Yamaguchi esterification: a key step toward the synthesis of natural products and their analogs—a review

The Yamaguchi reagent, based on 2,4,6-trichlorobenzoyl chloride (TCBC) and 4-dimethylaminopyridine (DMAP), is an efficient tool for conducting the intermolecular (esterification) reaction between an acid and an alcohol in the presence of a suitable base (Et₃N or ⁱPr₂NEt) and solvent (THF, DCM, or toluene). The Yamaguchi protocol is renowned for its ability to efficiently produce a diverse array of functionalized esters, promoting high yields, regioselectivity, and easy handling under mild conditions with short reaction times. Here, the recent utilization of the Yamaguchi reagent was reviewed in the synthesis of various natural products such as macrolides, terpenoids, polyketides, peptides, and metabolites.

1 Introduction

Ester linkage is the cornerstone of modern synthetic chemistry for containing carbonyl functionality and the structural part of most of the precursors in the synthesis of medicinally important natural and synthetic compounds (Haslam, 1980). Apart from the pharmaceutical industry, other industries (such as textile, cosmetics, fragrance, pesticides, fungicides, and coatings) are also dependent on the ester linkage-based synthetic intermediates. Therefore, esterification is an eminent conversion reaction that is usually performed between acid chloride and alcohol, acid anhydride and alcohol, or carboxylic acid and alcohol (Khan et al., 2021). With the profound interest in the ester linkage, several methodologies have been developed, and the most common methodologies are the Mitsunobu reaction (Munawar et al., 2022), Fischer esterification (involving a Lewis acid as the catalyst) (Joseph et al., 2005), Steglich esterification [usually takes place in the presence of DCC, 4-dimethylaminopyridine (DMAP), and DCM) (Munawar et al., 2024), and Yamaguchi protocol (Inanaga et al., 1979). Each of these methods have their limitations; for example, Fischer esterification is a slower reaction and provides a low yield of product (Khan et al., 2021), whereas Steglich esterification utilizes toxic carbodiimide (Jordan et al., 2021). Steglich and Yamaguchi’s methods are distinguished for the use of DMAP as a strong nucleophilic base. Among others, Yamaguchi esterification is a leading and beneficial tool for esterification and has gained significance in the regioisomeric synthesis of macrolides and many other natural products (Majhi, 2021).

The Yamaguchi coupling protocol was first developed by Masaru Yamaguchi et al. (in 1979) during the synthesis of ester (Inanaga et al., 1979). This methodology was mainly based on the reaction between acids and alcohols in the presence of 2,4,6-trichlorobenzoyl chloride (TCBC), with DMAP as the coupling agent and Et₃N as the base, providing corresponding esters in moderate-to-good yield. Later, this procedure was extended for the synthesis of a variety of macrolactones. The most commonly used solvents are THF, toluene, and DCM to smoothly furnish both primary and secondary esters. Yamaguchi esterification ensures wide substrate scope, mild conditions, and the formation of a regioselective product in moderate-to-good yield. Side by side, Yamaguchi esterification also has disadvantages of less reactivity of TCBC (due to its steric environment), decomposition of the substrates, or poor yield in the case of the total synthesis of very few compounds. Still, this reaction has a wide scope and has been extended to the synthesis of a variety of macrolactones with no epimerization of stereochemistry. The reaction usually takes place either in a single step (direct reaction of carboxylic acid and alcohol) or in two steps (via the formation of acid anhydride from carboxylic acid and 2,4,6-trichlorobenzoyl chloride, followed by the attack of alcohol). The two-step method has previously been reported for the synthesis of various lactones of a large ring size, such as 2,4,6-tridemethyl-3-deoymethynolide. The original Yamaguchi procedure was based on a two-step methodology that was later modified as a one-pot (single-step) reaction by Hikota et al. (1990). The detailed mechanistic pathway of this reaction was studied by Dhimitruka and SantaLucia, and the methodology was successfully used for the formation of a Lux-S aspartic acid suppressant. In their investigative studies, benzoyl chloride, p-tolyl chloride, and TCBC as an electrophile were used, and the formation of the regioselective product was confirmed only with 2,4,6-trichlorobenzoyl chloride (Yamaguchi reagent), which is the key feature of this esterification reaction (Dhimitruka and SantaLucia, 2006). As shown in Figure 1, the carboxylic acid after deprotonation (via the involvement of a base) provides the carboxylate. The coupling of this carboxylate with 2,4,6-trichlorobenzoyl chloride leads to the formation of an anhydride, which, after further coupling with another carboxylate, results in acid anhydride (Park et al., 2022). In the next step, the addition of DMAP results in the formation of pyridinium salt, followed by the nucleophilic attack of the base, which leads toward the formation of the desired ester.

Figure 1

Figure 1. General reaction and proposed mechanism of the Yamaguchi coupling reaction.

In 2014, a commendable strategy for esterification was introduced by Okuno et al. via the use of 2,4,6-trichlorobenzoyl-4-dimethylaminopyridinium chloride as a modified Yamaguchi reagent (Okuno et al., 2014). This TCB-DMAP reagent was prepared (in 90% yield) simply by a reaction between TCBC and DMAP in the presence of THF. It facilitates esterification for broad substrate groups, avoiding the formation of anhydride and can be stored for many years (Yamamoto and Muramatsu, 2019). In 2016, Nishio et al. synthesized a recoverable fluorous Yamaguchi reagent for the efficient esterification of several benzoic acids with alcohols (Nishio et al., 2016) (Supplementary Figure 1).

In addition to esterification and macro-lactonization, the Yamaguchi reagent is much significant for many other organic reactions, especially for the synthesis of carboxylic acid derivatives (Radha Krishna et al., 2022; Mukhopadhyay and Trauner, 2022). For instance, Chandra et al. (2018) utilized their own modified Yamaguchi reagent for amidation, thioesterification, and peptide synthesis. Zulquranain et al. (2020) synthesized pyrazine-2-carboxylic acid derivatives (via the use of the Yamaguchi reagent) to be a cytotoxic agent against Mycobacterium tuberculosis (Zulqurnain et al., 2023). In natural product synthesis, the Yamaguchi reagent has been involved in the synthesis of biologically active compounds (Kotammagari, 2014; Wu et al., 2012; Valeev et al., 2019; Molawi et al., 2010), such as stagonolide C (a herbicide isolated from Cirsium arvense) (Wu et al., 2012), amphidinolide W (a marine dinoflagellate and a cytotoxic agent against the murine lymphoma cell line with IC₅₀ = 3.9 μg/mL) (Shimbo et al., 2002), palmerolide A (exhibits cytotoxicity against melanoma cell line UACC-62 and renal cancer cell line RXF 393) (Pujari et al., 2011), and xyolide (bioactive against Pythium ultimum, a plant pathogen) (Maram and Das, 2015) (Supplementary Figure 2). Fascinated by the synthetic utility of the Yamaguchi reagent, Majhi et al. published a review article on the application of Yamaguchi’s method in the synthesis of biologically potent natural products in 2021 (Majhi, 2021). However, an updated compilation of its recent application (2021–2023) in the synthesis of natural products has been presented here.

2 Review of the literature

2.1 Synthesis of natural macrolides

Esterification and macrolactonization are the commonly involved reactions in the construction of macrolides consisting of simpler to complex frameworks. Here, we present various examples, demonstrating the strong potential of the Yamaguchi reagent in the synthesis of 10–30 (ring size)-membered macrolides.

