Synthesis of Bioactive Macrocycles Involving Ring-Closing Metathesis Strategy

Abstract

This review reports the synthesis of various bioactive macrocycles, involving ring-closing metathesis as a key step, developed since ca. 2000. These macrocycles exhibited biological activities such as antiviral, antifungal, antibacterial, and anticancer activities, and more. Thus, their syntheses and utilization are essential for both synthetic organic and medicinal chemists.

Key words

macrocycles - ring-closing metathesis - antiviral - antifungal - anticancer - antibiotic

Biographical Sketches

Nasrin Jahan was born in 1993 in Durgapur, West Bengal, India. She graduated in Chemistry (2015) from the University of Burdwan, West Bengal, India and obtained her M.Sc. degree (2017) from Kazi Nazrul University, West Bengal, India. Currently, she is pursuing her Ph.D. degree at the University of Burdwan­.

Dr. I. Ansary was born in 1983 in Raghunathpur, Purulia, West Bengal, India. He received his B.Sc. in Chemistry (2004) from The University of Burdwan, Burdwan­, India and obtained his M.Sc. degree (2006) from the University of Calcutta, Kolkata, India. He received his Ph.D. in Chemistry (July 2013) under the supervision of Dr. B. Roy from the University of Kalyani. He joined as an Assistant Professor in Chemistry in November 2012 at The University of Burdwan, West Bengal and teaches Organic Chemistry in the postgraduate level. His research interests are in the areas of development of new synthetic routes and methodologies to construct nitrogen and oxygen heterocycles of different ring sizes and their application on the basis of molecular modeling and docking studies. Recently, he has been working in the field of pesticide residue analysis. He has published 30 research articles and 2 book chapters. He also reviewed several research articles of some internationally reputed journals. Under his supervision 2 students have been awarded Ph.D. degrees and currently 3 students are still working in his group. Moreover, he also supervised more than 50 M.Sc. students to successfully submit their project-based term papers.

1

Introduction

Over a prolonged period of time, macrocyclic compounds constituting ester/keto/amide moiety have remained as the backbone of various natural products and clinical drugs. The naturally occurring compounds possessing macrocyclic skeletons have exhibited remarkable biological activities including antibiotic, anticancer, immunosuppressant, Hsp90 inhibitor, cytotoxic, etc.[1] Nonactin and valinomycin, a class of oxygen-bearing macrocycles, are examples of naturally occurring antibiotics obtained from Streptomyces species.[2] The actinoallolides, a family of complex polyketides, show potent activity against Trypanosoma protozoan parasites causing Chagas disease and African trypanosomiasis.[3] Solomonamides, a class of macrocycles with an amide moiety, isolated from the marine sponge Theonella swinhoei, display anti-inflammatory activity while preliminary biological evaluations of solomonamide precursors exhibited antitumor activity against various tumor cells.[4] In addition, several other macrocycles reported in the literature are the building blocks of distinguished natural products with significant pharmacological properties like antibiotic,[5] antiviral,[6] immunosuppressing,[7] and more.[8] [9] [10] [11] [12] [13] [14] [15] Owing to the broad spectrum of biological activities, several routes have been developed for the synthesis of various macrocycles on a large scale. Quite a few of them include the Dieckmann condensation,[16] Stille coupling,[17] radical reactions,[18] semipinacol rearrangement,[19] homologation of cyclic ketones with diazo compounds,[20] and ring-closing metathesis (RCM) reactions.[21] [22] [23] Among them, the RCM strategy has been recognized as an effective tool for furnishing simple ring systems,[24] heterocycles,[25] macrocycles,[26] polymers,[27] and natural products[28] as it seemed to be the most straightforward and reliable method to afford olefinic double bonds in cyclic as well acyclic systems. Incorporating the ideology of synthesizing macrocycles, exhibiting biological activities in the field of medicine, by using RCM protocol as a key step has initiated a whole new level of research. After garnering information about such research articles, we have realized in our limited knowledge that a recent review on the topic synthesis of bioactive macrocyclic compounds involving RCM strategy has still not been targeted upon. As we are currently engaging in the synthesis of macrocyclic compounds and subsequently we have published an article,[1] we decided to write a review article mentioning the synthetic routes developed since 2000, to graft bioactive macrocycles using RCM methodology. We are hopeful that this review will benefit researchers who are working in the field of medicinal chemistry to facilitate the development of novel macrocyclic compounds required for drug discovery.

2

Antiviral

Hepatitis C virus (HCV) is a worldwide epidemic and affects millions of individuals every year. It is the primary cause of liver disease and spreads through contaminated blood. Symptoms for the disease might take a prolonged period of time to appear until this ‘silent infection’ has already damaged the liver enough. Another common viral infection occurring globally is herpes simplex virus (HSV) which is both orally and sexually transmitted. It causes mild to severe painful blisters and the symptoms are recurring. In order to eradicate the diseases, the scientific community is always concerned about creating new drugs to ensure the treatment of affected people.

The 15-membered ring macrocyclic tripeptide BILN 2061 (6) is a potent inhibitor of HCV NS3-4A protease. In 2006, Yee et al. established an efficient large-scale synthesis of the tripeptide 6 by utilizing ring-closing metathesis as a crucial step (Scheme [1]).[29] The synthetic route commenced by using compounds 1 and 2 as the starting materials. A series of consecutive reactions led to the formation of RCM precursor 3 which was subjected to macrocyclization conditions using Hoveyda-I catalyst in DCM at 40 °C. The reaction afforded the macrocycle 4 in an excellent yield of 87%. Further reactions were carried out upon compound 4 and the target molecule BILN 2061 was obtained in 90% yield in the final step.

Scheme 1 Synthesis of HCV protease inhibitor BILN 2061

In order to combat the growing HCV infection, various clinical studies undertaken over the years exhibited that NS3, a dual function enzyme, could act as a target for treating HCV using peptide inhibitors. In 2007, a group led by Velázquez and Venkataraman designed a synthetic method to prepare macrocyclic inhibitors 17 and 23 of the HCV NS3 protease (Scheme [2]).[30] The investigation started with the synthesis of ω-unsaturated N-Boc-protected amino acid 10a and amine hydrochloride salt 11b. The monoester 7 was at first converted into α,β-unsaturated esters 8a and 8b through Knoevenagel condensation by using pent-4-enal and hex-5-enal, respectively. After two successive reactions the N-Boc-protected amino acids 9a and 9b were obtained which were later individually converted into 10a and 11b, respectively. HATU coupling of 10a with dimethylcyclopropyl proline 12 resulted in the formation of dipeptide 13 which upon further hydrolysis provided the acid 14. The amino acid 11b was next introduced in the reaction to develop the RCM precursor 15. The ultimate RCM reaction was conducted using Grubbs’ first-generation (Grubbs-I) catalyst in toluene at 60 °C to afford the corresponding macrocycle 16 in 93% yield as a mixture of E/Z isomers. The keto-amide moiety, which served as a serine trap in the class of inhibitors, was of interest for the researchers’ group and hence, it was incorporated within the 16-membered macrocycle 17 through a series of consecutive reactions. Further investigation was carried out by the group to introduce heteroatoms within the macrocyclic core. Construction of macrocycle 22 commenced when Boc-l-serine 18 was treated with methyl allyl carbonate and tetrakis(triphenylphosphine)palladium to produce 19. Several steps were carried out to afford the RCM precursor 21 which underwent macrocyclization with Grubbs-I catalyst in toluene at 60 °C to afford the metathesis product 22 as an E/Z mixture. A further six consecutive reactions were conducted to furnish the desired oxygen-containing macrocycle 23.

