Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review

Abstract

The Mitsunobu reaction plays a vital part in organic chemistry due to its wide synthetic applications. It is considered as a significant reaction for the interconversion of one functional group (alcohol) to another (ester) in the presence of oxidizing agents (azodicarboxylates) and reducing agents (phosphines). It is a renowned stereoselective reaction which inverts the stereochemical configuration of end products. One of the most important applications of the Mitsunobu reaction is its role in the synthesis of natural products. This review article will focus on the contribution of the Mitsunobu reaction towards the total synthesis of natural products, highlighting their biological potential during recent years.

1. Introduction

The Mitsunobu reaction is considered as an important reaction because of its great applications in organic synthesis. It was discovered by Oyo Mitsunobu during the mid-twentieth century. It is a dehydrative redox reaction that converts an alcohol to an ester by coupling with an acid/pronucleophile [1]. The pronucleophiles include oxygen pronucleophiles, such as carboxylic acids, nitrogen pronucleophiles, such as imides and sulfonamides, and sulfur pronucleophiles, such as thiols, etc. [2]. This reaction is mediated by phosphines, i.e., triphenylphosphine, and azodicarboxylates, i.e., diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc., and a solvent [3]. A general Mitsunobu reaction is represented in Scheme 1.

In case of sterically hindered alcohols, 4-nitrobenzoic acids or phthalimides are also used for coupling. Besides these, many other reagents, such as fluorinated alcohols and hydroxamates, can also be employed for Mitsunobu coupling [4]. In this way, this reaction allows the formation of C-C, C-N, C-O and C-S bonds formation owing to its diverse selection of reagents. The panoramic feature of this reaction is that it brings about inversion of configuration by coupling of a chiral secondary alcohol and a pronucleophile [5].

The Mitsunobu reaction has a wide range of applications in organic synthesis as it encapsulates the total synthesis of natural products, drugs, analogues, and semisynthetic derivatives of naturally occurring compounds, etc. It constitutes a key step in the synthesis of many of the natural products and other pharmaceuticals. Figure 1 describes a few examples where the Mitsunobu reaction has played its crucial role:

The total synthesis of sinodielide A 1, which is used as a flavoring, fragrance, medicine, and poison, employs the Mitsunobu reaction as an important step [6,7]. Similarly, the synthesis of anti-proliferative menaquinone 4, which is a homologue of vitamin K, and synthesis of cannabidiol derivatives 3, which is used for the treatment of arthritis, immune system disorders, and diabetes, include the Mitsunobu reaction as a key step [8,9]. It has played a great role in the synthesis of drugs and their derivatives, such as the synthesis of NPS R-568 2, which is a calcimimetic drug used for the treatment of primary and secondary hyperparathyroidism [10]. This paper reviews the importance of the Mitsunobu reaction in the synthesis of some of the natural products reported in recent years.

2. Review of the Literature

2.1. Alkaloids-Based Natural Product Synthesis

2.1.1. Yuzurimine Alkaloids

The Mitsunobu reaction has been used for the modification and synthesis of scaffolds for the total synthesis of natural products. The yuzurimine alkaloids are extracted from Daphniphyllum macropodum [11] and exhibit many biological activities. In 2019, Hayakawa et al. proposed the synthesis of the heterocyclic portion of yuzurimine-type alkaloids [12]. For this purpose, a protected alcohol 6 synthesized from precursor 5 underwent the Mitsunobu reaction for intramolecular alkylation and gave Ns amide 7 in a 69% yield. The next step involved selective deprotection of hydroxyl group to give 8 in a 75% yield. An intermolecular Mitsunobu reaction was performed to give a bicyclic product 9, which could be converted to the desired product deoxyyuzurimine 10 over a few steps (Scheme 2).

2.1.2. Phenanthrene Alkaloids

Phenanthrenes are known as chromophores that exhibit many physiochemical properties, such as photoconductance and electroluminescence [13]. Aristolactams are phenanthrene-related compounds that are isolated from Aristolochia argentina. These have been used in many folk medicines in the past [14]. Luong et al. reported the total synthesis of aristolactam 15 in 2019 [15]. To achieve the task an appropriate aldehyde 11 was converted to phenol 12 over a few steps. In the next step, an already synthesized alcohol 13 with an anti:syn ratio of 6:1 was utilized to couple with phenol 12 via a Mitsunobu reaction in the presence of diisopropyl azodicarboxylate (DIAD) and triphenyl phosphine (PPh₃) in toluene at 0 °C to 90 °C to obtain 76% of the coupled product 14. The last step included the global deprotection and cyclization of ether by using TFA in anisole that provided stereoselective (+)-aristolactam 15 in a 32% yield (Scheme 3).

2.1.3. Indole Alkaloids

Nauclefine is an indole alkaloid which was extracted from a West African tree named Nauclea latifola. It exhibits a number of biological activities, such as anti-tuberculotic, anti-inflammatory, and anti-neurodegenerative [16,17]. In 2021, Chen et al. proposed the total synthesis of nauclefine 24 by using commercially available starting materials [18]. The total synthesis was accomplished by employing the Mitsunobu reaction, Fischer indolization, and allylic oxidation in six steps. In the first step, the TMS-protected alkynol 16 was made to react with the hydroxy isoindolene derivative 17 via a Mitsunobu reaction in the presence of PPh₃ and DIAD in THF at 0 °C to room temperature to give alkyne 18 in a 94% yield. In the next step, the alkyne 18 was reacted with hydrazine monohydrate using MeOH/DCM and freshly prepared nicotinic acid in the presence of K₂CO₃, EtOAc/H₂O to yield nicotine amide followed by catalysis in the presence of 2.5 mol% of (Cp*RhCl₂)₂ as a catalyst and 3 eq. of CsOAc with TFE to furnish regioisomeric products 20 and 21 in the yield of 28 and 69%, respectively. Later on, naphthyridine derivatives were treated via Mitsunobu reaction conditions with PPh₃, DIAD, and THF in a reaction mixture to give tricyclic product 23 in a 76% yield. It was further oxidized in the presence of SeO₂ and Dess–Martin periodinane followed by Fischer indolization to yield the desired product, nauclefine 24 in a 66% yield (Scheme 4).