2.1.1 Synthesis of 10-membered macrolides

2.1.1.1 Reddy’s total synthesis of sumalactone A

Sumalactone A 10 is a 10-membered macrolactone that was isolated from Penicillium sumatrense, a marine fungus (Wu et al., 2017). This benzannulated macrolactone is famous for its numerous biological activities, such as anti-fungal, anti-cancer, and anti-inflammatory effects (Scheme 1) (Allu et al., 2019; Shahzadi et al., 2022). As an attractive target of various organic chemists, Reddy et al. (2022) performed the stereoselective synthesis of sumalactone A 10 using easily available inexpensive starting materials 1 and 2 (Reddy et al., 2022). The key steps in their synthetic part involve Yamaguchi esterification with the proper maintenance of stereochemistry of the reacting substrates. As illustrated in the scheme, acid 3 and alcohol 4 were successfully achieved from acid 1 and alcohol 2, respectively. Both the synthesized compounds, in hand, were subjected to esterification using a Yamaguchi reagent (2,4,6-trichlorobenzoyl chloride) in the presence of Et₃N, DMAP, and toluene, resulting in high (78%)-yielding ester 5. Furthermore, Grubb’s second-generation catalyst was used for the RCM reaction of ester 5, followed by its palladium-catalyzed reduction and deprotection in the presence of BBr₃ and DCM to finally afford sumalactone A 6 with 77% yield.

Scheme 1

Scheme 1. Synthesis of sumalactone A 10 and (−)-curvularin 11.

2.1.2 Synthesis of 12-membered macrolides

2.1.2.1 Radha Krishna’s total synthesis of (−)-curvularin

One of the 12-membered macrolides, curvularin, is a resorcylic acid lactone that is produced by various fungal sources, that is, Alternaria, Penicillium, and Curvularia. It exhibits diverse biological activities such as cell division prohibition and cytotoxicity against sea urchin embryogenesis (Zhan and Gunatilaka, 2005). With a great deal of interest, Radha Krishna et al. (2022) accomplished its total synthesis using Yamaguchi macrolactonization as a crucial step. For achieving the targeted product, (3,5-dimethoxyphenyl)acetic acid 7 was used as an easily available starting material to build compound 8. Next, compound 8 was subjected to a well-suited Yamaguchi reagent, leading to the formation of compound 9 with 74% yield. After this, the removal of the 1,3 dithiane group and deprotection of methyl ester groups in ester 9 resulted in the synthesis of (−)-curvularin 10 with 75% yield (Scheme 1).

2.1.2.2 Chambers’s total synthesis of 10-deoxymethynolide

Enones are unique synthetic intermediates that have widespread applications in the synthesis of many biologically active natural products. An enone, 10-deoxymethynolide contains a popular polyketide macrolide, having four stereogenic centers, and is expected to be a medicinally important natural product (Wei and Shi, 2013). Chambers et al. (2023) accomplished the efficient 14-step total synthesis of 10-deoxymethynolide 15 by using ester 11 as an easily available enantioenriched starting material (Scheme 2) (Chambers et al., 2023). The settlement of four stereocenters in the target compound was no doubt a challenging task that was successfully made possible using the Yamaguchi protocol. To set the stage for the Yamaguchi esterification protocol, the modification of compound 11 (over a few steps) into compound 12, followed by treatment with compound 13 in the presence of TCBC, triethyl amine (Et₃N), DMAP, and toluene, successfully furnished ester 14 with 56% yield. Next, the ring closure reaction of compound 14 using Grubb’s second-generation catalyst and subsequent desilylation completed the total synthesis of 10-deoxymethynolide 15 with 34% yield.

Scheme 2

Scheme 2. Synthesis of 10-deoxymethynolide 15 and pladienolide B 23.

2.1.2.3 Yoo and Krische’s total synthesis of pladienolide B

Pladienolides are 12-membered macrolides isolated from Streptomyces platensis in 2004. Owing to their anti-proliferative activity in multi-resistant human tumor cells, this unique family of natural products is gaining prominence as anti-cancer pharmacodynamics in medicinal chemistry (Sakai et al., 2004; Villa et al., 2012). To date, various synthetic reports on the synthesis of pladienolide derivatives have been published. Pioneering this groundbreaking endeavor, Yoo and Krische (2021) devised a robust and economical synthetic route for the synthesis of pladienolide B 23 (consisting of 10 stereogenic centers) in just 10 steps (Scheme 2) (Yoo and Krische, 2021). The salient feature of their synthesis lies in the strategic use of the Yamaguchi method as the leading tool for esterification. To set the stage for Yamaguchi esterification, compound 16 was turned into acid 17 over a few steps. Compound 17, in hand, was allowed to get esterified with fragment 18 in the presence of TCBC, Et₃N, DMAP, and THF to result in ester 19 with 63% yield. In the next step, the ring-closing metathesis of compound 19, followed by acetylation, resulted in compound 20 with 67% yield. Moving toward the final step, compound 20 was made to couple with compound 22 (from compound 21) under Suzuki conditions to successfully accomplish the target pladienolide B 23 with 65% yield.

2.1.3 Synthesis of 14-membered macrolides

2.1.3.1 Meyer’s total synthesis of amphidinolide R

Amphidinolides are cytotoxic macrolides, and these were isolated from Amphidinium sp. marine dinoflagellates by Kobayashi et al.. Structurally, amphidinolide R is 14-membered, while amphidinolide J and amphidinolide S are 15-membered macrolides (Ishibashi and Kobayashi, 1997; Shotwell and Roush, 2004). Meyer et al. (2023) accomplished the diastereoselective and enantioselective synthesis of amphidinolide R 28 (9 steps) and amphidinolide J 29 (9 steps), along with the first total synthesis of amphidinolide S 30 (10 steps). The achievement of the desired stereochemistry in the products was assured via the use of Yamaguchi esterification as a powerful step (Scheme 3) (Meyer et al., 2023). Their methodology involved the independent synthesis of fragments 25 and 27 from compounds 24 and 26, respectively. Then, fragments 25 and 27 were subjected to esterification using the Yamaguchi protocol in the presence of diethyl amine, TCBC, Et₃N, and THF. The esterified intermediate was then subjected to Grubb’s second-generation catalyst and DDQ, followed by corresponding work procedures under given conditions to furnish amphidinolide R 28 in 78% yield.

Scheme 3

Scheme 3. Synthesis of amphidinolide R 28, amphidinolide J 29, and amphidinolide S 30.

2.1.3.2 Nakazato’s total synthesis of (+)-neopeltolide

The tetrahydropyran ring is present in most biologically important natural products. One of the tetrahydropyran rings containing a natural product, (+)-neopeltolide 40, is a 14-membered macrolide, consisting of a lactone ring associated with a 2,4,6-trisubstituted tetrahydropyran scaffold. It was isolated from a deep-water sponge in Jamaica by Wright et al. (2007). It exhibits cytotoxic activity against A549 (human lung adenocarcinoma cells) and NCI-ADR-RES (human ovarian sarcoma cells) with IC₅₀ values of 1.2 nM and 5.1 nM, respectively. Furthermore, it also exhibits growth inhibition against Candida albicans with a MIC value of 0.62 μg/mL (Ulanovskaya et al., 2008; Bai and Dai, 2015). With these distinctive medicinal features, this scaffold has been the focus of various researchers, and more than 20 reports on its synthesis have been documented. Continuing with the ongoing effort, Nakazato et al. (2022) performed the 11-step total synthesis of (+)-neopeltolide 40 (with 12% overall yield) via Yamaguchi esterification of intermediates 32 and 34 as the key step (Scheme 4) (Nakazato et al., 2022). In their synthetic methodology, compounds 32, 34, and 37 were prepared from starting materials 31, 33, and 36, respectively. After this, the Yamaguchi esterification of compounds 32 and 34 in the presence of TCBC, Et₃N, DMAP, and TsOH successfully furnished ester 38 (with 90% yield) as a precursor for the construction of the 14-membered anti-cancer macrolide. Ester 38 then underwent a sequence of Meyer–Schuster rearrangement, Zhan-catalyzed RCM reaction, and Michael addition to result in tetrahydropyran 39 with 69% yield. Next, compound 39 was subjected to Zn-mediated methylenation, hydrogenolysis, and subsequent Mitsunobu coupling with compound 37 to afford the desired natural product 40 with 94% yield.

Scheme 4

Scheme 4. Synthesis of (+)-neopeltolide 40.