Scheme 2 Synthesis of macrocyclic inhibitors of HCV NS3 protease

Shu et al., in 2008, reported an improved method for the key RCM step while synthesizing the HCV protease inhibitor BILN 2061 (Scheme [3]).[31] The macrocyclization of substrates 24a–d was conducted using second-generation Ru catalyst 25 in toluene at various temperatures (60 °C or 110 °C) to afford the desired compounds 26a–d in good yields. In 2008, the Randolph group synthesized a P3 aza-peptide analogue of macrocyclic tripeptide inhibitor 32 which was closely related to BILN 2061 (Scheme [4]) via ring-closing metathesis reaction.[32] The synthesis advanced as esterification of heptenoic acid 27 took place followed by reduction to afford the aldehyde 28. Through various consecutive reactions, the RCM precursor tripeptide 29 was produced and finally subjected to macrocyclization. The initial studies were conducted using Hoveyda’s catalyst at 40 °C in DCM which furnished the macrocycle only in 50% yield after 3 days, in a 1:4 ratio of E/Z olefin products. On raising the temperature to 50 °C in toluene, the product was obtained in a 62% yield as a 2:3 ratio of E/Z olefin isomers leaving behind only a trace amount of precursor after 3 days of reaction. After separating the isomers and subjecting the macrocyclic tripeptide 31 to saponification, the target inhibitor 32 was achieved. The effect of the P3 aza-peptide modification on in vitro potency was next tested and found that it resulted in a loss in activity in both the enzyme inhibition and replicon assays.

Scheme 3 Synthesis of HCV protease inhibitor BILN 2061

Scheme 4 Synthesis of P3-aza peptide analog of a potent macrocyclic tripeptide HCV protease inhibitor

In 2013, Wei et al. reported an efficient synthesis to produce the macrocyclic HCV protease inhibitor BI 201302 (40) (Scheme [5]).[33] The synthesis progressed with the coupling of (S)-2-((cyclopentyloxycarbonyl)amino)non-8-enoic acid (33) and trans-hydroxy-proline ester 34 in the presence of cyanuric chloride and hydrolyzed to produce the dipeptide 35. Two successive reactions developed an intermediate which helped in a streamline one-pot preparation of the RCM precursor 36 which was subjected to macrocyclization in refluxing toluene by adding a solution of Grela’s catalyst in portions. Completion of the reaction led to the formation of RCM product 37 in 93% assay yield which was further deprotected from the Boc, acetyl, and ester groups to produce the acid intermediate 38 in 75% yield. It was next subjected to S_NAr reaction conditions with 39 by using t-BuOK. The tert-butyl carbamate analogue of BI201302 was the only significant impurity (1–2%) present within the medium which was removed by using potassium 3,7-dimethyl-3-octanoxide (KDMO) during the reaction. After crystallization, the target macrocycle BI201302 (40) was obtained as its meglumine (MU) salt in 74% yield.

Scheme 5 Synthesis of HCV protease inhibitor BI201302

MK-6325 (51), on being found to be a potent HCV NS3/4A protease inhibitor, was required to be clinically evaluated. Hence, in 2015 Li et al. developed a practical asymmetric synthesis of this bis-macrocyclic compound (Scheme [6]).[12] MK-6325 was curated using a 15-membered macrocycle 45 and the cyclopentyl building block 48. Synthesis of 45 involved the crucial ring-closing metathesis step and the entire route commenced from the quinoxaline derivative 41. On treating 41 with lithium hydroxide in THF and water, the acid 42 was obtained. Three consecutive reactions upon 42 produced the RCM precursor 44 which was subjected to metathesis conditions involving Zhan-1B catalyst and p-benzoquinone (BQ) in toluene at 80 °C for 1 h to afford the 15-membered macrocycle 45 as a solid crystal in 91% yield. Further deprotection of 45 using TFA produced the amine 46. Sequentially, the intermediate 48 was prepared from cyclopentanol 47 in two steps. Combination of 46 with 48 synthesized the BPin Suzuki–Miyaura substrate 49 and subsequent reactions afforded the desired compound MK-6325 (51) in 90% yield.

Scheme 6 Synthesis of HCV protease inhibitor MK-6325

On being identified as a potent HCV NS3/4A protease inhibitor, glecaprevir (56) was successfully synthesized by the Cink group in 2020 (Scheme [7]).[6] The synthetic pathway advanced with the coupling of the two fragments 52 and 53, using HATU as the coupling reagent, to afford the RCM precursor 54. The final macrocyclization step took place by subjecting 54 to metathesis conditions involving Zhan-1B catalyst in toluene at 40 °C to produce the trans-macrocycle 55 in 82% yield. Use of Grubbs-II catalyst instead of Zhan-1B also afforded the product 55 in 79% yield. Continuation of a series of reactions upon the macrocycle, furnished the target compound glecaprevir (56) in 89% yield.

Scheme 7 Synthesis of glecaprevir

Scheme 8 Synthesis of pochonin C

Pochonin C (67) was discovered to be a novel antiviral agent against herpes simplex virus (HSV). Belonging to a family of six related macrolides (pochonins A–F), pochonin C has the highest selectivity index (Tox50/IC50) against HSV. Barluenga et al., in 2004, developed a synthetic procedure in which the target macrocycle 67 could be disconnected into three main building blocks 57, 58, and 59 (Scheme [8]).[34] The trans-epoxides 58a and 58b were achieved from alcohol 68. Several consecutive reactions, ozonolysis, Brown allylation, epoxidation, and deprotection, led to the synthesis of 58b. Further reactions upon intermediate 69 yielded the oxirane 58a. In order to achieve 67, acid 57 was chosen as the starting material and subjected to protection of the two phenol groups with MOMCl to afford the toluic ester 60. Next, deprotonation of the benzylic position was carried out with LDA and quenched with the Weinreb amide 59 to yield the RCM precursor 61. On being treated with Grubbs’ second generation (Grubbs-II) catalyst in toluene at 120 °C, 61 underwent cyclization to afford the macrocycle 62 in 94% yield as an inseparable mixture of E/Z (1:1) products. To obtain the dihydroradicicol macrocycle 63, the thioether group could be removed under free radical conditions. Oxidation with H₂O₂ was also conducted upon 61 in a separate pathway to obtain the diene 64 which upon further exposure to macrocyclization conditions with Grubbs-II catalyst in toluene at 120 °C produced the compound 65 in 87% yield. Subsequently, 63 was also converted into 65 via oxidation with H₂O₂. Finally, chlorination of the aryl ring in 65 and stereoselective opening of the epoxide were carried out using excess SO₂Cl₂ followed by deprotection of the MOM groups to afford the target compound pochonin C (67) in 74% yield.

