and emphasized the transformative ability of organometallic cobalt catalyst particularly in organic synthesis.⁷ Cobalt catalysts were subsequently employed in the original industrial plants and later adopted in Russian facilities that have remained active since the 1950s. These systems closely resembled the cobalt carbonyl complexes first synthesized by Fischer in 1932, underscoring their foundational role in the development of modern catalytic chemistry.^8,9

Cobalt catalysts represent an important class of transition metal systems in organic synthesis, distinguished by their remarkable characteristics, favorable environmental attributes and accessible mechanistic pathways.^10–12 The ability of cobalt to adopt many oxidation states facilitates the generation of reactive intermediates that are often inaccessible with late noble metals. A well-defined cobalt catalyst offers adjustable steric and electronic environments important for attaining precise control over stereoselectivity and reactivity.¹³

Cobalt catalysis operates through two distinct regimes: low valent and high valent catalysis. Low valent cobalt catalysis was initially described by Yoshikai in 2010, and subsequently expanded upon by Ackermann, Nakamura, and others, which include the reduction of Co(II) salt through zinc or organomagnesium to produce reactive Co(I) complexes, important for C–H activation.^12,14–24 In 2013, Matsunaga and Kanai introduced high valent Cp*Co catalysis exhibiting reactivity like rhodium and iridium complexes, thereby offering excellent functional group tolerance, air stability and low catalyst loading features.²⁵ The higher nucleophilicity and Lewis acid properties of Co(III) species enable improved selectivity and new transformations.²³

There have been significant developments towards natural products synthesis owing to their diverse biological profiles.^26–28 Cobalt catalysis has been highly successful towards the total synthesis of a variety of naturally derived molecules for the formation of complex molecular skeletons such as antitumor sesquiterpene coriolin,²⁹ and lycopodium alkaloids such as fawcettidine, fawcettimine, and lycoflexine.³⁰ Apart from the formation of complex molecular skeletons, cobalt catalysis has helped to design stereoselective transformation methods (Fig. 1). These advances led to the preparation of highly complex targets such as peloruside A and hemibrevetoxin-B, which highlight the utility of cobalt catalysis in modern organic synthesis (Fig. 2).^31,32

Fig. 1 Structure of Co(II), Co(III) complexes.

Fig. 2 Structures of few natural products and pharmaceuticals compounds synthesized by Co-catalysis.

The pharmaceutical relevance of cobalt catalysis extends to the direct construction of drug scaffolds and late-stage functionalization of bioactive molecules.³³ Cobalt catalyzed C–H activation has enabled the synthesis of a variety of drug frameworks^20,34 whereas pharmaceutically active isoquinoline alkaloids have been accessed through Co-catalyzed annulation reactions.^35,36 Recently, cobalt catalysts have been used in asymmetrical synthesis of pharmaceutically relevant compounds for instance (S)-PD172938 and (S)-pazinaclone. Cobalt catalysts with (R)-Salox-9 ligand have also been employed in enantioselective synthesis for the formation of chiral molecules, that are crucial for the synthesis of several drugs.³⁷ This review aims to provide a comprehensive outline of the applications of the cobalt catalysis towards natural product synthesis and pharmaceuticals, reported since 2018.

2 Cobalt-catalysis in total synthesis of natural products

2.1 Synthesis of alkaloids

2.1.1. (±)-Monomorine. (±)-Monomorine refers to the racemic mixture of indolizidine alkaloid type monomorine I, extracted from Monomorium pharaonis. Synthetic chemists have been interested in it for long time because it is biologically active pheromone and has challenging molecular architecture. Roy et al. in 2018, demonstrated short synthesis of (±)-monomorine started from commercially available compound 1a which was subjected to a Co(II)-based metalloradical-catalyzed one-pot transannulation using Co(TPP) (5.0 mol%) under optimized conditions (TsNHNH₂ (1.2 equiv.), Cs₂CO₃ (2.0 equiv.), 1-hexyne (2.0 equiv.), PhH, 80 °C, 24 h). The N-tosylhydrazone in this reaction transformed the aldehyde group to 2-(diazomethyl)pyridine, which was subsequently activated by the Co(II) center to produce an α-Co(III)–carbene radical. A γ-Co(III)-vinyl radical was generated when this cobalt–carbene radical joined with the terminal alkyne. This radical then went through intramolecular radical cyclization to yield compound 1b in 87% yield. TEMPO trapping and deuterium-labelling studies supported the radical mechanism, and Co(TPP) proved particularly effective because screening of other metal catalysts and metal–porphyrin complexes (Fe(TPP)Cl, Ni(TPP), Cu(TPP), and Pd(TPP)) produced no product. Compound 1b was subsequently hydrogenated in methanol with platinum oxide and hydrobromic acid to produce (±)-monomorine 1c in 82% yield³⁸ (Scheme 1).

Scheme 1 Total synthesis of (±)-monomorine 1c (adapted from ref. 38).

2.1.2. (+)-Arboridinine. Arboridinine, a member of the Apocynaceae family, was isolated from the Kopsia genus of Malaysia in 2015 and is known for its unique pentacyclic structure. It belongs to the monoterpenoid indole alkaloid family, whose members are known for structural diversity. The specific biological properties of arboridinine itself remain unexplored due to limited material availability. Arboridinine possesses a sterically crowded pentacyclic indolenine framework bearing four contiguous stereocentres, two of which are quaternary, and a bridgehead tertiary alcohol. The molecule poses a significant synthetic challenge because of captivating structure coupled with its densely substituted cage system.^39–43 Zhang et al.⁴⁴ reported a 14-step enantioselective synthesis of (+)-arboridinine in 2019. The critical installation of the bridgehead hydroxyl at C11 relied on cobalt-catalyzed decarboxylative acetoxylation. Numerous alternatives including the Barton reaction, photoredox conditions, and Pb-, Ag-, Mn-, and CAN-mediated protocols failed at this sterically demanding bridgehead. The method employs Co(OAc)₂·4H₂O (10 mol%) with PhI(OAc)₂ as oxidant via a radical pathway: decarboxylative acetoxylation generates a bridgehead carbon radical intermediate, whose competitive hydrogen abstraction accounts for the formation deoxyarboridinine by-product. The employed cobalt involving route proved uniquely effective at the congested bridgehead where other decarboxylative methods failed. The synthesis commenced with organocatalytic asymmetric Michael addition of dimethyl malonate 2b to enone 2a (Cat-4, THF) to furnish enantioenriched ketone 2c. Dieckmann condensation and stereoselective double-Mannich reaction afforded bicyclic ketone 2e (60% yield), which was converted to ketone 2f over a few steps. Next, Peterson olefination with TMSCH₂Li delivered the silyl alcohol (92% yield), and subsequent debenzylation and KHMDS-mediated elimination furnished olefin 2g (66% yield over 2 steps). N-Alkylation, iodination, and intramolecular dearomative annulation converted 2g to the corresponding tetracyclic ester (21% over 3 steps), which upon saponification (NaOH, THF/MeOH, reflux, 12 h) afforded acid 2h (64% yield). Treatment of 2h with Co(OAc)₂·4H₂O (0.1 equiv.) and PhI(OAc)₂ (1.5 equiv.) in DCE at 100 °C, 8 hours, followed by saponification (K₂CO₃/MeOH), delivered (+)-arboridinine 2i (20% yield, 98%ee) alongside deoxyarboridinine 2j (35%) from competitive hydrogen abstraction of the bridgehead radical intermediate⁴⁴ (Scheme 2).

Scheme 2 Total synthesis of (+)-arboridinine 2i (adapted from ref. 44).

2.1.3. Angustine and angustoline. Angustine and angustoline are emblematic members of the indolopyridine alkaloids family, specifically classified within the Vallesiachotaman subclass of monoterpenoid indole alkaloids. These compounds were derived from Strychnos angustiflora Benth and they have gained significant attention due to their biological activities including antimalarial, antiinflammatory, renin inhibitory, antiviral and antiproliferative properties.^45–49 Peng et al. in 2020, have carried out the concise synthesis of these compounds, namely, angustine and angustoline, in five steps and six steps, respectively. The key reaction, cobalt-catalyzed carbonylative lactamization, formed the significant ring of the pentacycle. This reaction got failed by employing methyl chloroformate or dimethyl carbonate/n-BuLi system, resulting in decomposition or no reaction, and with the palladium-catalyzed carbonylation under CO. In this transformation, the catalytically active species is an alkylcobalt intermediate generated from Co₂(CO)₈ and ethyl chloroacetate. The synthesis began with 3,5-dibromo-4-methylpyridine 3a which underwent esterification at –Me group to form 3b, followed by aminolysis with tryptamine 3c, and vinylation by the Suzuki reaction to form the amide 3d in 51% overall yield, over three steps. The Bischler–Napieralski cyclization of 3d with POCl₃ at 80 °C formed the enamide 3e as inseparable isomers in 62%. The carbonylative cyclization of 3e with Co₂(CO)₈, ethyl chloroacetate, and K₂CO₃ in MeOH at 60 °C formed the natural product angustine 3f, in 78% yield. Mukaiyama hydration [Mn(dpm)₃, PhSiH₃, O₂, EtOH, r.t.] converted 3f to (±)-angustoline in 84% yield, which was resolved by preparative HPLC to give (+)-angustoline 3g and (−)-angustoline 3h. The anti-Zika virus (ZIKV) inhibitory activity of (−)-angustoline (IC₅₀ = 68.67 µM) and (+)-angustoline (IC₅₀ = 17.91 µM) was also evaluated (Scheme 3).⁵⁰

Scheme 3 Total synthesis of angustine 3f, (+)-angustoline 3g and (−)-angustoline 3h (adapted from ref. 50).