2.1.3.3 Depa’s total synthesis of neocosmosin A

Resorcyclic acid lactones are well known in the medicinal world for their remarkable biological profile as they exhibit estrogenic, cytotoxic, nematocidal, anti-viral, and anti-fungal biological activities (Patocka et al., 2013; Hellwig et al., 2003; Abid-Essefi et al., 2004). The 14-membered macrolides, neocosmosin A 47 and neocosmosin B 51, are resorcyclic acid lactones according to their structural composition. These were isolated in 2012 from Neocosmospora sp. of a fungal strain. Neocosmosin A 47 possesses an affinity for binding with human cannabinoid and opioid receptors (Gao et al., 2013). Depa et al. (2021) performed the efficient (14-step) total synthesis of this natural product using propylene oxide 41 and 4-methoxy salicylic acid 43 (as easily available starting materials) with a 4.45% overall yield (Scheme 5) (Depa et al., 2021). The construction of this targeted natural product with the desired stereochemistry entails Yamaguchi macrolactonization as a crucial step. The methodology involved the coupling of bromide 42 and dithiane 44, followed by hydrolysis and desilylation to furnish hydroxy acid 45 with 91% yield. Next, the Yamaguchi protocol was used for the esterification of acid 45 by treating it with TCBC, Et₃N, THF, DMAP, and toluene, which resulted in compound 46 with 66% yield. Proceeding toward the last stage of the total synthesis, the dithiane group was removed via the treatment of lactone 46 with calcium carbonate and methyl iodide, followed by TiCl₄-mediated deprotection to successfully afford neocosmosin A 47 with 78% yield.

Scheme 5

Scheme 5. Synthesis of neocosmosin A 47 and neocosmosin B 51.

2.1.3.4 Kumari’s total synthesis of neocosmosin B

Kumari et al. (2022) reported the first total synthesis of neocosmosin B 51 in 12 steps by using Yamaguchi macrolactonization as a key step (Scheme 5) (Kumari et al., 2022). Their synthesis commenced with easily available orsellinic acid 48, which, over a few steps, provided compound 49. In the following step, the Yamaguchi reagent was used for the macrolactonization of hydroxyl acid 49 by treating it with TCBC, Et₃N, THF, and then with DMF and toluene to finally furnish lactone 50 with 64% yield. Finally, the removal of dithiane groups and demethoxylation of lactone 50 successfully furnished the desired neocosmosin B 51 with 74% yield.

2.1.3.5 Dissanayake’s total synthesis of sanctolide A

Sanctolide A 57 is a 14-membered polyketide and peptide-based macrolide. It was isolated in 2012 by Orjala et al. from Oscillatoria sancta, a cyanobacterium (Kang et al., 2012). The structural framework of this hybrid scaffold comprises an N-methyl-substituted macrocyclic diester attached with a lipophilic side chain. With these significant structural features, this natural product is expected to show promising pharmaceutical effects. Dissanayake et al. (2023) performed both the total and formal syntheses of sanctolide A 57 by using Yamaguchi esterification as the main step (Scheme 6) (Dissanayake et al., 2023). As shown in Scheme 6, alcohol 53 (synthesized from compound 52 in several steps) was made to react with 2,4,6-trichlorobenzoyl chloride and diisopropylethylamine in THF. Then, carboxylic acid 55 (prepared from the reaction of isovaleric acid 54 and acryloyl chloride) was added to complete the esterification process in the presence of DMAP and toluene, resulting in ester (R)-56 with 78% yield. Hence, the coherence of stereochemistry in the reactants (alcohol 53 and acid 55) and the product (ester 56) highlights the success of choosing the Yamaguchi reagent for the esterification process. In the following step, the RCM reaction of ester (R)-56 and the subsequent treatment with (PPh₃)₃RuH(CO)Cl furnished the desired sanctolide A (R)-57 with 51% yield.

Scheme 6

Scheme 6. Synthesis of sanctolide A 57.

2.1.4 Synthesis of 15-membered macrolides

2.1.4.1 Meyer’s total synthesis of amphidinolide J and amphidinolide S

As mentioned previously, Meyer et al. (2023) accomplished the synthesis of amphidinolide R 28 and amphidinolide J 29 and the first total synthesis of amphidinolide S 30. Their simple and facile methodology involved the Yamaguchi esterification of compounds 25 and 27 and subsequent treatment with Grubb’s second-generation catalyst to furnish amphidinolide J 29 with 61% yield. Next, the MnO₂-induced oxidation of amphidinolide J 29 led to the formation of amphidinolide S 30 with 51% yield (Scheme 3).

2.1.4.2 Lai and Dai’s total synthesis of palmyrolide A

One of the neuroactive 15-membered macrolides, palmyrolide A, was isolated from an assembly of marine cyanobacteria consisting of Oscillatoria spp. and Leptolyngbya cf. It exhibits Ca influx suppression in cerebrocortical neurons (with an IC value of 3.70 μm) and Na channel suppression (with an IC value of 5.2 μm) (Pereira et al., 2010; Tan, 2007). Based on these captivating aspects, Lai and Dai (2021) enclosed the total synthesis of (−)-palmyrolide A 64a and (+)-5,7-epi-palmyrolide A 64b (Scheme 7) (Lai and Dai, 2021). Their multi-module strategic route toward synthesizing diasteroisomeric macrolides used Yamaguchi esterification as the main step. First, compounds 60 and 61 were subjected to the Negishi coupling reaction (in the presence of Pd(OAc)₂, Aphos-Y, and THF), followed by hydrolysis to provide acid 62 with 60% yield. In the next steps, acid 62 was esterified with alcohol 59 (from starting material 58) using a well-suited Yamaguchi protocol (TBSCl, ⁱPr₂Net, DMAP, and THF) to obtain an inseparable mixture of esters 63a and 63b with a combined yield of 71%. Furthermore, the ring-closing metathesis of compounds 63a and 63b (in the presence of Grubb’s second-generation catalyst) and subsequent treatment with RuH(PPh₃)₃(CO)Cl successfully provided (−)-palmyrolide A 64a and (+)-5,7-epi-palmyrolide A 64b with a combined yield of 42%.

Scheme 7

Scheme 7. Synthesis of (−)-palmyrolide A 64a, (+)-5,7-epi-palmyrolide A 64b, and (−)-vermiculine 70.

2.1.5 Synthesis of 16-membered macrolides

2.1.5.1 Liu’s total synthesis of vermiculine

(−)-Vermiculine 70 is a 16-membered macrodiolide and was first isolated from Penicillium vermiculatum in 1972 by Kuhr et al. (Fuska et al., 1972). It holds significant medicinal importance owing to its anti-cancer, anti-protozoal, and immunomodulatory biological effects (Fuska et al., 1972; Fuska et al., 1974; Horáková et al., 1976). Liu et al. (2021) devised a highly flexible and efficient synthetic route for the synthesis of (−)-vermiculine 70 (as well as its analogs) in 14 steps and 9% overall yield (Scheme 7) (Liu et al., 2021). The cornerstone of their synthetic scheme lies in the utilization of Yamaguchi esterification (for the efficient ligation of compounds 65 and 66) and Yamaguchi macrolactonization (for cyclization toward the construction of the 16-membered macrolide) as key steps. In their synthetic path, compounds 65 and 66 were subjected to Yamaguchi esterification in the presence of TCBC, diisopropyleyhylamine (DIPEA), DMAP, and DCM to achieve compound 67 with 94% yield. Dimer 67 was subjected to hydrolysis and TBS group removal to yield acid 68 (in 95% yield), which was proceeded further for macrolactonization under the Yamaguchi conditions, resulting in macrodiolide 69 with 80% yield. The oxidation of macrodiolide 69 in the presence of PdCl₂, O₂, and Cu(OAc)₂, followed by PMB group removal and its Dess–Martin oxidation, resulted in the desired vermiculine 70 with 83% yield.