3

Antifungal

Fungal infections are the most common health issues in today’s world as inhaling or coming in direct contact with fungal spores leads to skin infection. The effect of SARS-CoV-2 has worsened the scenario globally as the affected people who are dealing with intubation, ventilation, and long-term hospitalization are highly susceptible to develop fungal infections. Systemic fungal infections can affect organs, such as lungs, eyes, liver, and brain, particularly for immunocompromised patients while invasive fungal infections (IFIs) cause severe illness and high mortality among them.

The most predominant pathogenic species, Candida, is responsible for almost half the IFIs. In order to treat Candida infections, a limited number of chemotherapeutic agents were relied upon. Owing to their low toxicity and high degree of bioavailability, azoles helped in treating a wide range of candidiasis. However, the spread of drug resistant fungal species halted the use of classical antifungal drugs like fluconazole and posed a challenge amongst the scientific community to redevelop therapy and diagnosis to ensure eradication of fungal infections. Studies upon the antimycotics have advanced over the recent decades compelling various researchers to provide significant attention towards marine-derived fungi. Melearoride A and PF1163B are two novel 13-membered macrolides isolated from marine-derived fungi with inherent azole resistant antifungal property.

Bouazza et al., in 2003,[35] reported the synthesis of the macrocyclic antifungal agent (–)-PF1163B (77) (Scheme [9]). Preparation of the first building block 71 commenced from (S)-citronellene (70) whereas, the second building block 73 was synthesized from N-Boc-l-tyrosine 72 in a few sequential steps. Next, these two fragments were made to undergo an esterification process with DCC in DMF in the presence of DMAP to afford compound 74. After two subsequent steps, the RCM precursor 75 was achieved and subjected to metathesis conditions in refluxing dichloroethane with Grubbs-II catalyst for 6 hours. The macrocycle 76 was afforded in 60% yield as a mixture of E/Z isomers. Finally, the newly formed double bond was reduced followed by hydrogenolysis of the benzyl group and it resulted in the formation of the target compound PF1163B (77) as a colorless oil in 52% yield.

Scheme 9 Synthesis of antifungal agent PF1163B

In 2013, Sanguinetti et al. synthesized macrocyclic amidinourea derivatives 87a–c and 94a,b to investigate the effects of ring-size development and incorporation of polar/apolar moieties while evaluating their antifungal activity (Schemes 10 and 11).[9] The development of 87a–c (Scheme [10]) started off by using aldehyde 78 which was O-alkylated with alkenyl bromides and condensed with NH₂OH to produce oximes. Further reduction of the substrate in the presence of Zn resulted in the synthesis of amines 79a–c which underwent guanylation to create the guanidine-based fragments 80a–c. The building block 82 was synthesized in two steps as Cbz-aminooctanoic acid 81 was exposed to consequent amidation-reduction reactions. The two blocks 80a–c and 82 coupled to produce the RCM precursors 83a–c. On being treated with Grubbs-II catalyst at 40–80 °C in toluene/DCM solvent, 83a–c afforded the macrocycles 84a–c as a mixture of E/Z isomers in high yields. Reduction of the double bond present in the macrocyclic core and Cbz cleavage produced the primary amines 85a–c which upon further guanylation with N,N′-diBoc-N-crotyl-S-Me-isothiourea and treatment with trifluoroacetic acid furnished the desired derivatives 87a–c. In order to synthesize the second set of derivatives, β-alanine (88) was used as the precursor (Scheme [11]). Consequent reactions like guanylation and esterification of 88 led to the production of guanidines 89a,b. Further conversion of 89a,b into dienes 90a,b took place in refluxing toluene by using allylamine 82. The dienes served as the RCM precursors and underwent macrocyclization in the presence of Grubbs-II catalyst in DCM at 40 °C to afford the macrocycles 91a,b. On completion of this key step, 91a,b were hydrogenated, guanylated, and Boc deprotected to afford the desired derivatives 94a,b. The compounds 87a–c and 94a,b were assayed against clinical isolates of seven different wild-type Candida species and were found to exhibit antifungal activity. The presence of an aromatic substitution on macrocycles as seen in 87a–c caused those derivatives to show a stronger activity than the compounds 94a,b which bore ester moieties. The increasing ring size of macrocycles 87a–c from 13- to 15-membered also proved to effectively increase the antifungal activity towards all Candida species. A similar trend was noted in case of compounds 94a,b where the macrocycle with a larger ring size was evaluated to exhibit a stronger activity as compared to the one with smaller ring size.

Scheme 10 Synthesis of macrocyclic amidinoureas: series 1

Scheme 11 Synthesis of macrocyclic amidinoureas: series 2

Scheme 12 Synthesis of macrocyclic amidinoureas derivatives

Balestri et al., in 2022,[36] synthesized derivatives of macrocyclic amidinoureas 102a–f which were confirmed to be active on a large panel of Candida spp. and C. neoformans through biological evaluation (Scheme [12]). Their synthetic protocol began with the reduction of substituted 2-iodobenzoic acids 95a–f into benzyl alcohols 96a–f. Six consecutive steps led to the formation of diBoc-guanidino moiety 97a–f which was made to react with 98 to afford Boc-protected amidinoureas 99a–f. These substrates served as the RCM precursors and were exposed to macrocyclization in the presence of Grubbs-II catalyst in refluxing DCM for 16 h to obtain the macrocycles 100a–f in good yields (54–80%). Subsequently, the benzyloxycarbonyl (Cbz) protecting group was removed and the olefin was reduced simultaneously followed by guanylation with N-crotyl-guanylating agent to furnish derivatives 101a–f. Finally, the desired compounds 102a–f were achieved through Boc cleavage and were found to exhibit antifungal activity overall stronger than hit compounds BM1 and fluconazole.