2.1.4. Gusanlung D, 8-oxopseudopalmatine, and oxopalmatine. Gusanlung D, 8-oxopseudopalmatine and oxopalmatine are all berberine alkaloids and vinylene incorporation through Co(III)-driven annulative process made it easy to synthesize these natural products. Li et al. in 2020, designed a three-step synthetic route to all three alkaloids, based on a Cp*Co(III)-catalyzed C–H annulation reaction with a vinylene carbonate. A KIE of 2.7 was indicative of C–H activation as a rate-determining step, and competitive experiments supported electrophilic C–H cyclocobaltation. The Co-catalyzed vinylene transfer ring-formation reaction involved the coordination of amide and cobalt followed by the formation of cyclocobaltation intermediate, vinylene carbonate insertion, reductive elimination, oxidative addition of the C–O bond to Cp*Co(I), and subsequent β-oxygen elimination to liberate CO₂ and regenerated Co(III). Compared to a related Rh(III) approach, this protocol was regioselective and applicable to acrylamides. Amide coupling of arylethylamine derivatives 4b and 4g with benzoic acids 4a, 4h, and 4i using HOBt, EDCI, Et₃N, CHCl₃ conditions furnished the corresponding benzamides 4c, 4j, and 4k respectively. C–H functionalization of 4c, 4j, and 4k using Cp*Co(III)-catalyzed C–H annulation conditions i.e., [Cp*Co(CO)I₂] (10 mol%), AgSbF₆ (20 mol%), Zn(OAc)₂ (5 mol%), TFE, at 100 °C for 24–48 h provided the isoquinolinones 4e, 4l, and 4m respectively in a regioselective manner. The significant intermediate 4e afforded gusanlung D 4f over few steps,⁵¹ while 4l and 4m underwent intramolecular Heck cyclization (Pd (OAc)₂, TBAB, K₂CO₃, DMF, 120 °C, 24 h) to forge the tetracyclic protoberberine framework, delivering 8-oxopseudopalmatine 4n (45%) and oxopalmatine 4o (81%) respectively (Scheme 4).⁵²

Scheme 4 Total synthesis of gusanlung D 4f, 8-oxopseudopalmatine 4n, and oxopalmatine 4o (adapted from ref. 52).

2.1.5. Norzoanthamine and zoanthenol. Among the various zoanthamine alkaloids derived from marine zoanthids, norzoanthamine and zoanthenol represent particularly significant discoveries. Norzoanthamine was first isolated by the research group of Uemura in the mid-1990s from colonies of the genus Zoanthus, collected near the Amami Islands, Japan.^53–57 The molecule showed promising therapeutic potential in the fight against bone deterioration and was effective in preventing skeletal weakening in experimental mouse models.⁵⁸ Chen et al. (2023) described the asymmetric total synthesis of norzoanthamine (5j) and the formal synthesis of zoanthenol (5k) via the use of radical reactions to form the complex core structure. The synthesis was initiated with the use of chiral ketone 5a, which was obtained from (S)-(+)-carvone. The compound 5a was subjected to hydroxymethylation with DBU and aqueous formaldehyde in THF to produce compound 5b in 62% yield as the sole diastereomer. Ozonolysis and subsequent Cu(BF₄)₂/Fe(BF₄)₂-mediated fragmentation provided the corresponding enone in 65% yield, which after TES protection (90%) and Baylis–Hillman hydroxymethylation (80%) afforded enone 5c. A series of reactions provided the bicyclic intermediate 5d. Wittig olefination and subsequent TIPS removal provided alcohol 5e in 45% yield. Next, PTSA-mediated isomerization was followed by Dess–Martin oxidation to provide the corresponding aldehyde 5f in 90% yield. Addition of Grignard reagent 5g to 5f, followed by acetylation with Ac₂O and NEt₃, provided ester 5h in 65% yield over two steps. In the key step of the synthesis, the cobalt-catalyzed HAT radical cyclization was performed by treating 5h with Co(salen^t-Bu,t-Bu)Cl and PhSiH₃ in anhydrous acetone at 38 °C to provide the C-12 all-carbon quaternary center via the intramolecular Csp³–Csp² radical cyclization, assembling the A–B–C ring system. The one-pot sequence, including subsequent treatment with TBAF and aqueous NaOH, provided diol 5i in 74% yield as the sole diastereomer. This approach drew on Shenvi's cobalt-catalyzed radical hydroalkylation and Gao's HAT chemistry in the synthesis of viridin. A series of reactions were performed to achieve the total synthesis of norzoanthamine (5j). Zoanthenol (5k) was obtained via the formal synthesis method by using the established seven-step protocol by Miyashita's group to convert norzoanthamine hydrochloride (Scheme 5).⁵⁹

Scheme 5 Total synthesis of norzoanthamine 5j and zoanthenol 5k (adapted from ref. 59).

2.1.6. (S)-Norlaudanosine, (S)-xylopinine, (S)-laudanosine, (S)-sebiferine, (S)-cryptostyline II, (+)-solifenacin, FR115427 and (+)-NPS R-568. Tetrahydroisoquinolines represent one of the most significant classes of alkaloids, chiral 1-substituted THIQ frameworks appear widely across natural products, drug molecules, and bioactive substances.^60–63 Their pharmacological relevance is exemplified by compounds such as (S)-cryptostylines, dopamine receptor D1 probes,^64–66 and solifenacin, a clinically used antispasmodic drug.⁶⁷ Wu et al. in 2023, synthesized THIQ alkaloids i.e., (S)-xylopinine, (S)-sebiferine, (S)-cryptostyline II, (S)-norlaudanosine, (S)-laudanosine as well as asymmetrically constructed the intermediates, potentially leading towards (+)-NPS R-568, (+)-solifenacin and FR115427. They demonstrated that Co(II)-catalyzed enantioselective C–H/N–H annulation reactions between benzylamine picolinamides and alkynes proved as the chirality-inducing step. This formal (4 + 2) annulation employs Co(OAc)₂·4H₂O (10 mol%) and a chiral salicyloxazoline (Salox) ligand (15 mol%), Mn(OAc)₂·4H₂O (20 mol%) as the oxidizing agent, and PivONa·H₂O (50 mol%) in MeOH under O₂. Careful optimization of the reaction parameters suppresses competing dehydrogenative aromatization that would otherwise erode the C1 stereogenic center. The Co/Salox system also presented an environmentally friendly alternative to the use of precious metals such as Rh and Pd, and the reactions are successful with both electron-donating and electron-withdrawing substituents as well as heteroaromatic rings, operating on gram scale via desymmetrization and kinetic resolution with excellent enantioselectivities (up to 98% yield, >99%ee). The total synthesis commenced from 6a which was subjected to C–H annulation reaction with trimethylsilylacetylene 6r using Co(OAc)₂·4H₂O (10 mol%), (R,S)-L2 (15 mol%), Mn(OAc)₂·4H₂O (20 mol%), PivONa·H₂O (50 mol%), MeOH, O₂ at 60 °C for 12 h to afford C₁-chiral 1,2-dihydroisoquinoline 6b in 49% yield and 98%ee on a 5.0 mmol scale (1.42 g). Desilylation followed by hydrogenation using Pd/C, H₂, MeOH at 50 °C afforded 6c in 62% yield with >99%ee, from which PA₆ was removed using LiAlH₄ in THF to give (S)-norlaudanosine 6d in 71% yield with 99%ee. From 6d, cyclization using formaldehyde and formic acid afforded (S)-xylopinine 6e in 81% yield with 98%ee, while reductive amination using CH₂O and NaBH₄ afforded (S)-laudanosine 6f in 76% yield with 98%ee. Oxidative cyclization of 6f using PIFA, HPA, BF₃·Et₂O, MeCN afforded (S)-sebiferine 6g in 70% yield with 98%ee. Desymmetrization of 6h using 6r was conducted by employing Co(OAc)₂·4H₂O, (R)-L1 to afford 6i in 90% yield with 96%ee (1.52 g); sequential desilylation, hydrogenation, PA₆ removal, and N-methylation delivered (S)-cryptostyline II 6j in 99%ee. Similarly, desymmetrization of 6k with 6r using (R)-L1 gave 6l in 89% yield with 98%ee (3.13 g), a common precursor for (+)-solifenacin 6m and FR115427 6n. Finally, kinetic resolution of 6o ((R,S)-L2, 80 °C) recovered 6p in 48% yield with 98%ee (1.50 g), from which PA₆ removal afforded the precursor (58%, 99%ee) for (+)-NPS R-568 6q (Scheme 6).⁶⁸

Scheme 6 Total synthesis of (S)-norlaudanosine 6d, (S)-xylopinine 6e, (S)-laudanosine 6f, (S)-sebiferine 6g, (S)-cryptostyline II 6j, (+)-solifenacin 6m, FR115427 6n and (+)-NPS R-568 6q (adapted from ref. 68).

2.1.7. (±)-Halichonine B. Halichonine B, a sesquiterpene alkaloid extracted from the sponge Halichondria okadai, exhibits a C(sp³) rich framework characterized by unique quaternary methyl substitution. Biologically, halichonine B demonstrates potent cytotoxicity, notably triggering apoptosis in HL60 leukemia cells, highlighting its promise as an anticancer lead.^69–71 Yoshimura et al. in 2025 reported the total synthesis of (±)-halichonine B. A cobalt-catalyzed hydrocyanation served as the key C–CN bond-forming transformation. Starting from ethyl isobutyrate 7a, C-alkylation and LiAlH₄ reduction afforded alcohol 7b. Cobalt-catalyzed radical hydrocyanation (Cat-5, TsCN, PhSiH₃, EtOH, rt, 3 h) then delivered the branched nitrile 7c with high regiocontrol (73%, 2 steps). Next, transformation of 7c into 7d, followed by DIBAL-H reduction and Corey–Fuchs reaction led to the synthesis of 1,1-dibromoalkene 7e (87%, 2 steps). Cyano reduction and Horner–Wadsworth–Emmons olefination converted 7e to dibromide 7f, and treatment of 7f with Me₂CuLi (Et₂O, −78 to −20 °C) afforded bicyclic ester 7g (83%). Bicyclic ester was treated over several steps to deliver final compound (±)-halichonine B 7h (Scheme 7).⁷²

Scheme 7 Total synthesis of halichonine B 7h (adapted from ref. 72).