2.1.4. Discorhabdin Alkaloids

Discorhabdin is an alkaloid extracted from marine sponges and possesses anti-cancerous, anti-malarial, and antimicrobial properties, etc. [19]. Noro et al. explained the total synthesis of discorhabdin by employing a number of synthetic strategies in 2021 [20]. The main framework of discorhabdin consists of an aza-spirodienone-fused pyrroloiminoquinone having a pentacyclic core. In the first step, commercially available carboxylic acid 25 was reduced with LiAlH₄ in THF followed by Birch reduction using Li and NH₃ in EtOH/THF to yield cyclohexadiene 26. The acidic hydrolysis of cyclohexadiene pursued by ketone reduction by NaBH₄ and the selective protection of primary alcohol using TBSCl in DCM to yield cyclohexenol 27 in a 70% yield. Then, tryptamine derivative 28 was coupled with cyclohexenol 27 via the Mitsunobu reaction in the presence of DIAD and PPh₃ in toluene to yield 29. Further, the compound 29 was deprotected to yield 30 in quantitative yield that again was subjected to another Mitsunobu reaction in the presence of NsNHBoc, DIAD, and PPh₃ to yield Boc-protected tryptamine derivative 31 in a 67% yield. The tryptamine derivative 31 was then converted to discorhabdin 32 over a few steps (Scheme 5).

2.1.5. Lycopodium Alkaloids

Fawcettimine belongs to the Lycopodium alkaloid and is extracted from Lycopodium fawcetti [21]. This class of compounds consists of approximately 300 natural products, some of which are biologically active, e.g., fawcettimine. In 2020, Zeng et al., reported the total synthesis of fawcettimine over eleven steps using commercially available starting material (R)-(+)-pulegone [22]. For achieving the total synthesis of fawcettimine, Pd-mediated cycloalkenylation, Mitsunobu reaction, and an oxa-Diels–Alder reaction were utilized as key steps. (R)-5-Methyl-2-cyclohexen-one 33 was converted to intermediate 34 after few steps. It was further allowed to undergo the oxa-Diels–Alder reaction using EuFOD in the first step and para toluene sulphonic acid (PTSA) in acetone in the next step to obtain the aldehyde derivative 35 in a 93% yield. The aldehyde derivative 35 was further reduced with NaBH₄ in DCM/MeOH and subjected with MsCl in Et₃N and DCM to obtain mesylate 36 in a 64% yield. In the following step, mesylate 36 was aminated using p-NH₂Ns in K₂CO₃. Subsequently, Dess–Martin oxidation furnished the desired intermediate 37 in a 72% yield. The intermediate 37 underwent the Mitsunobu reaction for ring closure by using PPh₃, DEAD. and PhMe to obtain a 67% yield of 38. In the last step, desulfonylation of 38 was performed by using PhSH in MeCN and KOH to obtain the final product, fawcettimine 39, in an 81% yield (Scheme 6).

Lycopoclavamine-A [23] resembles fawcettimine-type alkaloids [21] having minor structural differences. Kaneko et al. reported the total synthesis of lycopoclavamine-A in 2019 with overall yield of 14.4% by featuring a stereoselective conjugate addition and the Pauson–Khand reaction as the main steps [24]. The total synthesis was initiated from crotonamide 40, which was converted to diastereomer 41 over a few steps. The Mitsunobu reaction of diastereomer 41 was performed in the presence of diethyl azodicarboxylate (DEAD) and triphenyl phosphine to introduce nitrogen in the ring to yield bicyclic compound 42 in a 92% yield. The next step involved the deprotection of group OTBDPS and the generation of the primary alcohol, which underwent an intramolecular Mitsunobu reaction to yield the tricyclic product 43 in a 74% yield. In the following step, two MOM groups were removed and a triflate group was deprotected in the presence of 12 N HCl and 1 N NaOH with dioxane in methanol to yield secondary alcohol 44. In the last step, the nosyl group was deprotected to yield the final product 45 in a 79% yield (Scheme 6). An epimer of 41 3-epi-24 underwent a similar strategy to provide the final product, lycopoclavamine-A, contributing to the overall yield (Scheme 7).