2.1.5.2 Schmidt’s total synthesis of berkeleylactone A

One of the 16-membered macrolides, berkeleylactone A 77, was isolated from a fungal strain. It is a famous anti-biotic that exhibits a strong anti-microbial effect against multi-drug resistant S. aureus (Stierle et al., 2017; Michel et al., 1977; Vakiti et al., 2022). Schmidt et al. (2023) disclosed a novel synthetic route toward the synthesis of berkeleylactone A 77 and its analog 78 via easily accessible intermediate 76 (Scheme 8) (Schmidt et al., 2023). The whole methodology was started from alkyne 71, which was reacted with propylene epoxide (under the given conditions) and then subjected to an alkyne zipper reaction, followed by treatment with potassium tertiary butoxide to result in alcohol 72 with 98% yield. In the next step, Yamaguchi esterification took precedence over Steglich esterification for furnishing ester in high yield as the substrate for te RCM reaction. Thus, the esterification of alcohol 72 with acid 73 was well managed with the exposure of the Yamaguchi reagent (TBSC, Et₃N, and DMAP) in toluene as the solvent provided access to ester 74 with 94% yield. The dihydroxylation of compound 74 using AD-mix-α and subsequent acetonide protection resulted in compound 75 (in 99% yield), which was transformed into compound 76 over a few steps. Compound 76 was exposed to Rosenmund’s catalyst for hydrogenation and deprotection using TFA, resulting in berkeleylactone A 77 with 87% yield, while its analog was acquired by the direct deprotection of compound 76. After the successful synthesis of both natural product 77 and its analog 78, both of these were subjected to biological analysis against various bacterial and fungal strains, that is, S. aureus, Candida glabrata, C. albicans, Enterococcus faecalis, and Enterococcus faecium. Both compounds exhibited average-to-good anti-microbial effects against these strains.

Scheme 8

Scheme 8. Synthesis of berkeleylactone A 77 and its analog 78.

2.1.5.3 Kumari’s total synthesis of aspergillide D

Aspergillide D 82 is a 16-membered macrolide that was isolated from a fungal strain of Aspergillus sp. SCSGAF 0076. Its first total synthesis was performed by Mohapatra et al. in 2017 (Jena et al., 2017). After that, many reports on the total synthesis of this natural product have been published, with a common issue of low yield. Kumari et al. (2023) presented a high-yielding 15-step synthetic scheme for the synthesis of aspergillide D 82 via an epoxide ring-opening reaction (Ahmad et al., 2018) and Yamaguchi macrolactonization as the main steps (Scheme 9) (Kumari et al., 2023). In their synthesis, 3-butene-1-ol 79, as a readily available compound, was utilized to produce hydroxy acid 80. In order to perform macrolactonization, hydroxy acid 80 was treated with TCBC, Et₃N, and DMAP in toluene to furnish highly regioselective lactone 81 with 67% yield. In the last step, deprotection was conducted in the presence of DDQ and DCM to produce the aspired aspergillide D 82 with 86% yield.

Scheme 9

Scheme 9. Synthesis of aspergillide D 82 and dysoxylactam A 87.

2.1.6 Synthesis of 17-membered macrolides

2.1.6.1 Yang’s total synthesis of dysoxylactam A

One of the 17-membered macrolide, dysoxylactam A 87, was isolated from Dysoxylum hongkongense. It is a macrocyclic lipopeptide, consisting of a C19-branched fatty acid (Liu et al., 2019). Owing to its potential to reverse the P-glycoprotein-mediated multidrug resistance in tumor cells, Chandankar et al. performed its first total synthesis in 2020, and after that, various researchers have performed its total synthesis (Chandankar and Raghavan, 2020). In the continuation of these studies, Yang et al. (2022) designed an easy and concise synthetic route toward the total synthesis of this attractive unprecedented natural product (Scheme 9) (Yang et al., 2022). Their synthesis was based on 12 steps, starting from 2-methylbutanal 83, and a 23.2% overall yield was acquired. After achieving compound 84 (from compound 83), the Yamaguchi reagent (TCBC), ⁱPr₂NEt, and DMAP played their role in its esterification with compound 85 to successfully produce ester 86 (in 91% yield) with no epimerization. After several steps, dysoxylactam A 87 was easily obtained from ester 86. The synthesized compound exhibited the cytotoxic activity in combination with vinorelbine (anti-cancer drug) with an IC₅₀ value of 3.5 nmol. L^‒1.

2.1.7 Synthesis of 18-membered macrolactones

2.1.7.1 Goda and Fuwa’s total synthesis of (−) enigmazole B

Among cytotoxic marine macrolides, enigmazoles were isolated from Cinachyrella enigmatica (Oku et al., 2010). (−)-Enigmazole A exhibits cytotoxic activity against a human cancer cell line, with GT₅₀ = 1.7 μm. The intriguing anti-cancer biological profile of the enigmazole family gained the attention of many organic chemists (Takada et al., 2023). With profound interest, Goda and Fuwa, (2023) performed the first total synthesis of (−)-enigmazole B 91 in 20 consecutive steps using Yamaguchi macrolactonization as a key step (Scheme 10) (Goda and Fuwa, 2023). Their methodology was commenced with the modification of compound 88 over a few steps to provide compound 89, which underwent macrocyclization via treatment with a well-suited Yamaguchi reagent in the presence of Et₃N, THF, DMAP, and toluene, resulting in macrolactone 90 with 93% yield. Next, macrolactone 90 underwent a sequence of DDQ-mediated deprotection (of the PMB group), phosphorylation, and K₂CO₃-mediated deprotection to successfully yield the desired natural product (−)-enigmazole B 91 with 89% yield.

Scheme 10

Scheme 10. Synthesis of (−)-enigmazole B 91 and sorangiolide A 97.

2.1.7.2 Sahana’s total synthesis of sorangiolide A

Sorangiolide A 97 is an 18-membered macrolide and a polyketide that was isolated by Jansen et al. from Sorangium cellulosum, a myxobacterial strain. Structurally, the heterocyclic cage of sorangiolide A 97 consists of four methylated centers, two trisubstituted olefins, and four hydroxylated centers. This natural product is renowned for its anti-bacterial activity against Staphylococcus aureus (a Gram-positive bacterium with a MIC value of 5–10 μg/mL) (Jansen et al., 1995; Irschik et al., 1995). Sahana et al. (2022) designed a convergent asymmetric synthetic tool for the first successful total synthesis of sorangiolide A 97 (0.9% overall yield) by using Yamaguchi esterification as a key step (Scheme 10) (Sahana et al., 2023). In their synthetic route, alcohol 93 (prepared from compound 92) was treated with triethyl amine, 2,4,6-trichlorobenzoyl chloride, DMAP, and toluene with the addition of acid 94. This Yamaguchi protocol successfully produced ester 95 with 79% yield. Compound 95 was then made to couple with aldehyde 96 (in the presence of sodium hydride and THF), followed by acetonoid group deprotection (by using PTSA) to provide the intermediate with 92% yield. After that, it was subjected to RCM and subsequent treatment with LiOH^.H₂O to successfully produce the target product 97 with 63% yield.

2.1.7.3 Salituro’s total synthesis of strasseriolides (A and B)

Strasseriolides (A and B) were first isolated in 2020 by Rayes et al. from the fungal strain of Strasseria geniculata (CF-247251) in New Zealand (Annang et al., 2020). Structurally, they are 18-membered macrolides having 2 trisubstituted alkenes, 5 methyl centers, and 1 free carboxylic acid group (Saha et al., 2020). Strasseriolide B shows anti-malarial potential against Plasmodium falciparum (the most virulent parasite) (Pérez-Moreno et al., 2016). Inspired by this fact, Salituro et al. (2022) reported a robust synthetic route for the first total synthesis of strasseriolide A 102 and strasseriolide B 103 in 15-step and 16-step sequences, respectively (Scheme 11) (Salituro et al., 2022). The methodology entails Yamaguchi esterification and the Nozaki–Hiyama–Kishi (NHK) reaction as key steps commencing from readily available starting materials, i.e., acid 98 and alcohol 99; both were explored for esterification under various protocols (EDCI, DCC, HBTU, and Shiina), but only the Yamaguchi method (TCBC, triethyl amine, and DMAP) was successful in the synthesis of the desired ester with 39% yield. The coupling intermediate underwent the NHK reaction to furnish compounds 100 and 101 with 73% combined yield (dr = 1.1:1). Compound 101 was oxidized in the presence of DMP, followed by hydrolysis, to produce strasseriolide A 102 with 64% yield. Furthermore, strasseriolide B 103 was easily acquired via the direct hydrolysis of compound 101, with 45% yield.