2.2 Synthesis of terpenoids/diterpenoids

2.2.1. Brasilicardins. Brasilicardins A–D are diterpenoid metabolites produced by the actinomycete Nocardia brasiliensis IFM 0406. They show a variety of biological activities such as potent immunosuppressive activity (IC₅₀ = 0.05 nM).^73–75 Yoshimura et al. in 2018 reported the total synthesis of brasilicardins A–D constructing tricyclic ester 8g as the common intermediate for all four congeners. From diol 8a, monosilylation, Swern oxidation, and HWE olefination afforded ester 8b (96%, two steps), which was treated over several steps to terminal alkene 8c. Cobalt-catalyzed hydrocyanation using Co(II) catalyst Cat-5, PhSiH₃, TsCN, and 2,6-di-tert-butylpyridine in ethanol converted 8c to secondary nitrile 8d (99%, three steps). Oxidation of 8d with TPAP/NMO followed by Z-selective HWE olefination employing 8e provided (Z)-α,β-unsaturated ester 8f (77%, two steps). Next, 8f was converted to tricyclic ester 8g, from which, two routes installed the amino acid component: route A gave β-methoxy-substituted 8h; route B gave 8i. Glycosylation of 8h or 8i with glycosyl donor 8j (Cp₂HfCl₂, AgOTf) followed by global deprotection provided brasilicardins A 8k (43%) and brasilicardins B 8l (37%), while analogous sequences yielded brasilicardins C 8m (94%) and D 8n (92%) (Scheme 8).⁷⁶

Scheme 8 Total synthesis of brasilicardins A 8k, brasilicardins B 8l, brasilicardins C 8m, brasilicardins D 8n (adapted from ref. 76).

2.2.2. Crinipellins. In 1979, Steglich and coworkers discovered a number of analogous diterpenoids including crinipellin A from the Crinipellis stipitaria.^77,78 Crinipellin A and crinipellin B exhibit antibiotic properties along with a potential to suppress the syntheses of proteins, DNA and RNA in Ehrlich carcinoma cells. The α-methylene ketone functionality marks these natural products as candidate irreversible chemical probes in medicinal chemistry.^79–84 Huang et al. (2018) achieved asymmetric total synthesis of (−)-crinipellin A 9j and (−)-crinipellin B 9k in 17 and 18 steps, respectively, using two intramolecular Pauson–Khand (PK) reactions to construct the tetraquinane core. Phenol 9a was converted over several steps to ketone 9b, whose Wittig olefination and acylation (n-BuLi, ClCO₂Et) gave enyne ester 9c (75%). Stoichiometric PK reaction of 9c [Co₂(CO)₈ (1.05 equiv.), NMO (3.5 equiv.), CO (balloon), DCE, rt to 76 °C] afforded ketoester 9d (40%, 98%ee after crystallization). This first PK reaction employed stoichiometric Co₂(CO)₈ with NMO to build the CD ring required pre-complexation at room temperature which was gradually increased to 76 °C as Co₂(CO)₈ complexation is sluggish owing to the low electron density of the alkyne. The ketoester 9d gave enyne 9e over a number of steps, followed by catalytic PK reaction [Co₂(CO)₈ (10 mol%), TMTU (60 mol%), PhMe, 60 °C, CO (1 atm), 12 h] to furnish 9f (21%) and C2 epimer 9g (42%). Thus, the second catalytic Co₂(CO)₈/TMTU PK reaction was established which gave only 21% of the desired diastereomer, prompting a switch to a Pd-catalyzed protocol (61%). Epoxidation of 9f with 9g (DMDO/Na₂HPO₄, then H₂O₂/NaHCO₃) gave 9h (7%) and 9i (38%), which was followed by its advancement to crinipellin A 9k (86%) crinipellin B 9j (74%), respectively (Scheme 9).⁸⁵

Scheme 9 Total synthesis of crinipellin A 9j and crinipellin B 9k (adapted from ref. 85).

2.2.3. (+)-Haperforin G. (+)-Haperforin corresponds to structurally distinctive member of the limonoid family of tetranortriterpenoids, it was first isolated from the Harrisonia perforata, a plant rich in diverse bioactive limonoids.^86–90 It exhibits potent therapeutic activity as a selective inhibitor of human 11β-hydroxysteroid dehydrogenase type 1 (IC₅₀ = 0.58 µM), presenting a promising therapeutic strategy for managing metabolic disorders such as Alzheimer's disease, vascular inflammation, cardiovascular disease and glaucoma.⁹¹ Its structural complexity and limited natural availability highlighted the importance of efficient synthetic development. Zhang et al. in 2020, accomplished a 20-step asymmetric total synthesis of (+)-haperforin G. A cobalt-mediated cyclisation served as the pivotal transformation, forging the cyclopentanone ring endowed with C10 all-carbon quaternary stereocenter (at bridgehead position) in a single operation. Optimization showed that stoichiometric Co₂(CO)₈ at 0.1 M afforded only 40% yield, whereas catalytic loading (20 mol%) at 0.01 M under CO balloon pressure raised the yield to 86% (d.r. > 20 : 1). The synthesis began with the formation of triol 10c from commercially available 3-methylbut-3-enoic acid 10a and alkyne 10b over a number of steps. Successive transformations including silylation (TBSCl/imidazole (95%)), desilylation (KHMDS/TMSCl (89%)), TPAP/NMO oxidation (89%), and Wittig olefination (87%) converted 10c to enyne 10d. In the key cobalt step, 10d was treated with Co₂(CO)₈ (20 mol%) in toluene (0.01 M) under CO (1 atm) at 110 °C for 36 h, affording PK product 10e in 86% yield (d.r. > 20 : 1) (Scheme 10). Further treatment of 10e over several steps gave enone 10f. Separately, (+)-MIB (Cat-6)-mediated addition of vinyl zinc 10h to aldehyde 10g afforded allylic alcohol 10i (93%, 99.5%ee) which was transformed to iodolactone 10j, over a few steps. Photoredox coupling of 10f and 10j with [Ir(ppy)₂(dtbbpy)]PF₆ (2.5 mol%), DIPEA, and Hantzsch ester (90 W blue LED, DMSO) delivered 10k as a single diastereoisomer (64%). Treatment of 10k with t-BuOK (THF, −78 °C), followed by SOCl₂/pyridine and DBU, furnished (+)-haperforin G (10l) in 50% overall yield (Scheme 10).⁹²

Scheme 10 Total synthesis of haperforin G 10l (adapted from ref. 92).

2.2.4. (+)-Waihoensene. Waihoensene possesses a densely functionalised cis-fused [6.5.5.5] tetracyclic framework featuring an angular triquinane motif, six consecutive stereocenters, four of them quaternary, and no heteroatom functionality.⁹³ It was first isolated by Weavers and co-workers in 1997 from Podocarpus totara var. waihoensis, a podocarp native to New Zealand.^94–96 Two total syntheses of (+)-waihoensene have been reported to employ an intramolecular cobalt-mediated Pauson–Khand (PK) reaction as the pivotal step to construct the angular triquinane core with its contiguous quaternary stereocenters. Qu et al. (2020) completed the synthesis in 15 steps and 3.8% overall yield, whereas Rosenbaum et al. (2021) achieved it in 14 steps (racemic) or 19 steps (enantioselective). In the Qu route, enyne 11e was subjected to Co₂(CO)₈ under N₂O (1 atm) in DCE at 80 °C for 22 h, affording tetracyclic enone 11f in 59% yield with 93%ee. Alternative promoters (TMANO, NMO, TMTU) and catalysts (PdCl₂/TMTU, [Rh(CO)₂Cl]₂) gave only 22–38% yield, underscoring the advantage of N₂O in this sterically congested cyclization. In the Rosenbaum route, PK precursor 11i was treated with stoichiometric Co₂(CO)₈ in refluxing xylene to furnish 11j in 46% yield. In both cases, Co₂(CO)₈ first forms a cobalt–alkyne complex, followed by intramolecular alkene insertion and CO migratory insertion, thereby resulting in well-established (+)-waihoensene's framework. The Qu approach provides a higher-yielding PK step, whereas the Rosenbaum route utilizes the concise synthetic route through a radical cyclization/thermal PK strategy. In the Qu synthesis, enone 11a (R = H) was converted to 11c via Grignard addition of 11l (98%) and Cu-catalyzed asymmetric conjugate addition (CuTc, L3, Me₃Al, n-BuOCH₂NEt₂) with m-CPBA oxidation (61%, 91%ee, two steps). Sakurai allylation of 11c afforded 11d (89%) followed by ozonolysis (65%), Ohira–Bestmann homologation (72%), and t-BuOK-mediated Conia-ene cyclization (83%), which resulted in enyne 11e. The PK reaction of 11e with Co₂(CO)₈ and N₂O delivered tetracyclic enone 11f (59%, 93%ee) which was converted to the natural product i.e., (+)-waihoensene 11k (90%, final step). In the Rosenbaum synthesis, alkylation of 11b (R = Me) with homopropargylic triflate 11m (LiTMP, DMPU, THF) afforded 11g (80%). Radical cyclization of 11g proceeded by epimerisation, and hydrazone formation gave 11h, which was converted to enyne 11i via catechol borane reduction (82%), Birch reduction (Na, NH₃(l)), Parikh–Doering oxidation (SO₃·pyr, NEt₃, DMSO), and Ohira–Bestmann alkynylation (K₂CO₃, MeOH, 65% over two steps). The PK reaction of 11i with Co₂(CO)₈ in refluxing xylene furnished tetracyclic enone 11j (46%). α-Alkylation (LiTMP, DMPU, then MeI; 63%), 1,4-addition of methyl cuprate (MeLi, CuCN, BF₃·OEt₂; 70%) of 11j followed by Wittig olefination (Ph₃PCH₂Br, KOtBu, PhMe, 110 °C; 91%) completed (+)-waihoensene 11k (Scheme 11).^97,98

Scheme 11 Total synthesis of (+)-waihoensene 11k (adapted from ref. 97 and 98).