Palhinine alkaloids belong to Lycopodium alkaloids [21], having a fused isotwistane and azonane in their skeleton. A number of strategies have been developed for the total synthesis of a palhinine skeleton. Han et al. reported the synthesis of a tetracyclic skeleton of palhinine alkaloids by employing the carbocyclization cascade mechanism in 2020 [25]. The first step involved the reaction of 1,3-cyclohexanedione 46 with 1,3-dibromopropane 47 followed by α-propargylation in the presence of 3-bromo-trimethylsilyl propyne 48 to yield 49 an 83% yield. In the next step, 1,2-addition of enone took place preceded by acid hydrolysis that provided 64% of compound 51. Further, an intermolecular Mitsunobu reaction in the presence of PPh₃, DIAD, and NsNH₂ in THF followed by desilylation produced 52 a 74% yield. Another intramolecular Mitsunobu reaction in the presence of triphenyl phosphine and diethyl azodicarboxylate was performed to afford 53 a 70% yield. The last step included the carbocyclization cascade to produce a diastereomeric tetracyclic skeleton 54 in a 28% yield and a by-product 55 in a 24% yield. The tetracyclic skeleton 54 could serve as a key intermediate for the total synthesis of palhinine alkaloids (Scheme 8).

2.1.6. Pyrrole Alkaloids

Parvistemonine is an alkaloid extracted from the roots of Stemona parviflora and has been used as a folk medicine. Matsuo et al., in 2020, reported the total synthesis of parvistemonine in ten steps by employing the Mukaiyama–Michael addition, an aza-Wittig reaction, a Paal–Knorr pyrrole synthesis and the Mitsunobu reaction, etc., to give the final product in a 19.6% overall yield [26]. The first step involved the reaction of γ-lactone 56 with n-butyllithium and then oxidation with IBX to produce keto aldehyde 57 in a 74% yield. It was further treated with azide 58 in the presence of triphenyl phosphine to give the required coupling product 59 in a 65% yield. The next step included acid-mediated annulation in the presence of toluene sulphonic acid and acetonitrile followed by deprotonation with LHMDS and methylation with MeI, which gave 83% of the product 60. Later on, the compound 60 was subjected to alkaline hydrolysis and then was reacted with di-2-methoxyethyl azodicarboxylate (DMEAD) and PPh₃ to give the final product 61 in a 77% yield (Scheme 9).

2.1.7. Oroidin Alkaloids

Nagelamides belong to a group of oroidin alkaloids [27] and are derived from a marine sponge. Bhandari et al., in 2020, proposed the total synthesis of nagelamides by employing the Mukaiyama–Michael addition, an acid-mediated annulation, an aza-Wittig reaction, and a Mitsunobu reaction as the key steps [28]. First of all, two fragments of imidazolyl iodide 63 and vinyl stannanes 65 were synthesized from diiodo imidazole 62 and imidazole iodide 64 in a 93% and 57% yield, respectively. These two fragments, 63 and 65, were coupled together in the presence of Pd₂dba₃ CsF, CuI, PPh₃, and DMF to give 75% of the coupled product 66. Further, 66 was treated with an excess of n-butyllithium and then an azido group was introduced into both imidazole groups followed by desilylation by using TBAF and THF to obtain diol 67 in a 78% yield. The Mitsunobu reaction was used to couple diol 67 and the dibromo dione derivative 68 in the presence of PPh₃, DIAD, and THF to obtain the dibrominated pyrrole derivative 69 in an 80% yield. The pyrrole derivative 69 was hydrolyzed by NaOH and deprotected by acidic methanol followed by the hydrogenolysis of azides to amino groups by using a Lindlar catalyst to produce nagelamide D 70 in a 51% yield over two steps (Scheme 10).

2.1.8. Communesin Alkaloids

Communesin alkaloids are polycyclic epoxide-containing alkaloids which exhibit a number of biological activities. These alkaloids were first extracted from Penicillium fungus. These alkaloids are cytotoxic, insecticidal, and anti-cancerous in their behavior [29]. The total synthesis of communesin alkaloids have been a challenging task for researchers due to their complex epoxide-containing structures. In 2019, Pompeo et al. proposed the total synthesis of two natural and six synthetic communesin alkaloids [30]. The total synthesis commenced from sulfonamide 71, which was condensed with N-methyl-4-bromoistan 71, followed by allylation with allyl magnesium bromide 72 along with ozonolysis in the presence of ozone and methanol to give 73 in an 85% yield. Further, the Mitsunobu reaction with N-carbobenzoxy-2-nitrobenzenesulfonamide gave 76% of the product 74. Over a few steps, 74 was converted to heterodimeric diamine 75. Finally, heterodimeric diamine 75 was reacted with tertiary butoxy lithium and neutralized with pyridinium p-toluene sulphonate (PPTS) along with TASF treatment to give communesin A 76 in a 77% yield. Similarly, heterodimeric diamine 75 underwent aminal rearrangement followed by acylation with sorbic anhydride to furnish communesin B 77 in an 86% yield (Scheme 11). The synthesized communesin alkaloids were selected for anticancer activities against five human cancer cell lines, namely, prostate carcinoma (DU-145), human lung carcinoma (A549), colorectal carcinoma (HCT-116), breast adenocarcinoma (MCF7), and cervical adenocarcinoma (HeLa) cell lines. Among the synthesized communesin alkaloids, communesin alkaloid B manifested the best cytotoxic potency, having IC₅₀ values as presented in Figure 2.