Scheme 13 Synthesis of (–)-melearoride A and (–)-PF1163B

Yasam and Pabbaraja were intrigued by the structural and stereochemical features of melearoride A (113) and PF1163B (114) differing only in alkyl chain appendage. In 2022, they developed an efficient, stereoselective approach to the synthesis of these two macrolides (Scheme [13]).[37] Interestingly, this was done through the development of a common macrocyclic skeleton 112 which was achieved from two building blocks 105 and 108. The fragment 105 was obtained from commercially available l-tyrosine (103). On being refluxed in methanol with SOCl₂, 103 afforded the methyl ester 104. Subjecting 104 to four subsequent reactions resulted in the production of amino acid 105. The second fragment 108 was produced from commercially available n-hexanal (106) by subjecting it to Keck asymmetric allylation to afford homallylic alcohol 107. Nine subsequent reactions upon 107 helped to furnish the alcohol 108. Esterification of acid 105 with alcohol 108 under Yamaguchi conditions afforded the ester 109 which upon Boc deprotection with TFA followed by acylation with pent-4-enoic acid using DIPEA/Pybop afforded the RCM precursor 110. Subsequently, it was exposed to metathesis conditions in refluxing toluene with Grubbs-II catalyst for 12 h to produce macrocycle 111 in 70% yield as a mixture of (E)- and (Z)-diastereomers. Reduction and debenzylation via hydrogenation gave the desired macrocyclic core 112 in 85% yield. Ultimately, the target molecule melearoride A (113) was achieved in 90% yield through O-alkylation of phenol 112 by using prenyl bromide. The other target macrolide PF1163B (114) was obtained in 87% yield via O-alkylation of 112 with (2-bromoethoxy)(tert-butyl)dimethylsilane and subsequent TBS deprotection.

4

Antibacterial

Antibiotic resistance has been one of the biggest threats known to mankind as it affects global health, food security, and development in the world. With a growing list of infections in our everyday life, scientists are always looking out to cope with these ever-emerging problems by investing in new research which ensures the development of new antibacterial agents.

Scheme 14 Synthesis of myxoviresin A₁ analogues

Myxovirescin A₁, an antibiotic produced by gliding bacteria of the Myxococcus species, had been very important amongst researchers due to its unique mode of action. Content, Dutton, and Roberts developed an efficient protocol in 2003 to synthesize the analogues of myxovirescin A₁ 127 and 133 (Schemes 14 and 15).[38] The target macrocyclic core could be fragmented into three main parts viz. A, B, and C (Scheme [14]). Preparation of fragment A 117 commenced by using the commercially available α-d-mannopyranoside 115 which was transformed into the hemiacetal 116. Seven consecutive steps led to the formation of 117. 11-bromoundecanoic acid (118) and the Grignard-derived from bromohexene 119 underwent a copper-catalyzed coupling reaction to afford the fragment B 120 (heptadec-16-enoic acid) whereas, l-norvaline (121) went through a double inversion of an intermediate nitronium species to produce 2-(S)-hydroxyvaleric acid and then it was converted into its SEM ester 122 (fragment C). The two fragments B and C were coupled together using the coupling agent 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide (CMC) to afford 123. The SEM group was subsequently removed to form intermediate 124 which was coupled with fragment A using CMC to furnish the metathesis precursor 125. Exposure of 125 to macrocyclization conditions by treatment with Mo-based Schrock’s catalyst in benzene at 60 °C for 15 h afforded the macrocycle 126 as a 2:1 mixture of inseparable isomers in 55% yield. Finally, the acetal groups were deprotected to afford the target molecule (triol) 127. After separating the two isomers, the desired E isomer was obtained in the majority. Another analogue of myxovirescin A₁ was produced by varying the triol unit of the molecule (Scheme [15]). The protocol advanced with the use of commercially available amino-sugar 129 which afforded the bis-acetonide 130 in just two steps. This fragment was coupled with the previously prepared intermediate 124 by using CMC to synthesize the metathesis precursor 131. After being subjected to Grubbs-I catalyzed macrocyclization conditions in DCM, the macrocycle 132 was obtained in 90% yield. Finally, deprotection with aqueous acetic acid gave the desired myxovirescin analogue 133 in 64% yield. Both the analogues 127 and 133 showed prominent antibacterial activity when assessed biologically.

Scheme 15 Synthesis of myxoviresin A₁ analogues

Kendomycin [(–)-TAN 2162], isolated as an antagonist for endothelin receptor, was reported to exhibit antibacterial activities against drug-resistant Staphylococcus aureus strains. Back in 2009, Magauer et al. reported a synthetic protocol to produce kendomycin (146) with RCM being its key step (Scheme [16]).[39] The RCM precursor 144 was constructed using the building blocks 135, 137, and 141. The carboxylic acid fragment 135 was synthesized in six steps from the aldehyde 134 whereas the ketoimide 136 underwent a three-step reaction to yield the aldehyde 137. The reaction of but-2-enyl-MgBr 138 with titanate 140 and methacrolein (139) afforded the alcohol 141. Esterification of the acid 135 with alcohol 141 produced the ester 142 which underwent two subsequent reactions to furnish the intermediate 143. Upon further treatment with n-BuLi, TMEDA, and 137, the RCM precursor 144 was formed as a diastereomeric mixture. On exposing 144 to macrocyclization conditions using Grubbs-II catalyst in refluxing DCM, the E-olefin 145 was achieved in 62% yield. Finally, the desired antibiotic kendomycin (146) was furnished in 30% yield after conducting a few more reactions upon 145.

Scheme 16 Synthesis of kendomycin

Mangrolide A, isolated from the SNA18 strain of Actinoalloteichus­ sp, is a natural product described to be active against Gram-negative bacteria, including Acinetobacter baumannii and Pseudomonas aeruginosa. In 2018, Hattori et al. reported first total synthesis of mangrolide A (158) and conducted its biological evaluation against bacterial pathogens (Scheme [17]).[40] The synthesis advanced with the preparation of azidodisaccharide donor 148 from methyl d-glucoside (147) in nine consecutive steps. Suzuki coupling between the synthesized iodide 149 and boronate 150 afforded an intermediate which was further transformed into the RCM precursor 152 via Yamaguchi esterification. Subsequently, 152 was subjected to macrocyclization with Grubbs-II catalyst in toluene at 100 °C for 2 h to afford the macrocycle 153. Subsequent hydrolysis led to the production of 154 as a mixture of E,E and E,Z isomers. Sequential TMS protection, separation of isomers, and silyl removal yielded the E,E isomer 155. The key fragment 148 was made to react with 155 to furnish the desired β-isomer 156 in 42% yield. The acetyl and TBS groups were removed to form 157 while reduction of the azide group with consecutive reductive amination afforded the target compound 158 in 25% yield. The synthetically produced mangrolide A (158) and its derivative 157 were tested against bacterial pathogens but, only minimal activity was observed.