2.2.5. (±)-Cephanolides A–D. The benzenoid cephanolide diterpenoids (A–D) were first isolated by Yue and co-workers from Cephalotaxus sinensis in 2017.⁹⁹ Their intricate frameworks, closely similar to harringtonolide and fortalpinoid G, are significantly renowned for their potent biological activities i.e., antitumor, antiviral and plant growth inhibitory properties^100–102 In 2021, Haider et al. demonstrated the total synthesis of (±)-cephanolides A–D via concise synthetic approach. The synthesis began with 7-hydroxy-4-methylindanone 12a, which was used to form indanone–pyrone 12b via triflation and Pd-catalyzed subsequent Suzuki couplings with 12l and 12m (80%, two steps). Enol ether formation and subsequent Diels–Alder cycloaddition (TMSOTf, DIPEA, DCM, 80%) gave 12c as a single diastereomer. Radical hydration (Co(thd)₂, O₂, Et₃SiH, TBHP, PhCF₃, r.t.) afforded 12d. This cobalt-catalyzed step was used to reduce the electron-deficient bridging olefin in 12c. Standard electrophilic functionalization (hydroboration, epoxidation) proved ineffective on this olefin, whose reactivity is suppressed by the adjacent lactone functionality. The peroxide 12d was converted to ketone 12e (NfF, DBU, THF, −78 °C, 42%). Subsequent olefination (Ti(Oi-Pr)₂Cl₂, CH₂(ZnBr)₂, 53%) gave 12f which was succeeded by hydrogenation (Pd/C, H₂, 99%, d.r. > 20 : 1) to give 12g. Divergent sequences from 12g furnished cephanolides C (12h), B (12j), D (12i) and A (12k) over a number of steps (Scheme 12).¹⁰³

Scheme 12 Total synthesis of cephanolide A 12k, cephanolide B 12j, cephanolide C 12h, and cephanolide D 12i (adapted from ref. 103).

2.2.6. Plebeianiol A. Plants of the Salvia genus are renowned for producing a wide variety of biologically active abietane-type diterpenoids,^104,105 which are recognized for their diverse molecular architecture and notable pharmacological potentials, for instance antioxidants¹⁰⁶ and anti-inflammatory activities.^107,108 A noteworthy advancement occurred in 2015, when Liang, Wu, and coworkers identified an important abietane diterpenoid which was previously unknown, designated as Plebeianiol A, from Salvia plebeia R. Br. The compound denotes a novel structural framework and biochemical evaluation revealed that it has free-radical scavenging capacity and demonstrated inhibitory effects on ROS generation and NO production.¹⁰⁹ A novel 11-step synthesis of the natural product plebeianiol A, along with its revision, was also carried out by Johnson et al. in 2021, with an overall yield of 13%, utilizing cobalt-catalyzed MHAT-induced radical bicyclization, which afforded the tricyclic core of the natural product in one step, drawing on precedent from cationic biogenetic annulations towards abietanes synthesis. This reaction is compatible with highly oxygenated substrates, including unprotected diols. The ozonolysis of 4-pentenenitrile 13a, followed by the Wittig reaction, afforded the acrylate ester 13b in 61% which was transformed into 13c over few steps. Bicyclization of 13c with Co(II) catalyst Cat-5, TMDSO, DTBP, and oxidant (3 equiv.), in the presence of HFIP at room temperature, afforded the tricyclic nitrile 13d in 78% yield, 1 : 1 dr. DIBAL-H reduction, followed by NaBH₄ reduction, afforded carbinol 13e in 85% yield over two steps in conjugation with deprotection employing 2 M HCl in aqueous MeOH, that afforded the desired natural product, plebeianiol A 13f in 99% yield (Scheme 13).¹¹⁰

Scheme 13 Total synthesis of plebeianiol A 13f (adapted from ref. 110).

2.2.7. (+)-Erogorgiaene and pseudopterosin A–F aglycone. Pharmaceutically important terpenoids (+)-erogorgiaene and pseudopterosins belong to marine invertebrates Pseudpterogorgia elisabethae. (+)-Erogorgiaene demonstrates significant inhibitory activity towards Mycobacterium tuberculosis.^111–119 In addition, pseudopterosins emphasize their powerful analgesic, cytotoxic and anti-inflammatory characteristics, for instance pseudopterosin A displays broad-spectrum antibacterial activity and has shown neuromodulatory effects in mammalian tissues. Movahhed et al. completed synthesis of (+)-erogorgiaene 14i in 7 steps (46% overall yield) and pseudopterosin A–F aglycone 14n in 12 steps (30% overall yield), using cobalt-catalyzed asymmetric hydrovinylation as the stereo defining transformation. The cobalt method employed air-stable Co(II) pre-catalysts was activated in situ by Et₂AlCl to access 14k. The corresponding Ni-based catalysts were oxygen-sensitive, demanding glovebox conditions that proved impractical and yielded inconsistent outcomes with the ortho-methoxy substrate 14j. For erogorgiaene, hydrovinylation of 4-methylstyrene 14a (Co(L4)Cl₂ (0.03 mol%), Et₂AlCl, CH₂Cl₂, −65 °C) gave 14b in 98% yield (98–99%ee). With utilization of ligand ent-L4 (0.03 mol%, −65 °C), 98–99%ee was reached. Hydroboration of 14b (9-BBN) gave 14c; Suzuki coupling with vinyl iodide 14e, prepared from propargylic alcohol 14d (84%), provided nuciferyl acetate 14f (91%). Cyclization (Me₂AlCl, CH₂Cl₂, −78 °C) was followed by carbonyl–ene reaction ((CH₂O)_n, Et₂AlCl, −70 °C) which afforded alcohol 14g (86%). Hydrogenation (Cat-7) furnished 14h (94%), and iodination/coupling with isocrotyl-lithium 14o afforded (+)-erogorgiaene 14i (72%). For pseudopterosin A–F aglycone, hydrovinylation of 14j (Co(L5) Cl₂, 5 mol%, Et₂AlCl, CH₂Cl₂, −20 °C, 6 h) gave 14k (87%, 84%ee). Hydroboration–Suzuki coupling, Friedel–Crafts cyclization, and carbonyl–ene reaction afforded aldehyde 14l followed by olefination with phosphonate 14p (82%) and AlCl₃-mediated cyclization (20 mol%, −5 °C) that gave amphilectane 14m (92%, d.r. = 95 : 5). Finally, demethylation (LiSEt, DMF, 160 °C) furnished pseudopterosin A–F aglycone 14n in high yield (96%) (Scheme 14).¹²⁰

Scheme 14 Total synthesis of (+)-erogorgiaene 14i and the pseudopterosin A–F aglycone 14n (adapted from ref. 120).

2.2.8. (−)-Triptolide. (−)-Triptolide, despite its trace concentration of only 0.001% in Tripterygium wilfordii Hook F, remains as the most significant metabolite with considerable pharmacological activity.¹²¹ Preparations derived from the plant, known as TwHF, have been used for centuries as part of traditional Chinese medicine for the treatment of autoimmune and inflammatory diseases.¹²² In 1972, it was first isolated, and ever since, it has been the focus of extensive synthetic and pharmacological investigation. In addition to its known anti-inflammatory and immunosuppressive properties, it has also shown promise as a potential drug candidate for the treatment of cancer, specifically pancreatic cancer.¹²³ Fang et al. reported the synthesis of (−)-triptonide from (R)-(−)-Taniguchi lactone 15a, which involved the use of Co(TPP) as the catalyst for the MHAT-initiated radical cyclization reaction that forged the C5–C10 bond. Fe(III) catalysts only afforded the desired product with an isolated yield of 41%, while the use of Co(TPP) with blue LEDs (465 nm) at 0.1 mol% catalyst loading afforded 15g with 68% yield as a single diastereomer. In the absence of blue LEDs, the substrate decomposed to unidentifiable side products, and no desired product was obtained (0% yield, 81% conversion by TLC). Cross metathesis between 15a and acrolein diethyl acetal 15j (Hoveyda–Grubbs II, CH₂Cl₂, 40 °C) afforded compound 15b with 68% yield. TIPS protection of 15c, Grignard addition, and PBr₃ treatment furnished 15d and then 15e. Alkylation of 15b with 15e (LiHMDS) and ketal hydrolysis (2 N HCl) afforded aldehyde 15f with 67% yield as a single diastereomer. MHAT cyclization of 15f (Co(TPP) (0.1 mol%), PhSiH₃ (1.5 equiv.), CH₂Cl₂/EtOH (10 : 1), blue LEDs, rt) gave 15g (68%). Treatment of 15g over several steps furnished (−)-triptonide 15h (Scheme 15).¹²⁴

Scheme 15 Total synthesis of (−)-triptonide 15h (adapted from ref. 124).