2.1.9. Pyrroloquinoline Alkaloids

Marine alkaloids, such as batzellines and isobatzellines [31], are renowned for their various biological activities. Deep water marine Caribbean sponge Batzella sp. Acts as a source of batzellines, which possess cytotoxic and anti-HIV activities. Yamashita et al. reported the total synthesis of batzellines in 2020 by employing a number of key steps, such as ring expansion of benzocyclobutenone oxime sulfonate and benzyne-mediated cyclization to design an efficient route [32]. The total synthesis began with the reaction of ketene silyl acetal 79 and 4-bromoveratrole 78 in the presence of LiTMP and THF, followed by subsequent treatment with aq. HF to give the primary alcohol 80 in an 84% yield. The next step involved the amide formation via Mitsunobu reaction conditions with NSNHBoc and DMEAD in the reaction mixture to obtain 78% amide derivative 81. Further, bromination of amide 81 with an NBS agent followed by condensation in the presence of NH₂OH.HCl and Boc protection with acetonitrile in DMAP gave oxime sulphonate 82. It was treated with NaSMe in MeCN preceded by cascade cyclization using an excess of LiTMP to pivotal aryl anion 83. The pivotal aryl anion 83 underwent an aqueous work up to give pyrroloindoles 85 and 86 in an 80 and 82% yield, respectively. Isobatzelline B 87 was synthesized from pyrroloindoles 85 by treatment with TFA followed by amino group addition to provide a 94% yield. The compound 86 was treated with a manganese reagent in the presence of oxygen to give batzelline A 88 along with a fragment 89, which, upon subsequent treatment with ammonium chloride and methanol, yielded isobatzelline A 90 in a 74% yield (Scheme 12).

2.1.10. Morphine Alkaloids

Morphine is an analgesic alkaloid isolated from the opium poppy plant. It has been ranked among the top medicines by the World Health Organization. Pharmacologically, it acts as an analgesic and sedative medicine [33]. The total synthesis of morphine, comprising of 16 steps, was first proposed by Zhang et al. in 2019 [34]. It was commenced from 3-butyn-1-ol 91, which was undergone for primary hydroxyl group protection, followed by the formation of a Weinreb amide 92 upon reaction with N-methoxy-N-methyl carbamoyl chloride. In the next step, boronation of the Weinreb amide 92 along with Suzuki coupling, followed by the addition of methyl magnesium bromide, gave 67% of the enone precursor 94. After the screening of a number of catalysts, 2,4,6-triisopropyl benzoic acid was used as the most effective catalyst along with an additive 95 for an enantioselective Michael addition followed by Robbinson annulation to give the tricyclic product 96. In the later step, a tetracyclic enone 98 was formed after the allylic group introduction along with Friedal-Crafts type cyclization. Later on, selective epoxidation followed by treatment with N₂H₄.H₂O and debenzylation in the presence of DDQ gave 52% of the desired alcohol 99. The alcohol 99 was converted to codeine 100 in a 68% yield by highly a regioselective intermolecular Mitsunobu reaction followed by redox reactions. In the last step, the demethylation of codeine in the presence of boron tribromide gave the desired morphine 101 in an 81% yield (Scheme 13).

Thebainone A is related to the family of morphine alkaloids [35]. It is extracted from Papaver sominiferum. Thebainone A has many applications in the medicinal field. It is used to relieve severe pain. Wang et al., in 2020, reported the total synthesis of (±)-Thebainone A [36]. The total synthesis commenced from isovaniline 102, which was converted to isoxazolidine 103 over a few steps. Next, isoxazolidine 103 was hydrogenolytically cleaved to obtain trihydroxy phenol 104. The trihydroxy phenol 104 was made to undergo the Mitsunobu reaction with diethyl azodicarboxylate (DEAD) and Et₃N.HCl to obtain morphinan 105 in a 52% yield. The cis-diol moiety in 105 underwent formamide acetal pyrolysis followed by esterification and then conversion to ethyl carbamate 106 in an 89% yield. The ethyl carbamate 106 was made to react with selenium dioxide and oxidized with Dess–Martin periodinane to get the enone 107 in a 21% yield. In the next step, the enone 107 was protected as dioxolane followed by reduction and deprotection to yield the final product (±)-Thebainone A 109 in a 96% yield (Scheme 14).

(−)-Thebainone A has also been synthesized by Hou et al. in 2021 [37]. They used a deconstructive methodology to achieve the total synthesis of (−)-thebainone A with enantioselective ratio of up to 99.5:0.5 by employing a C-O bond cleavage reaction and enantioselective C-C bond activation as key steps. The total synthesis commenced from a known anisole 110. It was converted into an alcohol derivative 111 through Birch reduction and formation of ketal in the presence of pyridinium p-toluene sulfonate (PPTS). In the next step, the Mitsunobu coupling with an alcohol 112 provided the derivative of the ketal substrate 113 in a 93% yield. In the next step, rhodium-catalyzed coupling with (R)-DTBM-segphos produced a tetra cycle 114 in a 76% yield, which, after a few steps, gave (−)-thebainone 115 (Scheme 15).

2.1.11. Calciphylline Alkaloids

Daphniphyllum is a large group of alkaloidal natural products. Calyciphylline-type alkaloids belong to this class of compounds. These are obtained from the leaves of Daphniphyllum calycinum and stems of D. subverticillatum [38]. These are biologically active substances and exhibit activity as cytotoxic substances against murine lymphoma (L1210) cells, and inhibit the aggregation of platelets. The synthesis of a common calyciphylline A, E bicyclic core was proposed by Kumar et al. in 2019 [39]. The key steps of this synthesis include the Ireland–Claisen rearrangement, the Mitsunobu reaction, an intramolecular aldol, and an aza-Michael reaction. The synthesis was started from cyclohexenol 116, which had undergone esterification with propanoyl chloride, followed by the Ireland–Claisen reaction and bromo lactonization to furnish lactone 117 and 118. The lactone 117 was converted to lactone 118 by isomerization and quenching with diethyl malonate. It was further undergone for reductive cleavage with Zn/EtOH to give alcohol 119 in a 70% yield. In the next step, a Mitsunobu conversion was performed in the presence of NsNH₂ with PPh₃ and DIAD at room temperature for 24 h to give sulfonamide 120 in a 65% yield. In the later step, oxidative cleavage via Jin’s protocol was employed, followed by treatment with piperidinium acetate to give aldehyde 122 in a 45% yield. In the last step, an intramolecular aldol reaction with sodium chlorate, along with a subsequent aza-Michael reaction and Pinnick oxidation in the presence of allyl bromide and trimethyl amine, furnished the bicyclic compound 123 in an 80% yield (Scheme 16).