Scheme 17 Synthesis of mangrolide A

Waser and Altmann developed an efficient strategy, in 2020,[5] to synthesize a potent antibiotic disciformycin B (171) (Scheme [18]). Disciformycin B showed a significant antibacterial activity against the Gram-positive bacteria, methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA/VRSA) strains. Synthesis commenced as N-acyl-oxazolidinone 159 was transformed into the syn-aldol product 160 in two steps with eight subsequent reactions to produce the carboxylic acid 161. Methyl angelate (162) yielded the aldehyde 163 by LiAlH₄ reduction and oxidation with activated MnO₂ which upon further treatment with (–)-Ipc₂Ballyl afforded 164. The tetraene 166 was gradually produced via Mitsunobu esterification of acid 161 and alcohol 164 with 165 serving as an intermediate. Finally the crucial RCM gave the desired macrocycle 167 in 37% yield using Grubbs-II catalyst in benzene at 80 °C for 6 h. The macrolactone 167 was further subjected to dehydrative glycosylation with TBS-protected d-arabinofuranose 168, followed by DDQ-mediated cleavage of PMB ether to produce the secondary alcohol 170. Through several subsequent reactions, the synthesis of desired antibiotic disciformycin B (171) was achieved in 71% yield.

Scheme 18 Synthesis of disciformycin B

5

Anticancer

Cancer, one of the leading causes for global death, occurs when abnormal cells grow uncontrollably in almost any organ or tissue of the body. Lung, prostate, stomach, liver, thyroid, breast cancer etc. are most common among people. It has been realized that cancer mortality can be reduced through early detection and treatment; so, the scientific community is engaging in new ways to find appropriate and effective methods to prevent and cure this disease.

The natural product bryostatin displays a wide range of biological activities, notably anticancer activity in vivo. In 2007, Trost et al. reported the synthesis of a bryostatin analogue 178 (Scheme [19]).[41] The total synthesis commenced by developing the synthons 173 and 175 separately. The fragment 173 was prepared from (R)-pantolactone (172) in several steps. Similarly, the other fragment 175 was obtained from d-glactonic acid 1,4-lactone 174 in many steps. The two synthons were then coupled in the presence of 2-methyl-6-nitrobenzoic acid anhydride to afford the metathesis precursor 176. The crucial macrocyclization step was conducted next using Grubbs–Hoveyda catalyst in benzene at 50–80 °C to furnish the 31-membered lactone 177 as a 1:1 E/Z mixture in an excellent yield of 80%. Finally, deprotection of the macrocycle led to the formation of the target compound 178 (36%) and compound 179 (46%) which were separated and tested against several cancer cell lines. It was observed that the bryostatin analogue 178 inhibits the growth of NCI-ADRsa breast cancer cell line.

Scheme 19 Synthesis of bryostatin analogue

Small-molecule kinase inhibitors were found to exhibit great potential as novel therapeutics in the treatment of cancer. In 2007, Tao et al. noted that the unique binding mode and kinase inhibition profile caused the urea-based protein kinase inhibitors to serve as a major focus of medicinal chemists.[42] They showed interest in a class of diaryl ureas as checkpoint kinase 1 (Chk1) inhibitors which significantly potentiated the cytotoxicity of DNA-damaging agents in cancer cells and hence, designed macrocyclic ureas 186a–e as a new class of kinase inhibitors (Scheme [20]). In order to synthesize them, various intermediates 180a–c were prepared. The synthesis of the advanced intermediate cyanopyrazine 182 commenced when methylpyrazine 181 was reacted upon in four consecutive steps following a patent literature procedure. 182 was gradually converted into 183a,b in two steps. Subsequently, the metathesis precursors 184a–e were achieved when 183a,b were coupled with aniline intermediates 180a–c in DMF or toluene at 90 °C. Finally, the urea products 184a–e cyclized via olefin metathesis in the presence of Grubbs-II catalyst in refluxing DCM and afforded the desired macrocycles 185a–e in moderate to excellent yield. The unsaturated macrocycles were next hydrogenated in the presence of palladium catalyst to produce the macrocycles 186a–e.

Scheme 20 Synthesis of macrocyclic urea kinase inhibitors

Scheme 21 Synthesis of pladienolide B

Pladienolides A–G, a class of 12-membered macrocyclic compounds, isolated from a culture of an engineered strain of Streptomyces platensis, were found capable of inhibiting the proliferation of human cancer cells and binding to the SF3b subunit of the spliceosome while inhibiting the splicing of pre-mRNA to translatable mRNA. In 2012, Ghosh and Anderson showed their interest in developing a synthetic pathway for most active pladienolide B (195) (Scheme [21]).[43] The plan commenced when the synthesis of alcohol 188 was carried out in five steps from prenyl alcohol 187. Subsequently, commercially available divinyl carbinol (189) was made to undergo a series of consecutive reactions to produce the acid 190. With access to two main intermediates for the construction of the macrocyclic core, esterification of acid 190 with alcohol 188 was carried out followed by DDQ oxidative removal of the PMB ether to provide the RCM precursor 191. The crucial metathesis reaction of 191 with Grubbs-II catalyst afforded the cyclized compound 192 in 95% yield. After treating the product with Ac₂O in pyridine, lactone 193 was obtained which on being further exposed to DDQ for 24 h, removed the trityl ether. Oxidation of the resulting alcohol with IBX furnished the macrocycle 194 in 75% yield. Finally, the 12-membered macrocycle pladienolide B (195) was assembled in 67% yield when several consecutive reactions were conducted upon the macrocycle 194.

Huang and Wang, in 2016,[44] reported the first asymmetric total syntheses of natural products nannocystin A0 (205) and nannocystin A (207) bearing anticancer activity (Scheme [22]). The synthetic route for production of nannocystin A0 proceeded by synthesizing the fragment 199. Compounds 196 and 197 were made to undergo Mitsunobu reaction to afford 198 upon which several reactions were conducted to prepare 199. Simultaneously, the acid 201 was prepared from (E)-3-bromomethacrolein (200) in seven consecutive steps followed by the preparation of acyl chloride 203 by the action of Ghosez reagent 202 upon the fragment 201. Subsequently, a solution of 203 dissolved in DCM was added dropwise to a solution of fragment 199 in DCM at –20 °C to afford the desired RCM precursor 204a. Finally, the target natural product 205 was achieved in 79% yield by exposing 204a to ring-closing metathesis conditions using Hoveyda–Grubbs-II catalyst in toluene at 60 °C. A similar synthetic sequence was applied for the synthesis nannocystin A (207) using 3,5-dichloro-d-tyrosine benzyl ester (206). The RCM precursor 204b in this case furnished the target 207 in 80% yield.