Scheme 11

Scheme 11. Synthesis of strasseriolide A 102 and strasseriolide B 103.

2.1.7.4 Sahana’s total synthesis of strasseriolide A

Pioneering the synthetic work on strasseriolides, Sahana et al. (2022) performed the total synthesis of strasseriolide A 102 in 22 steps with 1.0% overall yield (Scheme 11) (Sahana et al., 2022). In their synthesis, S-Roche ester 104 was used as the starting material, and Yamaguchi macrolactonization was used as a key step. After achieving compound 105 (from ester 104), it was allowed to undergo macrolactonization following the Yamaguchi protocol (as the leading tool) by using TCBC, Et₃N, DMAP, and toluene to obtain compound 106 (in 30% yield) with the desired stereochemistry. The whole synthetic scheme ended with the successful synthesis of strasseriolide A 102 (in 52% yield) by treating compound 106 with LiOH·H₂O.

2.1.8 Synthesis of 19-membered macrolides

2.1.8.1 Zhang’s total synthesis of 27-deoxylyngbyabellin A

Lyngbyabellins are two thiazole rings containing marine metabolites, which are famous for their anti-cancer pharmaceutical effects (Pirovani et al., 2015). A 19-membered macrolide, 27-deoxylyngbyabellin A 116 was first isolated from Lyngbya bouillonii (a marine cyanobacterium) (Matthew et al., 2010). It exhibits cytotoxic effects against HeLa cervical cancer cells and HT-29 colorectal adeno cancer cells with IC₅₀ values of 12 nM and 7.3 nM, respectively. Zhang et al. (2021) accomplished the total synthesis of 27-deoxylyngbyabellin A 116 in 10 consecutive steps with 9.7% overall yield (Scheme 12) (Zhang et al., 2021). Their efficient synthetic scheme began with the starting compounds 107 and 108, which were allowed to react in the presence of pentafluorophenyl diphenylphosphinate, PPh₃, and triethyl amine, followed by HCl-mediated Boc group removal and coupling with Boc-Gly-OH, which resulted in compound 109 with 68% yield. In the next step, compound 109 (after hydrolysis) was coupled with compound 111 (using DCC and DMAP), and the subsequent removal of allyl ester in the presence of morpholine and Pd(PPh₃)₄ produced acid 112. In the next step of esterification of acid 112 with alcohol 114, Keck esterification was attempted, but after its failure after a few attempts, the well-suited Yamaguchi reagent (2,4,6-trichlorobenzoyl chloride) was used in the presence of diisopropylethylamine as the base and THF as a solvent to result in the successful synthesis of ester 115 with 65% yield. After that, the TMSe and Boc groups were removed by treating ester 115 with TBAF and p-TsOH in a sequence, followed by its macrocyclization in the presence of diphenyl phosphorazidate and DMF to result in the successful synthesis of 27-deoxylyngbyabellin A 116 with 45% yield.

Scheme 12

Scheme 12. Synthesis of 27-deoxylyngbyabellin A 116.

2.1.9 Synthesis of 20-membered macrolides

2.1.9.1 Gosh’s total synthesis of iriomoteolide-1a and iriomoteolide-1b

Iriomoteolide-1a 126 and iriomoteolide-1b 127 are 20-membered macrolides that were isolated independently from the HY A024 strain of Amphidinium sp. (a dinoflagellate found in Japan) by Tsuda et al. (2007a) and Tsuda et al. (2007b). Both these natural marine products are structurally related to each other and are famous for their intriguing biological potential. In particular, iriomoteolide-1a exhibits cytotoxic activity against various human cell lines, that is, lymphocyte DG-75 and EBC-infected lymphocyte Raji cells with IC₅₀ values of 2 ng/mL and 3 ng/mL, respectively (Munir et al., 2023). Considering these interesting facts, Gosh et al. (2022) devised a robust synthetic route for the synthesis of (the proposed structures) these natural products by using Yamaguchi macrolactonization as the key step (Scheme 13) (Ghosh and Yuan, 2022). Their synthesis was initiated with the synthesis of key fragments 118 and 120 (from starting materials 117 and 119), followed by their coupling via the Julia–Kocienski reaction to result in olefin 121 with 83% yield. Olefin 121 (after benzyl group deprotection) was oxidized in the presence of DMP and NaHCO₃. As a result, the oxidized product was then coupled with sulfone 123 (from alcohol 122) via the Julia–Kocienski reaction, followed by PMB group and TBS group removal in sequence using DDQ and NaClO₂, yielding alcohol 124 with 72% yield. Next, the oxidation of alcohol 124 first with MnO₂ and second with NaClO₂ adjusted the stage for Yamaguchi macrolactonization as the resulting carboxylic acid was treated with TCBC, DIPEA, and DMAP to successfully furnish 20-membered macrolactone 125 with 61% yield. The next few steps involved the replacement of the TBS group with the TES group, bromocatecholborane-induced deprotection of the MOM group, TES-protected oxidation of the free hydroxyl group (by using DMP), and a final deprotection in the presence of HF/Py, which resulted in the desired natural products iriomoteolide-1a 126 (in 56% yield) and iriomoteolide-1b 127 (in 17% yield).

Scheme 13

Scheme 13. Synthesis of iriomoteolide-1a 126 and iriomoteolide-1b 127.

2.1.9.2 Bold’s synthesis of zampanolide analogs

The famous anti-cancer (−)-zampanolide 139 is a 20-membered macrolide, which was isolated from Fasciospongia rimosa by Tanaka and Higa (1996). This natural product was re-isolated by Field et al. from F. rimosa in 1996 (Field et al., 2009). The structural activity studies of this unique pharmacophore underscore the necessity of developing analogs to maintain a broad-spectrum medicinal library (Chen and Kingston, 2014). In 2021, Bold et al. synthesized morpholine analogs of (−)-zampanolide with the desired stereochemistry that was assured via the Yamaguchi reagent (Scheme 15) (Bold et al., 2021). The synthetic scheme was initiated from alcohol 128 that was subjected to tosylation and treatment with a base (KOH), followed by Jacobsen epoxidation and copper catalyst-induced hydrolysis to yield epoxide 130 with 65% yield and 99.5% ee. After the transformation of epoxide 130 into alcohol 131, it was reacted with epoxide 132 in the presence of butyl lithium and BF₃·OEt₂, providing compound 133 in 76% yield. In the next step, the tosyl group of compound 133 was removed via treatment with magnesium, which led to the formation of compound 134 with 85% yield. Compound 135 (with 96% yield) was achieved from the acylation of compound 134 in the presence of isopropenyl acetate. Meanwhile, the reaction of compound 134 with benzoyl chloride in the presence of triethyl amine and DCM provided benzamide 136 with 98% yield (Scheme 14). The Yamaguchi esterification of the synthesized compounds 135, 133, and 136 with alcohol 137 (in the presence of TCBC, TEA, DMAP, and THF) and the subsequent deprotection step resulted in the independent synthesis of compounds 138a–c with 78%–89% yields, which, after modification in some required steps, completed the synthesis of analogs 139a–c.

Scheme 15

Scheme 15. Synthesis of (−)-zampanolide analogs 139a–c.

Scheme 14

Scheme 14. Synthesis of compounds 135 and 136 toward the synthesis of (−)-zampanolide analogs.