2.1.12. Aspidosperma Alkaloids

The Mitsunobu reaction constitutes an important step in the total synthesis of natural products. Aspidosperma-derived monoterpene alkaloids are complex and biologically active natural products [40]. Liu et al. proposed the total synthesis of these monoterpene alkaloids in 2019 [41]. The total synthesis of mersicarpene was initiated from 2-methylaniline 124, which was converted to substituted indole (−)-125 over a few steps. The synthesized indole (−)-125 underwent the Mitsunobu reaction in the presence of 1.02 equivalents of diphenylphosphonic azide, 1.2 equivalents of diisopropyl azodicarboxylate, and 1.2 equivalents of triphenyl phosphine at 0 °C in THF to replace the OH group with an azide group, and afford azidoindole (+)-126 in an 98% yield. The next step involved the hydroboration of C=C in azidoindole (+)-126 to obtain the compound (−)-127 in a 71% yield. In the later step, 68% of N-acyl indole (+)-128 was obtained via Ley oxidation in the presence of NMO, TPAP, and methyl cyanide. The oxidation of the N-acyl indole via Kerr’s method followed by Staudinger–aza-Wittig reaction yielded 64% of (−)-mersicarpene 129 (Scheme 17).

Alkaloid-based natural products possess potent medicinal properties, and thus are employed for the treatment of a number of disorders. Alkaloids act as anti-bacterial, anti-fungal, and anti-cancerous agents, and against various other diseases, etc. Aspidosperma and Kopsia alkaloids are biologically active and structurally diverse compounds [42]. The total synthesis of kopsifoline D, beninine, and deoxoapodine was reported by Zhou et al. in 2019 [43]. The domino deprotection-Michael addition-nucleophilic substitution, Johnsan–Claisen rearrangement, and Corey–Bakshi–Shibata reduction reactions were employed as key steps to achieve the core framework of the aforementioned alkaloids. The total synthesis of (−)-kopsifoline D, (−)-beninine, and (−)-deoxoapodine was commenced from cyclohexan-1,3-dione 130, which was converted to allylic alcohol 131 over a few steps. The next step involved the Mitsunobu reaction with 1.1 equivalents of (2-chloroethyl)-2,4-dinitrobenzenesulphonamide 132 in the presence of 1.1 equivalents of diisopropyl azodicarboxylate (DIAD) and 1.05 equivalents of triphenyl phosphine (PPh₃) to give sulfonamide 133 in a 90% yield. The sulfonamide 133 further underwent allylic oxidation in the presence of chromium trioxide and tert-butyl hydroperoxide followed by intramolecular nucleophilic substitution to give tricyclic aminoketone 134 in a 70% yield. In the later step, 76% of indoline 135 was obtained by treating tricyclic aminoketone with phenylhydrazine followed by reduction with LiAlH₄. Further, Swern oxidation of indoline 135, accompanied by deprotection with TBAF, gave alcohol 136 in an 82% yield. The last step involved oxymercuration and demercuration in the presence of Hg (OTFAc)₂ to give 75% of deoxoapodine 137, and transannular cyclization in the presence of tert-butoxide and TsCl to obtain kopsifoline D 138 in a 46% yield. The synthesis of (−)-beninine was commenced from tricyclic aminoketone 134, which was reacted with o-methoxyphenyl hydrazine followed by reduction with triethyl silane and trifluoroacetic acid along with reduction by LiAlH₄ and direct acetylation to furnish acetate 139 in a 61% yield. Finally, acetate 139 underwent selective hydrolysis followed by oxymercuration and demercuration in the presence of Hg (OTFAc)₂ accompanying the removal of the acetyl group with hydrochloric acid to provide (−)-beninine 140 in an 87% yield (Scheme 18).

Leuconodines are aspidosperma-derived natural products [40]. These belong to the family of monoterpene alkaloids possessing a rare fenestrene core in their structure. These are biologically active compounds as these exhibit moderate cytotoxic properties and have found usage in traditional medicine for the treatment of yaws bacterial infections and worm infections. Leuconodine E manifests an important role as a cytotoxic substance possessing an IC₅₀ value of 9.34 µg/mL when employed with 0.1 µg/mL vincristine [40]. Leuconodines have complex structures that pose many hurdles in their total synthesis. After finding out alternative methods to cope with synthesis problems, Zhang et al. proposed the total synthesis of leuconodine D and E in 2019 [44]. The total synthesis was commenced from commercially available tryptophol 141, which was made to undergo TBS protection and was reacted with acyl chloride, followed by TBS deprotection and oxidative Heck cross coupling reaction in the presence of palladium acetate and ligands 143 and 144, to give 145 in an 88% yield. Next, the Mitsunobu reaction was performed in the presence of 1.5 eq. of sulfonyl carbamate 146, 1.5 eq. of diethyl azodicarboxylate (DEAD), and 1.5 eq. of triphenyl phosphine at 0 °C to rt for 10 h to give 147 in quantitative yield. In the next step, deprotection of the ortho-nitrosulfonyl group, followed by epoxidation in the presence of oxone and cyclization in acidic conditions, gave a mixture of diastereomer 148 and 149 in 1:1. In the next step, NaCN-mediated heating was used to cleave the methoxycarbonyl group and N-allylation with allyl iodide 150, followed by an HG-II mediated ring closing metathesis and Pd-catalyzed hydrogenation, which gave leuconodine E 151 in an 88% yield. The hydroxy group of 151 was converted to xanthate accompanied by a Barton–McCombie reduction to furnish 66% of leuconodine D 152 (Scheme 19).