2.2.9. 7-Hydroxyerogorgiaene and 9-deoxypseudopterosin A. 7-Hydroxyerogorgiaene and 9-deoxypseudopterosin A are phenolic diterpenoids from the marine source Pseudopterogorgia elisabethae that illustrates antimicrobial activity against Gram-positive pathogens. Schumacher et al. described the enantioselective syntheses of (+)-7-hydroxyerogorgiaene 16g (8 steps, 31% overall) and 9-deoxypseudopterosin A 16h (9 steps, 28% overall) with an enantioselective cobalt-catalyzed hydrovinylation serving as the stereodefining transformation. The asymmetric hydrovinylation of styrene 16a was mediated by catalyst, generated in situ from CoCl₂ and phosphoramidite ligand L6 (0.4 mol%). This method delivered 16b in 99% yield and 91%ee on multigram scale. Hydroboration/Suzuki coupling of 16b with vinyl iodide 16i gave 16c (71%). Cyclization precursor 16c was treated with Me₂AlCl to afford trans-calamenene 16d (92%, d.r. = 86 : 14). Carbonyl–ene reaction and HPLC separation provided 16e (77%), and hydrogenation with iridium catalyst Cat-8 furnished 16f (>99%, d.r. = 95 : 5). From 16f, (+)-7-hydroxyerogorgiaene 16g and 9-deoxypseudopterosin A 16h were obtained over a number of steps (Scheme 16).¹²⁵

Scheme 16 Total synthesis of (+)-7-hydroxyerogorgiaene 16g & 9-deoxy-pseudopterosin A 16h (adapted from ref. 125).

2.2.10. (−)-Illisimonin A. (−)-Illisimonin A was extracted by Yu and co-workers from the evergreen shrub Illicium simonsii that is frequently utilized in traditional Chinese medicine.¹²⁶ It exhibited neuroprotection in an SH-SY5Y oxygen–glucose deprivation resulting cell injury with half maximal effective concentration of ≈ 28 µM. Illisimonin A contains an unprecedented cage-like 5/5/5/5/5 pentacyclic scaffold. This compact ring network contains a strained trans-pentalene unit. Such motifs are exceedingly scarce among known natural products and present a major synthetic challenge.^126–132 Xu et al. in 2025, completed an asymmetric total synthesis of (−)-illisimonin A in 16 steps from (S)-carvone. The key cobalt-catalyzed step was Mukaiyama hydration of the trisubstituted olefin 17d [Co(acac)₂, PhSiH₃, O₂, THF], followed by thermal translactonization (toluene, 140 °C), giving γ-butyrolactone 17e in 67% yield. Starting from (S)-carvone 17a, α-allylation with 17h, ring-closing metathesis with epimerization (67% over 2 steps) followed by nucleophilic epoxidation afforded 17b (77%). Next, Wittig homologation of 17b with 17i then gave aldehyde 17c (91%). Further, treatment of 17c through several steps, resulted in the preparation of 17d. In order to install the desired –OH group on C-4, Co(acac)₂-catalyzed Mukaiyama hydration of 17d was carried out, followed by subsequent (one-pot) thermal translactonization to access 17e (67%). Next, benzyl protection of 17e, followed by MoOPH α-hydroxylation and Jones oxidation that gave 17f in 63% yield. Then, 17f was subjected to intramolecular aldol cyclization and hydrogenolysis to furnish (−)-illisimonin A 17g in 84% yield (Scheme 17).¹³³

Scheme 17 Total synthesis of (−)-illisimonin A 17g (adapted from ref. 133).

2.2.11. Pierisketone B. Pierisketone B belongs to a novel group of rearranged ent-kaurane diterpenoids, known for their tetracyclic 7/5/6/5 carbocyclic framework.^134–136 These molecules possess bioactivities such as antitumor, antibacterial and anti-inflammatory activity which rendered it a primary focus of synthetic exploration.^137,138 Gu et al. completed the first total synthesis of (+)-pierisketone B (3.4% overall yield from the known enone 18a), featuring an intramolecular Pauson–Khand reaction (PKR) to construct the bridged bicyclo [3.2.1] octane core. When the dihydro analogue of 18f was subjected to PK reaction conditions, only traces of product were observed, underscoring the critical role of the conformational constraint in Z-enyne, facilitating the PKR reaction. The synthesis commenced with CuBr·Me₂S-catalyzed 1,4-vinylation of 18a gave 18b (58%) in conjugation with ozonolysis which afforded aldehyde 18c (96%).¹³⁹ Julia–Kocienski olefination of 18c with BT-sulfone 18d (NaHMDS, −45 °C) provided Z-enyne 18e (82%), and methylenation with Nysted reagent furnished 18f (92%). PK reaction of 18f (Co₂(CO)₈, n-BuSMe, PhMe, reflux) delivered 18g (85%), whose structure was verified crystallographically. Elaboration of 18g over several steps afforded 18h followed by dimethylation to give 18i (91%). Deoxygenation of 18i and desilylation completed the total synthesis of (+)-pierisketone B 18j (78%) (Scheme 18).¹³⁹

Scheme 18 Total synthesis of pierisketone B 18j (adapted from ref. 139).

2.3 Synthesis of polyketides

2.3.1. (R)-Sarkomycin. (R)-Sarkomycin, a cyclopentenone of prominent biological relevance was first isolated from Streptomyces erythrochromogenes in 1953.¹⁴⁰ Beyond its antibacterial properties, it exhibits potent inhibitory activity against diverse human cancer cell lines and malignancies. Cabré et al. reported an enantioselective synthesis of (R)-sarkomycin methyl ester in five steps, who were the first to use the Pauson–Khand reaction (PKR) for ring construction of this natural product. Within the PKR reaction of steric hindrance involving substituents of internal alkynes, electronic effects direct the regioselectivity towards the electron withdrawing group i.e., –OMe carbonyl will be directed to the β-position. Ethylene glycol was used as an additive to minimize the NMO activation, thereby giving 85% yield of 19c. The synthesis initiated with the carboxylation and esterification of N-Boc-propargylamine 19a to give alkyne 19b in 74% yield. Subjecting 19b to the Pauson–Khand reaction (Co₂(CO)₈, toluene, ethylene (6 barG), NMO (6 equiv.), 4 Å MS, ethylene glycol, CH₂Cl₂, rt, 4 h) provided cyclopentenone 19c in 85% yield. Iridium-catalysed isomerization of 19c followed by hydrogenation over Pd/C delivered 19d in 73% yield and >99%ee. Finally, Boc removal and subsequent N-methylation/elimination afforded (R)-sarkomycin methyl ester 19e in 45% yield with 98%ee (Scheme 19).¹⁴¹

Scheme 19 Total synthesis of (R)-sarkomycin methyl ester 19e (adapted from ref. 141).

2.3.2. Monocillin VII. The resorcyclic acid lactones (RALs) are natural compounds that possess a β-resorcylate core fused to a 12-/14-membered macro lactone ring, obtained from numerous biological sources.¹⁴² Wei's group isolated a series of RALs from rice cultures of Paecilomyces sp. SC0924 including monocillin VII. It displays moderate antifungal efficacy against P. litchii (IC₅₀ value 41.0 µM) and potent cytotoxicity against HeLa, A549, and MCF-7 cell lines, with IC₅₀ values of 3.9, 4.1, and 4.9 µM, respectively.¹⁴³ In 2019, Mallampudi et al. reported the first asymmetric total synthesis of monocillin VII 20k in 16 longest linear steps via a convergent approach. Total synthesis commenced from the transformation of aldehyde 20a into alkyne 20b over a number of steps. The synthesis of second coupling partner i.e., aryl triflate 20e was initiated from acid 20c, which was converted to acetonide 20d under the presence of SOCl₂, DMAP, in acetone (giving 82% yield) followed by a sequence of steps to generate 20e. Sonogashira coupling of 20b and 20e provided 20f (76%), whose TBDPS removal gave 20g (85%). The major hurdle was macrolactonization of seco-acid 20g under De Brabander's conditions (NaH, THF, 0 °C) which were found to be highly unfavorable, yielding only 15% of desired product. On the other hand, the treatment of 20g with Co₂(CO)₈ in CH₂Cl₂ at 0 °C for 1 hour gave the alkyne–dicobalt hexacarbonyl complex 20h quantitatively. The resulting complex 20h was then finally transformed to afford the target natural product monocillin VII 20i (Scheme 20).¹⁴⁴

Scheme 20 Total synthesis of monocillin VII 20i (adapted from ref. 144).

2.3.3. Laurallene. Laurallene, a marine-derived C₁₅ acetogenin isolated from the red alga Laurencia nipponica Yamada in 1979, exemplifies the lauroxane family bearing medium-ring ethers. Its rare 2,9-dioxabicyclo[6.3.0]undecene framework, featuring an exocyclic chiral bromoallene, has rendered laurallene a promising target for total synthesis.^145,146 Asymmetric total synthesis of laurallene by Yoshimura et al. involved a 13-step approach with an overall linear sequence of 3.3% yield. Cobalt-mediated Mukaiyama oxidative cyclization, with a modification by Pagenkopf, utilizing Co(nmp)₂ catalyst, constructs the trans-THF ring from diol-alkene 21e. Yoshimura et al. used asymmetric epoxidation of trans-2-pentenal 21a, followed by one-pot Horner–Wadsworth–Emmons olefination to obtain epoxy ester 21b (64%, 97%ee). Copper-catalyzed opening of (S,S)-diepoxide 21c furnished the second coupling partner i.e., diol 21d (91%). In the next step, Pd-catalyzed alkoxy substitution of 21b with 21d, followed by NaIO₄ cleavage, provided branched ether 21e (75%). In the next step, cobalt-mediated Mukaiyama oxidative cyclization of 21e developed by Inoki and Mukaiyama, with a modification by Pagenkopf, utilizing Co(nmp)₂ catalyst (0.2 equiv.), TBHP (0.1 equiv.), O₂ (1 atm), MS 4A, i-PrOH at 55 °C furnished trans-THF 21f as a single diastereomer, whose TBS protection gave 21g (53%, two steps). Next, 21g was subjected to DIBAL-H reduction (93%) followed by Movassaghi reductive rearrangement to afford diene 21h (82%), which was converted to laurallene 21i via ring-closing metathesis, bromoallene installation, and C13-bromination (42%, three steps) (Scheme 21).¹⁴⁷

Scheme 21 Total synthesis of laurallene 21i (adapted from ref. 147).