2.1.9.3 Umana’s synthesis of (−)-zampanolide analog

In the continuation of work on (−)-zampanolide 139 analogs, Umana et al. (2023) developed a linear analog 139d of (−)-zampanolide as a potential anti-cancer agent (Scheme 16). The synthesis was commenced from alcohol 140, which was converted into compound 141 over a few steps. To set the stage for the incorporation of the side chain hemiaminal group, a challenging task with concern to attain the required configuration in the desired product, Yamaguchi esterification was preferred over any other step. Thus, alcohol 141 was made to undergo Yamaguchi esterification (with acid 142) by treating it with 2,4,6-trichlorobenzoyl chloride, triethyl amine, and DMAP to achieve ester 143 with 60% yield. Compound 143 was treated with methanol and HCl (for silyl group deprotection), followed by DMP-induced oxidation and installation of a hemiaminal side group (via reaction with compound 144), successfully producing the desired compound 139d with 40% yield.

Scheme 16

Scheme 16. Synthesis of (−)-zampanolide analog 139d–h.

2.1.9.4 Brutsch’s synthesis of (−)-zampanolide analogs

With the profound interest in the field of natural product synthesis, Brütsch et al. (2023) contributed their efforts to the synthesis of four desmethylene analogs of (−)-zampanolide 139d–h (Scheme 16). Among these, the synthesis of three analogs involves the use of the efficient Yamaguchi reagent. The compounds 145a–b were made to couple with compounds 146a–d (macrocyclization) under the presented Yamaguchi conditions (TCBC, Et₃N, DMAP, and toluene) to achieve the compounds 147a–d within the yield range of 74%–88%. Over a few steps, (−)-zampanolide analogs 139e–h were successfully attained from compounds 147a–d (Supplementary Figure 3).

2.1.9.5 Wender’s synthesis of bryostatin analogs

Bryostatin is a 20-membered polyketidic macrolide, which was isolated from Bugula neritina. It has various medicinal applications as it is used in the treatment of cancer, AIDS, Alzheimer’s disease, and many other degenerative diseases (Farlow et al., 2019; Gutiérrez et al., 2016). Considering the remarkable pharmacophore of bryostatin, Wender et al. (2022) introduced a novel strategy for the synthesis of its analog 152 (Scheme 17) (Wender et al., 2022). In their methodology, compound 149 (prepared from compound 148 in a few steps) esterified with alcohol 150 in the presence of a Yamaguchi reagent, Et₃N, DMAP, and toluene, to obtain ester 151 with 70% yield. The deprotection of ester 151 in sequential steps using PPTS and HF/Py successfully produced bryostatin analog 152 with 65% yield.

Scheme 17

Scheme 17. Synthesis of bryostatin analog 152.

2.1.10 Synthesis of 22-membered natural macrolides

2.1.10.1 Fritz’s total synthesis of pulvomycin D

A famous antibiotic, pulvomycin D, is a 22-membered macrolide that was isolated from Streptomyces sp. by Zief et al. (1957), and its structure was confirmed by Moon et al. (2020). This polyketidic macrolide also shows remarkable anti-cancer effects and has structural stability even under strong acidic and basic conditions (Kim et al., 1990). These interesting facts prompted Fritz et al. to perform its total synthesis in 2021 (Fritz et al., 2022). The synthesis of the precursor was achieved in consecutive steps with 0.23% overall yield via the use of a Yamaguchi reagent for the installation of the C1–C7 fragments (Supplementary Scheme 1).

2.1.11 Synthesis of 23-membered natural macrolides

2.1.11.1 Decultot and Clark’s total synthesis toward amphidinolide F

In 2022, Decultot and Clark performed the facile synthesis of precursor 162 toward the total synthesis of amphidinolide F 163 using Yamaguchi esterification as a key step (Scheme 18) (Decultot and Clark, 2022). In their synthetic path, alcohol 153 was subjected to DMP-promoted oxidation, followed by a reaction with the Grignard reagent, TMS group deprotection, and Sonogashira coupling reaction (with Me₂CCHBr) to afford compound 154 with 83% yield. After a few steps, ketone 155 was acquired from compound 154. Ketone 155 was allowed to react with aldehyde 157 in the presence of dicyclohexylboron chloride to generate a diastereomeric pair of alcohols 158a and 158b with 55% and 10% yields, respectively. In the next step, compound 158a proceeded for TBS protection and subsequent hydrolysis, producing alcohol 159 with 77% yield. For the esterification of compound 159 with alcohol 161, the well-optimized Yamaguchi protocol (Et₃N, DMAP, and TCBC) was used to successfully produce fragment 162 with 69% yield.

Scheme 18

Scheme 18. Synthesis of fragment 162 toward the synthesis of amphidinolide F 163.

2.1.12 Synthesis of 28-membered polyketidic macrolides

2.1.12.1 Babczyk and Menche’s total synthesis of pentamycin

Pentamycin 176 belongs to the class of polyene macrolides and polyketides. It was first isolated in 1958 from Streptomyces pentaticus (Hamilton-Miller, 1973). The unique structural framework of this macrolide consists of a 28-membered core with an adjacent polyol fragment, having 12 stereomeric centers. Pentamycin 176 exhibits remarkable biological activities against C. albicans and Trichomonas vaginalis. Furthermore, it can also be used as an anti-cancer agent along with bleomycin (Kranzler et al., 2015; Payero et al., 2015). These fascinating features prompted Babczyk and Menche to perform its total synthesis by using Yamaguchi esterification as the crucial step (Scheme 19) (Babczyk and Menche, 2023). For the accomplishment of this task, fragment 166 (from compounds 164 and 165) and fragment 168 (from compound 167) were subjected to coupling reaction (in the presence of LDA and DMPU), followed by Birch reduction to produce compound 169 in 84% yield. In the four steps for the synthesis of alkyne 171, acetyl group protection and TBS group deprotection of compound 169 provided favorable conditions for subsequent oxidation and Bestmann–Ohira homologation (with compound 170). Alkyne 171 was then subjected to a sequence of stannyl-cupration (under TES protection), methylation, iodination, IBX-induced oxidation, and Pinnick oxidation to furnish compound 174 with 76% yield. To perform the challenging esterification of this sterically hindered carboxylic acid 174 with alcohol 173, the well-suited Yamaguchi protocol was used by using TCBC, Et₃N, and DMAP, which yielded ester 175 with 84% yield. After a few steps, the successful synthesis of the targeted pentamycin 176 was achieved gratifyingly.

Scheme 19

Scheme 19. Synthesis of pentamycin 176.

2.1.13 Synthesis of 30-membered macrolides

2.1.13.1 Lizzadro’s synthesis of disorazole C₁ and analogs

Disorazoles are an intriguing class of natural products well known for their anti-tubulin and anti-cancer effects. They were isolated in 1994 from S. cellulosum, a myxobacterium, by Hofle and Reichenbach (Jansen et al., 1994; Jensen, 1994). One of the disorazoles, (−)-disorazole C₁ 181, is a 30-membered macrolide. It exhibits a highly cytotoxic effect in various mammalian cell lines (Hopkins and Wipf, 2009). Lizzadro et al. (2021) devised an efficient and well-designed strategy for the total synthesis of (−)-disorazole C₁ (Scheme 20) (Lizzadro et al., 2021). The interesting features of their synthetic scheme involved both Yamaguchi esterification and Yamaguchi macrolactonization as the main steps to obtain the 30-membered macrolide (Supplementary Scheme 2). The Yamaguchi esterification was made possible by reacting synthesized compounds 177 and 178 in the presence of 2,4,6-trichlorobenzoyl chloride, triethyl amine, DMAP, and toluene, producing ester 179 with 75% yield. For the intramolecular reaction, a sequence of silyl group deprotection and hydrolysis of ester 179, followed by exposure to Yamaguchi conditions for macrolactonization, resulted in cyclic macrocycle 180 with 70% yield. In the end, metal-catalyzed reduction of compound 180, followed by a reaction with HBr in acetonitrile and water, resulted in the synthesis of the targeted natural product 181 with 56% yield. After the successful synthesis of (−)-disorazole C₁ 181, Lizzadro et al. (2022), extended their methodology for the synthesis of three novel analogs of disorazole as potent cytotoxic agents against cancer (Lizzadro et al., 2022) (Supplementary Figure 4).