2.1.13. Amaryllidaceae Alkaloids

(+)-Lycoricidine and conduramines belong to family of Amaryllidaceae alkaloids [45]. These alkaloids have gained much attention because of their biological significance. On account of their biological properties, these act as antitumor, antimicrobial, anti-fungal, and analgesic compounds [46]. Lo et al. proposed the total synthesis of lycoricidine and conduramines in 2019 by employing a diastereoselective mechanism [47]. The total synthesis of ent-conduramine [48] was commenced from cyclic diol 153, which underwent [3,3] sigmatropic rearrangement for the azido group introduction to obtain allylic azide 154 in a 70% yield. The next step was used to obtain the required configuration via the Mitsunobu reaction in the presence of triphenyl phosphine and diethyl azodicarboxylate and benzyl ether to obtain a 1,4-syn type azido alcohol 155 in an 87% yield. The last step involved the reduction of the azide group with lithium aluminum hydride (LAH) accompanied by deprotection and peracylation to give 89% of tetraacetyl ent-conduramine F-1 156 (Scheme 20).

2.2. Neolignans-Based Natural Product Synthesis

Plant-based lignans exhibit a number of biological activities, such as antileishmanial, antiparasitic, trypanocidal, and antitumor [49,50]. Surinamensinols are lignan-based natural products, which exhibit anti-inflammatory and anti-cancerous activities. Surinamensinol A and B demonstrate appreciable anti-cancerous activity against A549, SK-MEL-2, HCT-15, and SK-OV-3 cell lines [51]. Various research groups have reported the total synthesis of surinamensinols consisting of lengthy schematic pathways. In 2020, Avula et al. reported an expeditious method for the total synthesis of surinamensinols by using commercially available starting materials consisting of six steps [52]. The first step involved the reaction of allyl alcohol 157 and benzyl bromide in NaH and anhydrous THF to give a 98% product, which was further reacted with 9-borabicyclo [3.3.1] nonane solution (9-BBN) in THF, followed by reaction with 4-bromo-2-methoxyphenol 158 in Pd(PPh₃) and THF via Suzuki–Miyaura coupling to yield 86% of phenol benzyl ether 159. In the following step, phenyl benzyl ether 159 was made to couple with (S)-ethyl lactate 160 by Mitsunobu reaction in the presence of diisopropyl azodicarboxylate (DIAD), triphenyl phosphine, and anhydrous THF under reflux for 24 h to give the required chiral ester 161 in the yield of 88%. The compound 161 was then reduced by using DIBAL-H, and then subjected to a reaction with 3,4,5-trimethoxyphenyl magnesium bromide to yield a anti and syn diastereomeric mixture of products 162. This mixture of products was then deprotected by using 10%Pd/C and ethyl acetate. The final products 163 and 164 were obtained in overall 14% and 22% yields, respectively (Scheme 21).

Lignans are natural compounds which have a number of medicinal properties, i.e., anticancer, antimicrobial, anti-inflammatory, antiviral, antifungal, and neurotoxic etc. [53]. Aglacins are referred to as aryl tetracyclic lactone lignans, which are isolated from Aglaia cordata. Xu et al. proposed the total synthesis of aglacins by employing an asymmetric photoenolization/Diels–Alder (APEDA) reaction as a key step, in 2021 [54]. 2-Methyl benzaldehyde 165 and bromo furan derivative 166 were combined to give compound 167 over a few steps, which was reduced in the presence of LiAlH₄ to yield 168 in an 88% yield. A Mitsunobu reaction was employed in the presence of triphenyl phosphine and di-tert-butyl-azodicarboxylate to form a cyclic ether ring followed by TIPS deprotection by using tetrabutylammonium fluoride to obtain (−)-aglacin E 169 in a 50% yield. Aglacin E was further converted into (−)-aglacin A 170 in a 49% yield by employing the Mitsunobu reaction and (−)-aglacin B 171 in a 90% yield by reductive dihydroxylation (Scheme 22).

Furthermore, synthesis of (+)-linoxepin 177 commenced from the APEDA reaction of 172 and dienophile 166, which provided 76% of tricyclic product 173 with 93% enantioselectivity. Next, the desired triflate 174 was obtained by oxidation in the presence of DMP and sodium bicarbonate accompanied by triflation in the presence of Tf₂O in an 84% yield over two steps. In the following step, a Pd-catalyzed Suzuki–Miyaura coupling reaction between triflate 174 and compound 175 was performed in the presence of Pd(PPh₃), 1,4-dioxane and phosphoric acid to obtain the desired coupling product 176 in a 60% yield. The next step involved the removal of TBS and two methyl groups followed by an intramolecular Mitsunobu reaction for seven-membered cyclo-ether ring formation along with the addition of a methyl group in the presence of methyl iodide to obtain the final product (+)-linoxepin 177 in a 40% yield over two steps (Scheme 23).