2.3.4. (+)-Iso-A82775C. (+)-Iso-A82775C and its oxidized analogue (+)-16-oxo-iso-A82775C are important epoxyquinoid intermediates involved in the biosynthesis of structurally complex natural products such as pestalofones and chloropupukeananin. They are now important targets in synthetic and biosynthetic studies owing to their distinct cyclohexane frameworks and reactivity.¹⁴⁸ Kim et al. accomplished the total synthesis of (+)-iso-A82775C 22g and (+)-16-oxo-iso-A82775C 22h from p-methoxyphenol, with cobalt-mediated alkyne protection as the key reaction. α-Iodination of enone 22a afforded α-iodinated product 22b in 62% yield. The Stille cross-coupling of 22b with organostannane 22c using Pd (OAc)₂, AsPh₃, and CuI in THF afforded enyne 22d in 87% yield. The conjugate reduction of enyne enone 22d failed because the alkyne π-system rendered the C10 position less-electron deficient, leading to exclusive carbonyl reduction at C16. Coordination of the alkyne with Co₂(CO)₈ to give dicobalt hexacarbonyl complex 22e avoids the less electrophilicity tendency at C10 position as alkyne gets masked in this process, thereby leading to facile selective 1,4-reduction with K-selectride. Thus, treatment of 22d with Co₂(CO)₈ (1.0 equiv.) in CH₂Cl₂ at 22 °C provided cobalt complex 22e in 90% yield. Conjugate reduction of cobalt-complexed enone 22e with K-selectride followed by CAN-mediated decomplexation, and Et₃N-catalysed tautomerization furnished allene 22f with complete diastereoselectivity (40%, three steps). From 22f, Sc (OTf)₃-catalysed desilylation (MeCN/H₂O, 63 °C) furnished (+)-16-oxo-iso-A82775C 22h in 43% yield, whereas chemoselective reduction with LiEt₃BH followed by TBAF desilylation afforded (+)-iso-A82775C 22g in 66% yield, over two steps (Scheme 22).¹⁴⁹

Scheme 22 Total synthesis of (+)-iso-A82775C 22g and (+)-16-oxo-iso-A82775C 22h (adapted from ref. 149).

2.3.5. Amphirionin-2. The linear polyketide metabolite amphirionin-2 was isolated from cultured cells of the marine benthic dinoflagellate Amphidinium sp. KCA09051 strain. Amphirionin-2 demonstrated significant potent cytotoxic activity against the human non-small cell lung adenocarcinoma A549 cell line, human colon carcinoma caco-2 cell line and revealed anticancer efficacy in vivo toward murine tumor P388 cells (T/C 120% at 0.5 mg kg⁻¹).^150,151 The first total synthesis of amphirionin-2 23p and diastereomer 23q was accomplished by Kato and co-workers in 2021, consisting of 17 linear steps (from diol 23a), by relying on iterative cobalt-mediated Mukaiyama cyclization to synthesize the tetrahydrofuran rings. Afterwards, Hartung–Muakiyama cyclization illustrated that several radical terminators have the potential to trap the centered carbon radical intermediate to afford trans-tetrahydrofyran derivatives. Diol 23a was converted to iodide (82%), then to γ-hydroxy olefin 23b via vinyl cuprate addition (92%). Co–I-catalyzed cyclization of 23b afforded 23c (68%, d.r. >20 : 1) using cat-11, t-BuOOH, i-PrOH, O₂, which was transformed into olefin 23d over a few steps. Co–I cyclization of 23e gave 23f (61%, d.r. >20 : 1), whose further acetylation and PMB removal provided 23g. Ru–I cross metathesis of 23d and 23g furnished 23h (84%, E/Z 5 : 1), whose Co-II (16 mol%) catalyzed Hartung-Mukaiyama cyclization (γ-terpinene/toluene, air, 80 °C) gave 23i (83% from E, 73% from Z). The compound 23i was treated over several steps to access 23j. Next, another Co-I cyclization of 23k afforded 23l followed by its transformation to 23m over a few steps. Co-II (3 mol%) cyclization of 23m afforded 23n (84%, d.r. > 20 : 1) in conjugation with DIBAL-H reduction (94%) and Takai olefination to furnish iodoolefin 23o. Finally, coupling of 23j and 23o/23o′ resulted in the synthesis of amphirionin-2 23p and its diastereomer 23q respectively, over a few steps (Scheme 23).¹⁵²

Scheme 23 Total synthesis of amphirionin-2 23p and its diastereomer 23q (adapted from ref. 152).

2.3.6. Plakortolides E and I. Endoperoxides are a structurally distinctive class of natural products isolated from both marine and terrestrial organisms. These compounds display diverse and relatively underexplored biological activities. Notably, polyketide-derived members such as plakinic acids, plakortides, and plakortolides have shown promising antitumor, antibacterial, and antifungal effects. The polyketide-derived endoperoxides plakortolides E and I were obtained from marine sponges.^153–155 Leisering et al. (2021) achieved a concise, seven-step route to both natural products starting from (R)-linalool 24a, employing a tandem cobalt-mediated endoperoxide cyclization as the pivotal transformation. (R)-Linalool (24a) was converted to butenolide 24b via vanadium-catalyzed epoxidation, cyanide opening, and one-pot hydrolysis/lactonization/elimination (69%). Butenolide 24b was treated over few steps to access allyl acetate 24c. Iron-catalyzed allylic substitution of 24c afforded olefin 24d (66%), which underwent cobalt-catalyzed hydro peroxidation followed by oxa-Michael addition. These conditions were not successful for the conversion of precursor, then addition of protic solvent (i-PrOH as co-solvent) facilitated the reactivity of olefin 24d to afford the synthesis of desired natural products, which prevented the formation of by-products. However, the products were observed to be decomposed. At 0 °C, oxa-Michael addition was slowed and corresponding silyl peroxide was trapped. This challenge was handled by in situ TBAF/TFE desilylation, thereby preventing Weitz–Scheffer epoxidation. As a result, (−)-plakortolide I 24e in 42% and (+)-plakortolide E in 24f (77% combined, d.r. 1.2 : 1), were obtained via this endoperoxide formation (Scheme 24).¹⁵⁶

Scheme 24 Total synthesis of (−)-plakortolide I 24e and (+)-plakortolide E 24f (adapted from ref. 156).

2.3.7. Prorocentin. Prorocentin, a secondary metabolite generated by the strain P. lima PL021117001, was collected from the Northern Taiwan coastline. Prorocentin exhibits weak cytotoxicity towards two human cancer cell lines and shows no antimicrobial activity against S. aureus.¹⁵⁷ Zachmann et al. in 2023, reported the total synthesis of actual prorocentin from fragments 25d and 25f. The key cobalt-catalyzed step is an oxidative Mukaiyama cyclization, which resulted in 2,5-trans-disubstituted tetrahydrofuran 25c. Krische allylation of 25a ((Ir(cod)Cl)₂, L6, Cs₂CO₃, THF) gave 25b (81%, 96%ee) which was subjected to significantly selective cobalt-catalyzed oxidative etherification (Cat-13, tBuOOH, iPrOH, O₂, 55 °C) to afford trans-THF 25c (72%, d.r. > 20 : 1) as a single diastereomer, involving selective 5-exo-trig cyclization, even though the substrate bearing two chemically distinct olefin units adjacent to the hydroxyl group. The resulting THF 25c was converted to vinyl iodide 25d over a sequence of reaction steps. D-Glucose 25e was converted to 25f which was subjected to Sonogashira coupling with 25d to access 25g in 91% yield. Finally, its gold-catalyzed spirocyclization furnished product 25h (69%) which was transformed to prorocentin 25i over a number of steps (Scheme 25).¹⁵⁸

Scheme 25 Total synthesis of prorocentin 25i (adapted from ref. 158).

2.3.8. (+)-Muricatetrocin B. (+)-Muricatetrocin B, a naturally occurring product, was isolated by McLaughlin et al. from the ethanol extracts of the defatted seeds of Annona muricata.¹⁵⁹ This chemical has attracted significant attention because of its cytotoxic efficacy against A549 (lung), MCF-7 (breast) and HT-29 (colon) cancer cells.¹⁶⁰ Minami et al. in 2023, published an effective method to establish (+)-muricatetrocin B, which featured a late-stage Co(II)-catalyzed Hartung–Mukaiyama cyclization to construct the core 2,5-trans-tetrahydrofuran ring. The total synthesis commenced from the synthesis of olefin 26e which was obtained from sulfone 26a on coupling with aldehyde 26b under KHMDS in THF, gradually warming from −78 °C to rt to afford compound 26c. Compound 26c was converted to diol 26d via Sharpless dihydroxylation and then diol 26d was converted into olefin 26e over a few steps. On the other hand, alcohol 26f was transformed to 26g, via few synthetic steps. In addition, the coupling partners i.e., 26e and 26g were combined through second-generation Grubb's complex (G-II) using CH₂Cl₂ to synthesize hydroxy olefin 26h in 69% yield. Finally, an important step of Hartung–Mukaiyama cyclization of hydroxy olefin 26h was carried out to form tetrahydrofuran 26i in 50% yield. Furthermore, in deprotection conditions (80% aq. AcOH at 50 °C), tetrahydrofuran 26i synthesized final targeted natural product (+)-muricatetrocin B 26j in 72% yield (Scheme 26).¹⁶¹

Scheme 26 Total synthesis of (+)-muricatatrocin B 26j (adapted from ref. 161).