Scheme 22 Synthesis of nannocystin A0 and A

A macrolactam named dysoxylactam A, isolated from the bark of Dysoxylum hongkongense, was found to hold the ability to reverse multidrug resistance in cancer cells and inhibit the function of P-glycoprotein, a key mediator in multidrug resistance.[45] In 2020, Reddy and Yu established a total synthesis of dysoxylactam A (212) using RCM as its key step (Scheme [23]).[45] The process advanced with the preparation of the polypropionate fragment 209 being achieved in a stereocontrolled manner through 10 sequential reactions from commercially available pent-4-enal (208). This was followed by the esterification of 209 with N-Boc-l-valine in the presence of EDCI and an excess amount of DMAP in DCM to afford an inseparable epimeric mixture of the esters formed at the valine residue. Subsequently, the Boc-protected esters were converted into free amines as their TFA salts and made to react with hex-5-enoic acid to give the RCM precursor 210 (epimeric mixture). Ring-closing metathesis with Grubbs-II catalyst in refluxing DCM was conducted next to afford macrocycles 211 as an inseparable diastereomeric mixture. Finally, 211 were hydrogenated with Pd/C under 1 atm H₂ to furnish the desired macrocycle dysoxylactam A (212) in 43% yield and its C-2′ epimer 213 in 29% yield.

Scheme 23 Synthesis of dysoxylactam A

6

Miscellaneous

Scheme 24 Synthesis of macrocyclic nonylprodigiosin

We would also like to throw light upon certain areas of synthetic organic chemistry which helped develop bioactive macrocycles for treatment of various other diseases and medical issues. The drugs required for the treatment of inflammation, sleeping sickness, obesity, leukemia, and many more have always been a topic of concern for medicinal chemists. In 2001, the Fürstner group reported the total synthesis of naturally occurring macrocyclic nonylprodigiosin (218) involving RCM methodology (Scheme [24]).[46] The RCM precursor 216 was prepared by Suzuki reaction between heteroaryl triflate 214 and boronic acid 215. The subsequent metathesis reaction in refluxing DCM with catalyst 227 (see Figure [1]) afforded 217 which furnished the target compound 218 via hydrogenation in 65% yield. By replacing the synthon 215 with different functionalized boronic acid derivatives, several other RCM precursors 219–223 were prepared (Figure [1]). The hydrochloride salts of precursors 220–222 were subjected to RCM to obtain the corresponding nonylprodigiosin analogues 224–226 in excellent yields (Figure [1]). The thiophene derivative 223 resisted ring closure while 219 afforded a dimer under RCM conditions. Comparison of the newly synthesized prodigiosin derivatives 218 and its analogues with undecylprodigiosin 228 was done in two different experiments: (i) proliferation of murine spleen cells induced by lipopolysaccharides (LPS) and concanavalin A (Con A), and (ii) vacuolar acidification of baby hamster kidney (BHK) cells. These macrocycles were found to suppress the Con A induced T-cell proliferation in a manner stronger than the LPS-induced B-cell proliferation although derivative 218 exhibited lower activity than its parent compound 228. Macrocycle 218 prevented vacuolar acidification but 224–226 either exhibited trace effects or had no effect at all. It was concluded that three pyrrole units were required for the exhibition of inhibitory activity of prodigiosins on vacuolar acidification.

Figure 1 Some macrocycles and their precursors

Oxytocin, a mammalian nonapeptide hormone, was modified by the Vederas group[47] in 2003 to create its fully saturated dicarba analogue 233. They synthesized 231 (Z) and 232 (E) olefinic analogues of oxytocin through RCM (Schemes 25 and 26). The linear peptide 230 was first synthesized by replacing cysteine with allylglycine on Rink amide NovaGel resin (Scheme [25]). The resin-bound linear peptide 230 was next subjected to macrocyclization conditions involving Grubbs-I catalyst in refluxing DCM for 24 h to afford a mixture of olefinic products. DMSO was consecutively added to the resin-bound peptide, the Fmoc group was removed, and side chain deprotection synthesized a 4:1 mixture of 231 (Z) and 232 (E) isomers in 45% yield. Hydrogenation of the mixture led to the reduction of the olefinic double bond in 231 without altering the nature of 232 and ultimately, the saturated derivative 233 was obtained (Scheme [26]). All three analogues (231–233) were biologically tested on rat uterus strips and it was concluded that the Z isomer 231 was the most active analogue with an EC50 value 14-fold less than that of oxytocin. The E isomer 232 and the saturated analogue 233 were found to be less active than the Z isomer.

Scheme 25 Synthesis of oxytocin analogues

Scheme 26 Synthesis of a saturated oxytocin analogue

The melanocortin receptor (MC4-R) regulates the body weight in mammals and has been found to be associated with obesity. On finding it as a target for drug design, in 2005 the Liskamp group synthesized a novel potent cyclic peptide MC4-ligand 237 via metathesis (Scheme [27]).[48] By using an automated peptide synthesizer, peptide 235 was synthesized on ArgoGelTM-OH resin 234. Next, it was cleaved through aminolysis of the ester linkage using a saturated solution of ammonia in methanol. The linear peptide 235 was afforded in a high yield and subjected to macrocyclization conditions using Grubbs-I catalyst at 100 °C in 1,1,2-trichloroethane. After an hour, the second portion of catalyst was added on cooling the reaction mixture 40 °C. Finally, through deprotection and purification, the production of cyclized peptide 237 resulted in 63% yield as a mixture of E and Z isomers.

Scheme 27 Synthesis of melanocortin (MC-4) ligand

Analogues of the neuroprotective agent glycyl-l-prolyl-l-glutamic acid (GPE) were synthesized by Harris and Brimble in 2006 (Scheme [28]).[49] In order to synthesize the macrocycle 242, proline methyl ester 238 and Cbz-(S)-allylglycine 239 were chosen as the starting materials. Subsequent reactions produced the RCM precursor 240 which underwent macrocyclization using Grubbs-I catalyst in refluxing DCM to afford an isomeric mixture of 241. Reduction of 241 followed by deprotection of the benzyloxycarbamate and the benzyl esters furnished the desired macrocycle 242 in 58% yield (E). Similarly, the macrocycle 246 was produced using ester 243 and 239 as the starting materials. Through consequent reactions in three steps, the precursor 244 was produced and made to undergo metathesis using Grubbs-II catalyst in benzene at 40 °C to obtain the olefinic macrocycle 245 (E/Z mixture). Hydrogenation and deprotection of 245 followed next to produce the target compound 246 in 58% yield as a 65:35 mixture of E/Z isomers.