Lignans are an important class of natural products that possess a number of biological activities, such as antitumor, anti-inflammatory, anti-bacterial, and immunomodulators. 7S-HMR is converted to (−)-enterolactone by intestinal bacteria and exhibits chemo preventive effects on the development of mammary carcinoma induced by DMBA. Furthermore, it possesses anti-oxidant potential and exhibits chemopreventive effects in an ApcMin mice model of human familial adenomatous polyposis [55]. These are present in many fruits, vegetables, and seeds. 7R-Hydroxymatairesinol belongs to lignans which have polyphenolic structures. It is reported to have chemotherapeutic and metabolizing effects. In 2021, Colombo et al. reported the preparation of a 7R-HMR isomer from a 7S-HMR isomer using kinetic reduction, Mitsunobu reaction for epimerization, and ester hydrolysis as key steps [56]. In the first step, the protection of phenolic functional groups in the 7S-HMR 178 isomer was completed by using TBSCl and imidazole in DMF to obtain alcohol 179 in a 68% yield. In the next step, a Mitsunobu reaction was performed in the presence of PPh₃, DIAD, THF, and p-nitrobenzoic acid at room temperature for 24 h to obtain 180 with an inverted OH group in a 43% yield. The final step involved hydrolysis to ensure complete inversion, followed by deprotection using TBAF and AcOH in THF to obtain 7R-HMR 181 in a 72% yield (Scheme 24).

Neoflavones are naturally occurring compounds and act as important scaffolds for the synthesis of drugs and biologically active compounds. Prenyl groups enhance the bioactivity of respective compounds. They exhibit protease inhibition in COVID-19 [57]. Prenylneoflavones are derivatives of neoflavones whose synthesis has been reported by Lozinski et al. in 2020. They employed a Mitsunobu reaction, olefin cross-metathesis reaction, and Claisen rearrangement as key steps to obtain a 5% overall yield in six steps [58]. The first step involved the conversion of 3-methoxyacetophenone 182 to neoflavone 183 in a 52% yield via Claisen rearrangement in the presence of diethyl carbonate, and Pechmann condensation in the presence of resorcinol in sulfuric acid. Next, the Mitsunobu reaction with allyl alcohol in the presence of diazo-dicarboxylate (DIAD) and triphenyl phosphine at 0 °C gave 7-allyloxy-neoflavone 184 in a 78% yield. Further, Claisen rearrangement with Eu(fod)₃ along with acylation gave an acetylated product 185 in a 79% yield. The 7-acetoxyneoflavone was further treated with Grubbs second generation catalyst to yield prenylneoflavone 186 in a 65% yield (Scheme 25).

Lignans are polyphenolic compounds that possess many biological and medicinal properties [59]. Ligraminol D and E are lignans which are isolated from Acorus. gramineus and exhibit anti-proliferative activity against tumor cells and inhibit the production of nitric oxide in BV-2 cells [60]. Mane et al. proposed the total synthesis of Ligraminol D and E in 2019 [61]. The synthesis of Ligraminol E was commenced from known aldehyde 187, which was converted to a chiral diol 188 over a few steps. Next, diol 188 was made to react with benzoyl chloride for the selective protection of the hydroxyl group and production of secondary alcohol 189 in a 90% yield. It was further treated with acetate 190 via Mitsunobu reaction in the presence of DEAD and PPh₃ in anhydrous THF under reflux for 6 h to give 88% of ether 191, which was hydrogenated in the presence of Pd/C followed by a global reduction to yield Ligraminol E 192 in a 93% yield (Scheme 26).

For the synthesis of Ligraminol D, alcohol 194 obtained from aldehyde 193 over a few steps was made to undergo a Mitsunobu reaction with ester 190 in the presence of PPh₃ and DEAD in anhydrous THF under reflux for 6 h to give 195 in an 87% yield. It was converted to Ligraminol D 196 by debenzylation in a 93% yield (Scheme 27).

Sesquineolignans

Princepin and isoprincepin are sesquineolignans obtained from Joanessia princeps. These compounds show biological activity as anti-estrogenic and anti-oxidant compounds [62]. Kobayashi et al. explained the total synthesis of princepin and isoprincepin in 2019 [63]. The total synthesis was commenced from aldehyde 197 and alcohol 198, which underwent condensation via a Mitsunobu reaction in the presence of DIAD and PPh₃ at room temperature for 2 h, followed by pinacol conversion to give 199. Next, the compound 199 underwent TIPS and benzyl ether deprotection followed by Dess–Martin oxidation to give isomer 200 in a 93% yield. A total of 85% of isomer 201 was obtained by deprotection of 199 and the benzyl group introduction in the presence of basic conditions and BnBr followed by Dess–Martin oxidation. For diastereo and regio divergent synthesis of target compounds, isomer 201 was converted to the 7R,8R isomer of princepin 203 and isomer 200 was converted to the 7S,8S isomer of princepin 202 over a few steps. (Scheme 28).