2.3.9. Sylvaticin. Sylvaticins are distinctive members of the annonaceae-derived acetogenins, important because of non-adjacent bis-THF motifs linked via 1,4-diol unit. Among them, cis-sylvaticin and sylvaticin are epimeric at a single THF ring yet both display notable anti-cancer abilities that have inspired synthetic researchers.^162,163 Dey and Prasad in 2025 described an enantiospecific formal total syntheses of (+)-cis-sylvaticin and (+)-sylvaticin from a C₂-symmetric furyl carbinol. The cis-THF rings were assembled by OsO₄-mediated oxidative cyclisation, whereas the trans-THF motif was installed through a cobalt-catalyzed Mukaiyama oxidative cyclization using Co(modp)₂ with tBuOOH and O₂, to generate trans-THF 27e. The synthetic strategy initiated with the addition of BnO(CH₂)₃MgBr to bis-Weinreb amide 27a, which gave diketone 27b in 98% yield which was further treated over several steps to achieve tetra-TBS ether 27c. In the next step, Finkelstein reaction and Boord olefination afforded alkene 27d which was followed by cobalt-catalyzed Mukaiyama cyclization using Co(modp)₂, tBuOOH, O₂ in iPrOH at 55 °C to furnish trans-THF 27e (57%, 63% BRSM). In the next step, triflation and Grignard coupling (75%) delivered 27f followed by its transformation to (+)-sylvaticin 27g over few steps (Scheme 27).¹⁶⁴

Scheme 27 Formal total synthesis of (+)-sylvaticin 27g (adapted from ref. 164).

2.4 Synthesis of macrolides

2.4.1. Chagosensine. Marine sponges are renowned for harboring complex microbial colonies that serve abundant sources of bioactive natural products with notable structural complexity. Among these, the macrolide chagosensine, obtained from the calcareous sponge Leucetta chagosensis collected in the Gulf of Aqaba, showcased remarkable molecular diversity.^165,166 Heinrich et al. (2018) reported the total synthesis of putative chagosensine 28g, wherein cobalt-catalyzed oxidative Mukaiyama cyclization was used to construct both trans-tetrahydrofuran rings. In this process, Co(nmp)₂ (10 mol%) with tBuOOH (10 mol%) and O₂ (1 atm) in iPrOH at 55 °C were employed. Although 28c contains two distinct olefin sites, the cyclization proceeded with outstanding regio- and diastereoselectivity (d.r. > 20 : 1, regioselectivity >12 : 1). (S)-Citronellal 28a was converted to 28b via acetalization (98%) and ozonolysis (97%) followed by its conversion to alcohol 28c, which was subjected to cobalt-catalyzed cyclization to afford 28d (69%, pure isomer). Modified Parikh–Doering oxidation of 28d with (iPr)₂NEt and Carreira alkynylation provided 28e (d.r. = 11 : 1, 65% over two steps). Next, resulting product 28e was subjected to desilylation (85%) and palladium-catalyzed destination with (Bu₃Sn)₂ and [(t-BuNC)₂PdCl₂] (10 mol%) in THF resulted in bisstannane 28f (93%), which was transformed to putative chagosensine 28g over few steps (Scheme 28).¹⁶⁷

Scheme 28 Total synthesis of putative chagosensine 28g (adapted from ref. 167).

2.4.2. Halichondrin. Halichondrin B, a prominent member of the halichondrin family, was isolated from a marine sponge. Structurally, it is a complex polyether macrolide featuring multiple fused cyclic ether rings and numerous stereocentres, and it displays potent antitumor activity. Notably, the clinically approved anticancer drug eribulin is a structurally simplified analogue of halichondrin B.^168,169 Nicolaou et al. in 2021 reported a 25-step convergent route to halichondrin B, ranking amongst the most concise approaches to this target, till date. The key strategic innovation inverted the conventional ether-ring construction order: cobalt-mediated Nicholas etherification installed C–O bonds prior to radical-mediated C–C ring closure, thereby reversing the classical approaches in which C–C bonds preceded C–O cyclization. Co₂(CO)₈ coordinated the alkyne of a propargylic alcohol to form a hexacarbonyldicobalt complex. Treatment of the cobalt–alkyne complex with BF₃·Et₂O produced a cobalt complex, that upon exposure with alcohol generated ether–cobalt complex. Subsequent oxidative removal of the cobalt template with CAN delivered the propargylic ether. This cobalt etherification was applied uniformly to construct all four fragments of the natural product. Cobalt-catalyzed Nicholas etherification of propargylic alcohol 29a with hydroxy bromide methyl ester 29b (Co₂(CO)₈; BF₃·Et₂O; CAN) afforded 29c (31%) and 29d (39%). Treatment of 29d over few steps afforded tetrahydropyran 29h (72%, 5 : 1 dr), which was later converted to aldehyde 29i (70% overall). Analogously, 29j and acetylene 29k were also subjected to cobalt catalysis under similar conditions to afford 29l (25%) and 29m (43%), leading to compound 29n (80%) over few steps. Similarly, 29o and hydroxy acetylene 29p gave 29q (31%) and 29r (38%) upon cobalt-catalyzed Nicholas etherification followed by conversion of 29r to compound 29s (55%). Next, coupling of 29e and 29i afforded 29t, which was reacted over several steps to afford the synthesis of halichondrin B 29u (Scheme 29).¹⁷⁰

Scheme 29 Total synthesis of halichondrin B 29u (adapted from ref. 170).

2.5 Synthesis of glycoside based natural products

2.5.1. Varitriol. Varitriol is a vinyl C glycoside with encouraging properties against several cell lines linked to cancer. C-Glycosides, valued for their biological activities and important in vivo stability, serve as significant motifs in natural products and drug design. Wang et al. in 2025 prepared varitriol 30c via cobalt-catalyzed hydroglycosylation of a terminal alkyne, employing a bench-stable ortho-iodobiphenyl (oIB) sulfide as glycosyl donor. In this stereoconvergent process, a cobalt hydride, formed by the reaction of the Co(I) pre-catalyst with (EtO)₃SiH, underwent reaction with the terminal alkyne with cis selectivity. The resulting vinylcobalt intermediate was made to react with the oIB donor to produce alkene intermediate and an aryl radical that initiated an intramolecular S_H2 cyclization to release the glycosyl radical intermediate, whose recombination with alkene intermediate generated Co(III) species, whose subsequent reductive elimination from Co(III) delivered the E-configured vinyl α-C-glycoside along with the regeneration of Co(I). The less bulky bis(oxazoline) ligand L9 is critical for regioselectivity outcome, as smaller bis(oxazoline) ligands gave appreciable quantities of 1,1-disubstituted regioisomers by-products. Coupling of oIB sulfide 30a with aryl alkyne 30b using CoI₂ (10 mol%), L9 (12 mol%), (EtO)₃SiH (3.0 equiv.), K₃PO₄·H₂O (3.0 equiv.) in DME at rt for 12 h under N₂ atmosphere, followed by ester hydrolysis (LiOH, MeOH, rt, 1 h), afforded varitriol 30c in 36% overall yield (Scheme 30).¹⁷¹

Scheme 30 Total synthesis of varitriol 30c (adapted from ref. 171).

2.5.2. Fortimicin B. Fortimicin B belongs to a distinctive subgroup of aminoglycosides obtained from Micromonospora species, characterized by its unusual pseudodisaccharide framework.^172–174 Among its analogs, fortimicin B shows potent antibacterial activity with far lower kidney and ear toxicity, making it a promising scaffold for developing next-generation aminoglycoside antibiotics. In 2025, Lu et al. completed the asymmetric total synthesis of fortimicin B in 12 steps. The key cobalt-catalyzed step was a Cr(II)/Co(I)-mediated C–C bond coupling, based on the Takai–Utimoto protocol (CrCl₂, 4 equiv.; vitamin B₁₂, 20 mol%; DMF, 30 °C). This mild radical coupling replaced prior routes to access 6-epi-purpurosamine B fragment (up to 16 steps or 20 kbar pressure). Cu(II)-catalyzed IEDDA reaction of 31a and 31b gave 31c (98%, 97%ee), which was treated over few steps to achieve glycosyl acceptor 31d. Cr(II)/Co(I) coupling of aldehyde 31e and alkyl bromide 31f were treated via cobalt-catalyzed Takai and Utimoto's protocol involving CrCl₂ and vitamin B12 followed by Swern oxidation that delivered ketone 31g (59%, two steps). The resulting ketone was treated over few steps to give glycosyl donor 31h. Next, Au(I)-catalyzed glycosylation 31d and 31h afforded 31i (76%, α : β = 6 : 1), which was treated over some steps to accomplish the synthesis of desired natural product i.e., fortimicin B 31j (76%) (Scheme 31).¹⁷⁵

Scheme 31 Total synthesis of fortimicin B 31j (adapted from ref. 175).