Scheme 28 Synthesis of neuroprotective agent GPE analogues

In 2010, Sliwa et al. [50] synthesized 1,3-bridged azetidin-2-ones by RCM reaction from 1,3-bis-ω-alkenoyl-3(S)-aminoazetidin-2-one precursors (Scheme [29]). Through computational study the target molecules were found to be potent inhibitors of R39 d,d-carboxypeptidase, a bacterial model enzyme for penicillin binding proteins (PBPs). The synthetic route advanced with the production of compound 249 from Boc-l-serine 247 and 250 from Boc-Me-l-serine 248. The RCM precursor N-Boc bis-acylated monocyclic azetidinones 251a–c were next furnished in one step by treating 249 with alkenoyl chlorides in the presence of lithium hexamethyldisilazanide. Another set of precursors 252a–c and 253a–c were prepared by subsequent reactions of 249 and 250.

When the precursors with n = 1(251b, 252b, and 253b) were exposed to macrocyclization conditions with Grubbs-II catalyst in DCM at 40 °C, the products 254a, 255a, and 256a, respectively, were obtained. Similarly, precursors with n = 2 (251c, 252c, and 253c) afforded the macrocycles 254b, 255b, and 256b, respectively, in (10–30%) yields. It was noted that all the isolated compounds formed cyclic dimers. The RCM precursors with n = 0 did not undergo cyclization and only one monomer 257 was obtained in a very poor yield (9%). The monomer 257 and dimers 254–256a,b were subjected to catalytic hydrogenation and the olefins were reduced to produce the saturated macrocycle 261 and 258–260a,b, respectively. The tests done for biological activity showed promising results using the R39 serine-enzyme. The bicyclic β-lactams 257 and 261 were confirmed to be good inhibitors of d,d-peptidase. The macrocycles 254c, 255b,c, and 259b,c also exhibited remarkable inhibitory effect.

Scheme 29 Synthesis of 1,3-bridged azetidin-2-ones

In 2013, Zhou et al. targeted the menin–mixed lineage leukemia 1 (MLL1) protein–protein interaction as it blocked MLL1-mediated leukemogenesis.[15] They designed a class of macrocyclic peptidomimetic inhibitors of the menin–MLL1 interaction by using ABI 433 peptide synthesizer with proline preloaded 2-chlorotrityl chloride resin (Scheme [30]). Cleavage of the peptides by treatment with TFA in DCM followed by coupling with corresponding amines (CH₂=CH-(CH₂)_nNH₂) led to the formation of RCM precursors 263. Macrocyclization was conducted next by using Grubbs-I catalyst in DCM solvent to afford 264. The newly formed double bond was gradually reduced through catalytic hydrogenation and subsequent deprotection afforded the desired macrocyclic compounds 265. Within this generated class of macrocycles, compound 266 was found to be most potent macrocyclic peptidomimetic.

Scheme 30 Synthesis of inhibitors of the menin-mixed lineage leukemia 1 interaction

Scheme 31 Synthesis of glucocorticoids

In 2015, Biju et al. initiated the synthesis of novel corticosteroids from widely used anti-inflammatory steroid prednisolone (267a) (Schemes 31 and 32).[51] Following up the structural design of a reported compound, two macrocycles 16-membered 270a and 13-membered 275 were furnished from commercially available prednisolone (267a). Another set of macrocycles 270b,c were prepared from 6-methylprednisolone (267b), and 16-methylprednisolone (267c). The synthetic route proceeded by conversion of prednisolones into their corresponding mesylates 268a–c (Scheme [31]). Two subsequent steps resulted in the production of RCM precursors 269a–c which were gradually subjected to metathesis reaction in the presence of Grubbs-II catalyst in refluxing DCM to afford the macrocycles 270a–c as E isomers in 28%, 31%, and 23% yields, respectively. Mesylation of prednisolone 271 followed by displacement with N-allyl-2-mercapto-benzimidazole produced 272 which upon treatment with pent-4-enoyl chloride and DMAP in DCM developed a metathesis precursor 273 (Scheme [32]). On subjecting 273 to RCM conditions, the corresponding macrocycle 274 was formed in 66% yield as the E isomer. Further deprotection led to the formation of the desired 13-membered macrocyclic compound 275 in 48% yield. Commercially available 276 was converted into the olefinic precursor 277 and upon macrocyclization through RCM, 278 was achieved as a 3:1 mixture of isomers in 13% yield.

Scheme 32 Synthesis of glucocorticoids

In 2017, Estrada-Ortiz et al. synthesized a library of novel macrocycles 285a–k of various ring sizes (12, 13, 18, 19, and 24) using RCM and classical Ugi four-component (U-4CR) reactions as key steps (Scheme [33]).[14] These macrocycles were found to target the hydrophobic region around Tyr67, Gln72, His73, Val93, and Lys94 and inhibit the p53–MDM2 interaction. The Ugi-adduct was synthesized through four building blocks benzylamines 279a–h, 6-chloro-indole-3-carbaldehyde 280, aliphatic carboxylic acids 282a–c and the isocyanides 281a,b. The benzylamines 279a–h were either commercially available or synthesized through Williamson ether synthesis. Vilsmeier–Haack formylation reaction afforded the aldehyde 280 using a 6-chloro-indole derivative. The isocyanides 281a,b were synthesized from their corresponding formamides while the carboxylic acids 282a–c were obtained commercially. On irradiation at 120 °C for 1 h in a microwave oven, the equimolar mixture of the four components furnished the RCM precursors 283a–k. Finally, the metathesis reaction was conducted in refluxing DCM using Grubbs-II catalyst to afford compounds 284a–k in 10–96% yield as a mixture of E/Z isomers. The cyclized products were next hydrogenated on Pd/C to isolate the compounds and finally ester hydrolysis was conducted to obtain compounds 285a–k in 11–70% yield. The inhibitory affinities (K_i) of the macrocycles against MDM2 were determined and most of them were found to be active towards MDM2. The affinity was noticed to improve as the ring size increased from 12 to 18 whereas one large 24-membered macrocycle showed decreased activity.

Scheme 33 Synthesis of macrocyclic inhibitors of the p53-MDM2 interaction

In 2017, Li et al. designed a series of macrocyclic analogues following up the cocrystal structure of small molecule plasma kallikrein (pKal) inhibitor 286 (Scheme [34]).[13] The synthesis advanced with the initial condensation of 3-aminocrotononitrile (287) and 2-cyanoacetic acid (288) with acetic anhydride to afford bis-nitrile 289 which underwent three consecutive reactions to produce the intermediates 4-alkenyloxy-2-aminopyridines 290 and 291. Next, 2-hydroxy-4-methylbenzoic acid (292) was made to react with acetone under acidic conditions to furnish the acetonide 293. Subsequently, the acids 294a,b were formed in two steps and coupled with either amine 290 or 291 to give the RCM precursors 295a–c. On subjecting them to RCM reaction with Grubbs-II catalyst in DCE at 70 °C, the macrocycles 296a–c were synthesized as E/Z isomers. The isomers of 296a were found to exhibit weak inhibition of pKal when compared to the small molecule 286. Hydrogenation of 296a produced its corresponding saturated macrocycle 296a′ which was found to be even less potent than 296a E and Z. The macrocycle 296b, with a 9-atom linker, was found to be 250-fold more potent than 296a E and Z whereas the macrocycle 299 formed via RCM by using 297 was found to be 40-fold less potent than 296a E and Z isomers.