Scheme 20

Scheme 20. Synthesis of disorazole C₁ 181.

2.2 Synthesis of natural metabolites

2.2.1 Gillsch’s total synthesis of ophiofuranones (A and B)

Ophiofuranone A and ophiofuranone B, belonging to the class of fungal metabolites, were isolated from Ophiosphaerella korrae by Lou et al. (2019) (Li et al., 2019). In 2022, Gillsch et al. disclosed the first total synthesis and microbial analysis of ophiofuranone A and ophiofuranone B by using cheap starting materials, i.e., tiglic acid and methallyl alcohol (Gillsch et al., 2022b). The challenging molecular architecture (with 4 stereogenic centers) of these 2 natural products was easily built in 16 steps by using Yamaguchi esterification as a powerful step (Supplementary Scheme 3).

2.2.2 Gillsch’s total synthesis of thiocarboxylic acid and analogs

A fungal metabolite, thiocarboxylic acid, was isolated from Penicillium sp. Sb62. This unique natural product exhibits anti-microbial activity against S. aureus, Escherichia coli, and C. albicans with MIC values of 1.7–3.0 μg/mL (Chang et al., 2020). Gillsch et al. (2022) devised an efficient 14-step synthetic route toward the synthesis of thiocarboxylic acid and its three analogs (Gillsch et al., 2022a). The key step entails the Yamaguchi esterification, which assisted in the separation of E and Z isomers with no scrambling (Supplementary Scheme 3).

2.2.3 Wittman’s synthesis of the JBIR-141 analog

Cancer is the second leading cause of death, and it has numerous causes. So, the search for new anti-cancer drugs with improved cytotoxicity has always remained a significant interest of scientists. Among some anti-cancer compounds, JBIR-141 inhibits the transcription of Foxo3a with an IC₅₀ value of 23.1 nM. It is a tetramic acid metabolite that was isolated from the 4587H4S strain of Streptomyces sp. Furthermore, this natural product possesses significant structural features for having N-nitrosohydroxylamine, 3-acyltetramic acid, and oxazoline-4-carboxamide adorned with six stereogenic centers (Kawahara et al., 2015; Yasoshima et al., 2022). With great interest, Wittman et al. (2022) devised an efficient strategy for the synthesis of a close analog of JBIR-141245 using readily available starting materials _L-threonine 189, _L-alanine 187, and _L-glutamic acid 182 (Scheme 21) (Wittmann et al., 2022). The synthesized compounds 184 and 185 (from starting compounds 182 and 183), in hand, were subjected to Yamaguchi conditions (TCBC, Et₃N, DMAP, and toluene), facilitating a smooth esterification process. The resulting ester was then treated with HCl and ethyl acetate to yield compound 186. For the synthesis of key fragment 188, compound 187 was protected by using carbazole chloride. On the other hand, compound 189 was turned into ester 190 via its treatment with SO₂ and methanol. The resulting ester (in 100% yield) was then made to react with protected compound 188 under the given conditions for condensation, followed by cyclization in the presence of (NH₄)₆Mo₇O₂₄^.4H₂O, to provide dipeptide 191 with 82% yield. Next, the removal of the carbazole group of compound 191 was made possible by hydrogenolysis in the presence of formaldehyde. This was followed by CsOH-promoted saponification, coupling of the intermediate with ester 186 (in the presence of EDC, DIPEA, HOBt, and DCM), and a final step of debenzylation, leading to the target analog 192 with 92% yield.

Scheme 21

Scheme 21. Synthesis of JBIR-141 192.

2.2.4 Jansen’s total synthesis of desferri-exochelin 772SM

Exochelins are mycobacterial secretions that are used to chelate iron (as is necessary for the replication and energy metabolism of these microorganisms). One of these natural products, desferri-exochelin 772SM 202, was first isolated by Horwitz et al. from M. tuberculosis in 1995 (Horwitz and Horwitz, 2014; Gobin et al., 1995). Their significant Fe-chelating capability prompted Jansen et al. (2023) to devise a convergent and concise synthetic route for the total synthesis of desferri-exochelin 772SM 202 in 11 consecutive steps with an 8.6% overall yield (Scheme 22) (Jansen et al., 2023). The key step in the synthesis entails the coupling of advanced, hugely decorated fragments using Yamaguchi esterification. In their methodology, the easily available starting material 193 was transformed into compound 194 over a few steps. On one hand, compound 194 was used for the synthesis of alcohol 197 with the assistance of Pd(PPh₃)₄-mediated deprotection and PyBOP-induced coupling with N-ethylmorpholine of compound 194, resulting in intermediate 196 (with 46% yield). Subsequently, the Boc group protection of compound 196 was performed, followed by its PyBOP-induced coupling with 3-hydroxybutanoic acid, resulting in cobactin 197 with 84% yield, while in another route, compound 194 was made to react with monomethyl pimelate bis-(trichloromethyl)carbonate, 2,4,6-collidine, and THF to yield compound 195, proceeded by Boc-group deprotection, PyBOP-assisted amide coupling (with compound 199), and allyl group deprotection, to provide acid 200 (ready to esterify). Next, the essence of the Yamaguchi protocol can be realized as it was applied for the esterification (after the failure of other methods) of compound 200 with already synthesized alcohol 197 in the presence of TCBC, Et₃N, DMAP, and toluene to produce ester 201 in 36% yield. In the final step, ester 201 was treated with hexafluoroisopropanol (HFIP) in the presence of sunlight to successfully produce desferri-exochelin 772SM 202 with 62% yield.

Scheme 22

Scheme 22. Synthesis of desferri-exochelin 772SM 202.

2.3 Synthesis of natural polyketides

2.3.1 Morishita’s total synthesis of nhatrangin A

Nhatrangin A 207 belongs to the class of polyketide natural products and is a truncated derivative and a synthetic intermediate of oscillatoxin D and aplysiatoxin. Nhatrangin A 207 was first isolated from Lyngbya majuscula, a marine cyanobacterium, by Orjala et al. in 2010 (Chlipala et al., 2010). More interestingly, aplysiatoxin is renowned for its anti-inflammatory and anti-tumor activities (Fujiki et al., 1984). Being the synthetic intermediate of aplysiatoxin, nhatrangin A 207 gained the attention of various research groups; Morishita et al. (2023) accomplished its total synthesis and confirmed its configuration with a previously reported synthesis (Scheme 23) (Morishita et al., 2023). Their synthesis commenced with the efficient Yamaguchi esterification of compound 203 (after silyl protection) with compound 205 (from compound 204) in the presence of TCBC, Et₃N, DMAP, and toluene to yield compound 206 with 90% yield. Subsequently, compound 206 was subjected to ozonolysis (in the presence of ozone and triphenyl phosphine), Pinnick oxidation (with 2-methyl-2-butene), and TBS-group deprotection in sequence to successfully produce the targeted nhatrangin A 207 in 92% yield.

Scheme 23

Scheme 23. Synthesis of nhatrangin A 207 and (−)-4-epi-englerin A 213.