2.6 Synthesis of flavagline

2.6.1. Rocaglaol. Rocaglaol belongs to the flavagline family, whose members share a compact cyclopenta[b]benzofuran core bearing four to five contiguous stereocentres. It exemplifies this complexity while exhibiting diverse biological properties, for example anti-inflammatory, antiviral, and anticancer activities.¹⁷⁶ Notably, the benzofuran scaffold continues to inspire novel synthetic methodologies, exhibiting promising biologically active properties such as anti-HCV and anti-cancer activities.^177,178 Xu et al. in 2022, described a stereodivergent synthesis of eight rocaglaol stereoisomers via synergistic Co(II)(or Ni(II))/Ir dual catalysis. The chiral N,N′-dioxide–Co(II) complex enabled activation of the benzofuranone via Lewis acid-promoted enolization, while the activation of allylic electrophile was carried out by Ir-mediated oxidative addition, resulting in Ir-π-allyl species. Co(II) was found to be better than Cu-based catalysts (which gave 54% yield with 1.1 : 1 dr). Benzofuranones 32a (R = Br) or 32b (R = OMe) were reacted with carbonate 32c, Co(BF₄)₂·6H₂O (10 mol%), L11-PiPr₂ (10 mol%), (Ir(cod)Cl)₂ (2 mol%), K₂CO₃ (1.3 equiv.), DCM/DCE (1 : 1), 35 °C: (S_a,S,S)-L12 to afford 32d (97%, 2 : 1 dr) and employment of (R_a,R,R)-L11 gave 32e (96%, 2 : 1 dr). The resulting compounds 32d and 32e were independently treated over few steps to synthesized rocaglaol 32f (58%, 19 : 1 dr) and 32g (55%, 19 : 1 dr), respectively (Scheme 32).¹⁷⁹

Scheme 32 Total synthesis of rocaglaol 30f and ent-rocaglaol 32g (adapted from ref. 179).

2.7 Total synthesis of pharmaceutically active compounds

2.7.1. PARP inhibitor PJ-34. PJ-34 functions by inhibiting PARP (poly (ADP-ribose) polymerase), a small molecule with therapeutic potential in oncology and neuroprotection. Ling and co-workers in 2018 efficiently synthesized PARP inhibitor PJ-34 via 3-step sequence started from compound 33a which underwent cobalt(II)-catalyzed oxidative cyclization, featuring a Co(II)-catalyzed intramolecular C–H functionalization/carbonylation that directly constructs the phenanthridinone ring system. This strategy eliminates the need to use both toxic CO gas and stoichiometric metal oxidants (Ag or Mn salts), required in all previously reported Co-catalyzed C–H carbonylation methods, to form intermediate 33b in 95%. The second step involved nitration of 33b with HNO₃ followed by reduction using Fe/HCl to achieve compound 33c in 76% yield. In the final step, coupling of 33c with N,N-dimethylglycine via EDC, HOBt, and DIPEA in DMF furnished PJ-34 33d in 87% yield (Scheme 33).¹⁸⁰

Scheme 33 Total Synthesis of PARP inhibitor PJ-34 33d (adapted from ref. 180).

2.7.2 MK-0371. MK-0371, a potent inhibitor of the kinesin spindle protein, was synthesized by Wu and coworkers in 2018. They demonstrated the utility of Co(II)/bisoxazoline-catalyzed asymmetric allylation of cyclic ketimines with the synthesis of a key intermediate for MK-0731. The synthesis of MK-0371's intermediate was accomplished via highly enantioselective cobalt-catalyzed coupling. The initial step involved the reaction of ethyl ester sulfonamide 34a with potassium allyl trifluoroborate 34b in the presence of cobalt catalyst Co(ClO₄)₂·6H₂O to afford intermediate 34c in 95% with 99%ee enantiomeric excess. Subsequent reduction of 34c using LiAlH₄ in THF followed by acetylation with trichloro acetyl chloride and Et₃N furnished compound 34d in 99% yield with 99%ee. Then the treatment of 34d with sodium naphthalide at room temperature formed compound 34e in 51% yield with 99%ee. Finally, 34e was converted to MK-0371 34f via several synthetic steps (Scheme 34).¹⁸¹

Scheme 34 Total synthesis of MK-0731 34f (adapted from ref. 181).

2.7.3. BET inhibitor A and B. Ying et al. developed a cobalt-catalyzed C–H carbonylation of naphthylamides using TFBen as a CO source and applied this approach to synthesize BET inhibitors A and B.¹⁸⁰ The cobalt system afforded free (NH)-products directly, unlike the PdCl₂/Cu(OAc)₂ system which required gaseous CO/O₂ and only afforded N-alkyl products (37–71%). In the catalytic cycle, Co(II) is oxidized to Co(III) by Ag(I), enabling C8–H activation; CO coordination and reductive elimination form the Co[I] complex, and subsequent hydrolysis released the product, while Co(I) is reoxidized to regenerate the catalyst. On gram scale, naphthylamide 35a was treated with TFBen (1.75 equiv.), CoCl₂ (30 mol%), Ag₂CO₃ (2.5 equiv.), PivOH (1 equiv.), and Et₃N (3 equiv.) in 1,4-dioxane under N₂ at 130 °C for 20 h, furnishing 35b in 60% yield. N-Alkylation (CH₃CH₂I, NaH, DMF, rt) of 35b gave 35c. For BET inhibitor B, 35c was subjected to nitration, iron reduction, and sulfonamide formation to afford 35d in 50% yield (three steps). Furthermore, 35c also underwent chlorosulfonation and reaction with pyrrole/DiPEA to furnish BET inhibitor A 35e in 55% yield (two steps) (Scheme 35).¹⁸²

Scheme 35 Total synthesis of BET inhibitor A 35e and BET inhibitor B 35d (adapted from ref. 182).

2.7.4. Nirmatrelvir. Nirmatrelvir, marketed as part of Paxlovid with ritonavir, is a tripeptide like inhibitor targeting the SARS-CoV-2 main protease. Shekhar et al. used Co(II)-catalyzed reductive dimethylcyclopropanation as the key step to introduce the gem-dimethylcyclopropane-fused proline core that enhanced protease inhibitory potency.¹⁸¹ Mesylation of hydroxy proline benzyl ester 36a followed by selenylation with diphenyl diselenide and NaBH₄ afforded selenide 36b in 78% yield. Oxidative elimination of selenide 36b with H₂O₂/pyridine then afforded alkene 36c (75%). Co(II)-catalyzed dimethylcyclopropanation of 36c using CoBr₂(2-tBuPDI), Zn, 2,2-dichloropropane and ZnBr₂ in dry THF at 25 °C (60 h) resulted in bicyclic amino acid 36d (68%). Furthermore, Boc deprotection of amino acid 36d with 4 N HCl in 1,4-dioxane at 0 °C gave amine hydrochloride 36e, which over several steps afforded nirmatrelvir 36f (Scheme 36).¹⁸³

Scheme 36 Total synthesis of nirmatrelvir 36f (adapted from ref. 183).

2.7.5. (S)-Pazinaclone and (S)-PD172938. (S)-PD172938 is a selective dopamine D4 receptor ligand, having notable pharmacological relevance. In contrast, (S)-pazinazclone, has been explored as benzodiazepine receptor agonist for the management of the anxiety disorders.¹⁸⁴ Teng et al. in 2024, demonstrated the first cobalt-catalyzed enantioselective C–H carbonylation by preparing both targets from common intermediate 37b. Kinetic resolution of 37a with CoCl₂ (10 mol%), Salox ligand L12 (15 mol%), AgNO₃ (2.0 equiv.), and NH₄OAc (1.5 equiv.) under CO (1 atm) (used as C1 source) in DCE at 60 °C for 60 h, gave 37b in 41% yield with 95%ee. Mesylation of 37b followed by substitution reaction with 6,7-dimethyl-1,2,3,4-tetrahydroisoquinoline gave (S)-PD172938 37e (84%, 94%ee). Next, oxidation reaction of 37b and amide coupling with 1,4-dioxa-8-azaspiro[4.5]decane delivered 37c (59%, 95%ee over two steps) whose Buchwald–Hartwig coupling provided (S)-pazinaclone 37d (84%, 94%ee) (Scheme 37).¹⁸⁵

Scheme 37 Total synthesis of (S)-pazinaclone 37d and (S)-PD172938 37e (adapted from ref. 185).

2.7.6. (R)-(−)-Eliprodil. (R)-(−)-Eliprodil is the enantiomer of the neuroprotective drug eliprodil. Song et al. demonstrated its efficient synthesis in 2025. They described a four-step synthesis of 38e, including the first earth-abundant metal-catalyzed asymmetric hydrogenation of an α-hydroxy ketone. A nonredox Co(II) cycle is enabled with the use of an additive containing salicylic acid, which formed two hydrogen bonds with the substrate. Asymmetric hydrogenation of 38a (Co(OAc)₂ (6 mol%), (S,S)-Ph-BPE (5 mol%) with salicylic acid (10 mol%), H₂ (50 bar), toluene, 70 °C, 48 h) resulted in diol 38b (98% yield, 92%ee) followed by its tosylation (p-TsCl, DBTO, TEA, DCM, rt) to obtain 38c, whose base-mediated epoxidation (NaOH, Et₂O) afforded 38d. Finally, the ring-opening of 38d with 4-(4-fluorobenzyl)piperidine (i-PrOH, reflux, 4 h) delivered (R)-(−)-eliprodil 38e in 64% yield with 97%ee (Scheme 38).¹⁸⁶

Scheme 38 Total synthesis of (R)-(−)-eliprodil 38e (adapted from ref. 186).

3 Conclusion

The current review summarizes the applications of cobalt catalysis towards the synthesis of diverse classes of natural products and pharmaceutically active compounds, reported since 2018. Cobalt catalysis has made significant progress in the synthesis of natural products and biologically relevant compounds and has established itself as a crucial step for forming bonds between atoms within multi-step synthetic sequences. Diverse classes of natural products including alkaloids, terpenoids/diterpenoids, polyketides and macrolides along with glycoside-based natural products and several pharmaceuticals have been reviewed to be obtained by employing cobalt catalysis as one of the key steps in corresponding synthetic schemes. The thorough analysis unveiled that the asymmetric cobalt catalysis, involving the use of chiral ligands, led to significantly high yields of corresponding products with significant stereochemical control. Future research advances will likely require the development of more efficient asymmetric cobalt-catalytic approaches, which are primed to deliver high levels of enantiomeric control for future synthetic and biologically active targets.

Conflicts of interest

The authors declare no conflicts of interest.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

Authors are thankful to the facilities provided by Government College University Faisalabad, Pakistan.

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