Scheme 34 Synthesis of macrocyclic inhibitors of plasma kallikrein

Neurotensin (NT) is a tridecapeptide known to induce a strong analgesic action when administered to rodents. In 2018, Sousbie et al. reported macrocyclic peptide analogues of NT 304 by employing RCM methodology (Scheme [35]).[10] The precursor 300 was produced by using Fmoc solid-phase peptide synthesis (SPPS). Fmoc-Tyr(3-allyl)-OH helped in the insertion of the first allyl group required for metathesis. Consecutively, Fmoc was deprotected, the nosyl group was introduced on resin, and acetylation of the tyrosine phenol was conducted. The second allyl group was inserted through optimized Fukuyama–Mitsunobu conditions to afford the RCM precursor 301. The crucial macrocyclization step was carried out next using Hoveyda–Grubbs-II catalyst in p-benzoquinone in DCE at 50 °C to afford macrocycle 302 which underwent deprotection of the nosyl and acetyl groups to produce the desired compound 303. Following this similar strategy, several analogues 304 of various ring sizes (21–25) were prepared by changing their N-terminal amino acid and linkers.

Scheme 35 Synthesis of macrocyclic peptide analogues of neurotensin (NT)

Neglected tropical diseases like Chagas disease and sleeping sickness caused by protozoan parasites of the genus Trypanosoma have caused adverse effects on the health of people.[3] Taking this factor into consideration, in 2020, the Paterson group developed an efficient total synthesis of the potent anti-trypanosomal macrolide (+)-actinoallolide A (310) (Scheme [36]).[3] Construction of the target macrocycle progressed with the preparation of the acid 307 and the alcohol 308. (S)-Lactic acid (305) was subjected to several reactions in seven consecutive steps to prepare 307 whereas the chain fragment 308 was synthesized by exposing an ethyl ketone derivative 306 to subsequent reactions in eight steps. Yamaguchi esterification between fragments 307 and 308 developed the macrocyclic precursor which finally, produced the 12-membered macrolactone 309 when treated with Hoveyda–Grubbs-II catalyst in refluxing toluene. Several steps followed the key step of RCM to afford their target compound actinoallolide A (310) in an excellent yield of 99%.

Scheme 36 Synthesis of actinoallolide A

Scheme 37 Synthesis of sanglifehrin spirolactams

Scheme 38 Synthesis of sanglifehrin A and B

In 2021, Chang et al. reported the total synthesis and biological evaluation of immunosuppressants sanglifehrin A (324a) and sanglifehrin B (324b) (Schemes 37 and 38).[7] Sanglifehrin, a class of macrolides, derived from the isolates of Streptomyces sp. A92-308110 in 1999, were screened to identify novel immunosuppressants which target cyclophilin A (CypA).[7] Construction of the 22-membered macrocycles commenced with the production of building blocks 313 and 315. In order to prepare the ketone 313, a readily available aldehyde 311 was chosen as the starting material (Scheme [37]). Upon adding an ethyl group to 312 following Grignard addition, the substrate could ultimately be oxidized using Dess–Martin periodinane to furnish 313. The synthesis of the aldehyde 315 was carried out in two steps from the iodide 314. With these building blocks in hand, pyran-4-one 316 was synthesized through cross-aldol coupling of 313 and 315 followed by oxidation and acid-catalyzed cyclization. Several reactions like regioselective debenzylation, TEMPO-mediated oxidation, and one-pot amide transformations were consecutively followed to produce 317. The primary amide 317 underwent a series of reactions to afford the sanglifehrin B spirolactam moiety 318b in five steps while sanglifehrin A spirolactam moiety 318a was synthesized in six steps. Subsequently, the fragment 320 was obtained in sequential reactions starting from the allyl alcohol 319 (Scheme [38]). Amide coupling between the acid 320 and tripeptide 321·TFA synthesized the RCM precursor 322 which on treatment with Hoveyda–Grubbs-II catalyst in BQ at 80 °C afforded the macrocycle 323 in 12% yield. It was improved to 24% upon using modified Hoveyda–Grubbs-II catalyst and up to 48% upon using catalytic amount of 2,6-bis(trifluoromethyl)phenylboronic acid. Stille–Migita cross coupling of macrocycle 323 with 318a and further deprotection of silyl and ketal groups afforded the desired compound sanglifehrin A (324a) in 50% yield. A similar methodology was followed to afford sanglifehrin B (324b) in 60% yield. Evaluation of biological activities of both sanglifehrin A and B clarified that they exhibited moderate antiproliferative effects in Jurkat cells but sanglifehrin B proved to be more potent. Structural modification about the spirolactam, specifically at the C40 position, enhanced the activity of sanglifehrin analogues against Jurkat cells. Also, it was found that sanglifehrin A preferentially forms higher-order protein complexes between CypA and IMPDH2.

The stimulator of interferon genes (STING) pathway has an increased viability as a drug target for treatment of various diseases including infections, cancers etc. In 2021, Kim et al. developed a synthetic route to create E7766 using RCM as a crucial step (Scheme [39]).[52] Commercially available 325 was made to react with allyl alcohol to produce alkene 326. After several consecutive reactions, the RCM precursor 327 was synthesized which upon exposure to metathesis conditions with Hoveyda–Grubbs-II catalyst in refluxing toluene, the desired macrocycle-bridged construct 328 was obtained in 39% yield as the E isomer. The two 2-nitrobenzyl groups were removed with PhSH/TEA consecutively as well as the two benzoyl groups with ammonium hydroxide and ultimately E7766 (329) was furnished in 70% yield. Through various tests it was found that E7766 showed superior and pan-genotypic activity against four major human STING variants than 2′,3′-cyclic guanosine monophosphate–adenosine monophosphate (cGAMP).

Scheme 39 Synthesis of macrocyclic-bridged STING agonist E776

7

Conclusion

In conclusion, we have reported several synthetic methods for the development of various biologically active macrocycles involving ring-closing metathesis (RCM) as a key step. It served as a crucial step of macrocyclization in each synthetic route presented in this review. These macrocycles exhibited inherent properties like antiviral, antifungal, antibacterial, anticancer, and more. Hence, their development and utilization has been very crucial in the medicinal and synthetic organic chemistry field.

Conflict of Interest

The authors declare no conflict of interest.

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Publication History

Received: 31 January 2023

Accepted after revision: 03 April 2023

Article published online:
23 May 2023