2.4 Synthesis of natural terpenoids

2.4.1 Kumar Palli’s total synthesis of (−)-4-epi-englerin A

The natural extracts of the plant Phyllanthus engleri are renowned for their cytotoxic activity against renal cancer cells (Ratnayake et al., 2009). One of these natural products includes (−)-4-epi-englerin A 213, which is a sesquiterpenoid. The first total synthesis of this medicinally important scaffold was performed by Christmann in 2009 (Willot et al., 2010). Kumar Palli et al. (2021) also reported a valuable approach (based on 22 steps) for its total synthesis (with 4% overall yield) by using Yamaguchi esterification as the crucial step (Scheme 23) (Kumar Palli et al., 2021). Their synthesis started with compound 208, which was modified into diol 209 through a few steps. Next, the standard conditions for strategic Yamaguchi esterification were adjusted by reacting diol 209 with protected alcohol 210 in the presence of TCBC, Et₃N, DMAP, and CH₂Cl₂ (solvent) to attain ester 211 with 85% yield. Then, ester 211 was allowed to react with trans-cinnamoyl chloride 212, followed by desilylation to gain the desired (−)-4-epi-englerin A 213 with 86% yield.

2.5 Synthesis of natural peptides

2.5.1 Chen’s total synthesis of colletopeptide A and colletotrichamide A

Colletopeptide A 223 and colletotrichamide A 224 are cyclic depsipeptides that were isolated independently from Colletotrichum gloeosporioides JS419 and Colletotrichum sp. S8 (Feng et al., 2019). These natural products are renowned for their broad range of biological activities. In particular, colletopeptide A 223 exhibits cytotoxic activity against RAW264.7 macrophages with IC₅₀ = 8.3 μM (Oh et al., 2006; Ohno et al., 2004). With a profound interest in these medicinally active peptides, Chen et al. (2023) devised an impressive strategy for the first total synthesis of colletopeptide A 223 (in 15 steps) and colletotrichamide A 224 (in 17 steps) via a common precursor 221 (Scheme 24) (Chen et al., 2023). Their successful stereoselective synthesis entails Yamaguchi esterification as the main step. In the first step, the easily available starting materials, i.e., alkenes 214 and 215, were subjected to cross-metathesis to produce alkene 216 with 81% yield. Next, ester 218 was easily obtained in the desired stereochemistry using the Yamaguchi protocol for esterification. For this, compounds 216 and 217 were treated with TCBC and Et₃N, yielding ester 218 with 76% yield. Compound 218 was treated with TMSOTf (for removal of the Boc group), and its amide coupling reaction with compound 219 led to the synthesis of tridepsipeptide 220 with 61% yield. It took a few steps for the achievement of precursor 221, which, after TBS removal, directly furnished colletopeptide A 223 with 67% yield. However, for the synthesis of colletotrichamide A 224, the precursor 221 was allowed to react with mannose derivative 222 in the presence of DTBMP, Tf₂O, and DCM, followed by sequential steps involving benzyl group and TBS group removal under given conditions, to successfully achieve the desired natural product 224 with 83% yield.

Scheme 24

Scheme 24. Synthesis of colletopeptide A 223 and colletotrichamide A 224.

2.5.2 Bauer and Kazmaier’s total synthesis of thiamyxins (A, B, C, and E)

Thiamyxins (A, B, E and C) are depsipeptides in nature, and these were isolated by Muller from a myxobacterial variant of the Myxococcaceae (MCy9487) family (Haack et al., 2022). These thiazoline-containing natural products are popular owing to their anti-viral activities (more particularly against Zika, dengue, and Coronavirus). These interesting features prompted Bauer and Kazmaier (2023) to perform their challenging total synthesis by using Yamaguchi esterification as a key step for macrolactonization with the careful embellishment of stereocenters (Supplementary Scheme 3) (Bauer and Kazmaier, 2023).

2.6 Synthesis of natural α-pyrone

2.6.1 Zhao’s total synthesis of brevipolide H

Brevipolides A–J are α-pyrone-based natural products. Brevipolides G–I were isolated from Lippia alba by Hegde et al. (2004). Structurally, these are dihydro-α-pyrone motifs containing a cyclopropane ring in their side chain. This family of natural products shows anti-cancer activities against various cell lines (Deng et al., 2009). Considering their impressive pharmaceutical profile, Zhao et al. (2023) conducted the total synthesis of brevipolide H 293 in 12 consecutive steps with 8.65% overall yield (Zhao et al., 2023). The methodology was based on the synthesis of allylic alcohol 291 starting from _D-galactal 289, covering a few steps. Next, envisaging the Yamaguchi protocol as a leading tool for esterification, compound 291 was subjected to Et₃N, TCBC, and DMAP with the addition of p-methoxycinnamic acid to provide ester 292 with 73% yield. In the final step, HCl-mediated acetyl group deprotection of ester 292 produced brevipolide H 293 with 77% yield.

2.7 Synthesis of natural biosurfactants

2.7.1 Mittendorf’s total synthesis of (+)-aureosurfactin 1a and (−)-aureosurfactin 1b

Biosurfactants are important (ecofriendly) natural products, with extensive applications in the textile, cosmetic, food, and pharmaceutical industries (Singh et al., 2007; Mulligan, 2005). One of the biosurfactants, aureosurfactin, was isolated first by Yun et al. from Aureobasidium pullulans in 2016 (Kim et al., 2016). Structurally, aureosurfactin is an ester of acyclic dimer 3,5-dihydroxydecanoic acid. In 2023, Mittendorf et al. devised a concise strategy for the total synthesis of both enantiomers, i.e., (+)-aureosurfactin 299a and (−)-aureosurfactin 299b with 18% and 13.5% overall yields, respectively (Mittendorf et al., 2023). In their synthetic scheme, valeraldehydes 294a and 294b (as starting materials), in a few steps, provided acids 296a and 296b (independently), which further underwent methylation and TES group deprotection to result in alcohols 297a and 297b in 78% and 67% yields, respectively. Next, the key fragments 296a and 297b, as well as 296b and 297b, were subjected to coupling via the use of a well-compatible reagent, i.e., TBSCl, Et₃N, and toluene (Yamaguchi esterification) to generate esters 298a and 298b with 92% and 93% yields, respectively. Finally, an additional HF/Py-mediated deprotection step (independently) generated both enantiomers, namely, (+)-aureosurfactin 299a and (−)-aureosurfactin 299b, in 99% and 79% yields, correspondingly.

3 Conclusion

The formal and total syntheses, structural elucidation, and revision of (newly isolated, as well as previously existing) natural products are meticulous steps in the design and development of drugs. In this endeavor, many organic reactions and reagents play prominent roles, as reported in the literature. The Yamaguchi reagent (2,4,6-trichlorobenzoyl chloride) is one among such reagents, and it is responsible for esterification between an acid and alcohol in the presence of DMAP as a coupling reagent. This reagent (despite its limitations including low yield and high cost) has been efficiently used in the synthesis of a wide variety of esters and lactones that are present in various biologically active natural products as key structural motifs. Our article presents an up-to-date compilation of Yamaguchi reagent-based synthetic schemes utilized for the synthesis of natural products and is aimed at helping related research groups in possibly devising further synthetic routes toward the synthesis of a diverse range of natural products (whose total syntheses are yet to be unlocked) using this reagent.

Author contributions

RM: data curation, methodology, and writing–original draft. AZ: resources, writing–original draft, writing–review and editing, project administration, and conceptualization. MA: writing–review and editing, resources, and data curation. AM: data curation, resources, software, and writing–review and editing. AlI: data curation, methodology, resources, software, and writing–review and editing. AC: writing–review and editing, resources, and investigation. AhI: writing–review and editing, resources, and investigation. KK-M: data curation, funding acquisition, resources, software, and writing–review and editing. MG: funding acquisition, resources, and writing–review and editing. MM: data curation, funding acquisition, resources, and writing–review and editing.

Funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The research was partly financed by the following research projects: Collegium Medicum, the Mazovian Academy in Plock, and Medical University of Lublin (DS 730). A. Irfan acknowledges the Deanship of Research and graduate studies at King Khalid University for funding this work through the Large Groups Research Project under grant number RGP2/156/45.

Acknowledgments

Author A. R. Chaudhry acknowledges the Deanship of Graduate Studies and Scientific Research at the University of Bisha for supporting this work through the Fast-Track Research Support Program.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2024.1477764/full#supplementary-material

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