2.3. Synthesis of Polyketides-Based Natural Products

Resorcyclic acid lactones are a major class of naturally occurring compounds [64]. Paecilomycin A-F are polyketides that belong to resorcyclic acid lactones and are isolated from mycelial culture of Paecilomycessp. They exhibit a number of medicinal and biological properties, such as anti-malarial, antibacterial, anti-enzymatic, anti-parasitic, nematicidal, and anti-fungal. Paecilomycins are found to express anti-plasmodial activity in opposite to Plasmodium falciparum. Among all paecilomycins, paecilomycin E exhibited the best activity with an IC₅₀ value of 20.0 nM [65]. In 2019, Reddy et al. proposed the total synthesis of paecilomycin A-F by employing the key steps of Alder–Rickert, Mitsunobu esterification, and ring closing metathesis [66]. The total synthesis was commenced from D-ribose 204, which was converted to alcohol 205 in a few steps. Then, the Mitsunobu reaction was performed to couple alcohol 205 and acid 206 in the presence of triphenyl phosphine (PPh₃), diethyl azodicarboxylate (DEAD), and toluene at room temperature for 6 h to obtain esterification product 207 in an 89% yield. Further, Hoveyda Grubbs second generation catalyst was used to perform ring closing metathesis that furnished cyclized trans-macrolactone product 208 in an 80% yield. In the last step, paecilomycin E 209 was obtained in an 82% yield by employing the global deprotection of macrolactone in the presence of CH₂Cl₂ and BCl₃ (Scheme 29).

Styryllactones are naturally occurring organic compounds which are isolated from a number of natural sources, such as Goniothalamus dolichocarpus and Cryptocarya caloneura [67]. Since these compounds are biologically active, they have been used in Thai traditional medicine and exhibit anti-cancerous activity [68]. Kotammagari et al. proposed the total synthesis of goniothalamin and its epimers by using Ferrier reaction, Jones oxidation, acid-mediated transition metal free epimerization, and Mitsunobu reaction as key steps, in 2019 [69]. The total synthesis was commenced from triacetyl-O-D-glucal 210, which was converted to compound 211 over a few steps. Next, 85% of alcohol 212 was obtained, which underwent a Mitsunobu inversion to invert stereochemistry of the OH group in the presence of p-nitrobenzoic acid (PNBA) and diethyl azodicarboxylate (DIAD) at 0 °C to room temperature for 12 h, followed by deprotection of the ester to obtain 60% of epimerized alcohol 213. Further, the epimerized alcohol 213 was protected in the presence of tert-butyl dimethyl-silyl chloride (TBSCl) and imidazole followed by Jones oxidation and deprotection of the TBS group in the presence of BF₃.OEt₂ to furnish the final compound (−)-5-hydroxygoniothalamin 214 in a 30% yield along with its C-5 epimer. The compound 211 was converted to 62% of (+)-5-hydroxygoniothalamin and its C-5 epimer by oxidation in the presence of Jones reagent and deprotection in the presence of BF₃.OEt₂. The synthesis of (−)-5-acetylgoniothalamin 216 was accomplished by the acetylation of (−)-5-hydroxygoniothalamin 214 in an 85% yield (Scheme 30).

Limaol is a cytotoxic agent extracted from a marine dinoflagellate, P. lima [70]. Hess et al. reported the total synthesis of limaol in 2021 [71]. Stille reaction, asymmetric propargylation, a gold catalyzed-spirocyclization, Mitsunobu reaction, and substrate-controlled allylation were employed as key steps for the synthesis of limaol 223. The synthesis commenced with the preparation of fragments 219 and 220 from commercially available starting substances, such as 217, which were prepared from 217 and 218 over a few steps. Fragment 219 and 220 were made to couple together in the presence of MgBr₂.OEt₂ and dichloromethane to yield 88% of the coupled product 221. In the next step, the Mitsunobu reaction was performed in the presence of 4-nitrobenzoic acid, triphenyl phosphine, diethyl azodicarboxylate, and toluene at 0 °C to room temperature to invert the configuration of the OH group at C-27 in compound 222 with a yield of 91%. Finally, compound 222 was converted to limaol 223 with a yield of 32% over a few steps (Scheme 31).

Petromyroxol belongs to acetogenins, which possess cytotoxic, anti-pyrexial, anti-helminthic, and anti-cancer properties, etc. [72]. Petromyroxols are isolated from a larval sea lamprey and exhibit a good olfactory response. Mullapudi et al. proposed the total synthesis of (+)-petromyroxol and its diastereomers in 2020 [73]. For the synthesis of (+)-petromyroxol, allyl glycoside 224 was made to undergo a Mitsunobu reaction in the presence of para-nitrobenzoic acid to give unsaturated compound 225 in an 81% yield. In the next step, the compound 225 was subjected to olefin oxidative cleavage followed by two-carbon homologation to give unsaturated ester derivative 226 in a 69% yield. In the later step, hydrogenation by Pearlman catalyst along with saponification of both esters yielded (+)-petromyroxol 227 in a 77% yield (Scheme 32).

For the synthesis of 6-epi-(−)-iso-petromyroxol 231, the allyl glycoside 228 was subjected to a Mitsunobu reaction in the presence of para-nitrobenzoic acid (PNB), DIAD, and PPh₃ at 0 °C to room temperature for 3 h to obtain the PNB-substituted product 229 in an 86% yield. In the next step, olefin oxidation of the substituted product 228 followed by two-carbon homologation gave 71% of ester 230. The last step included Pearlman catalyst-mediated hydrogenation, followed by saponification of ester 230 to give the final product 6-epi-(−)-iso-petromyroxol 231 in a 74% yield (Scheme 32). Some other diastereomers of petromyroxol were also synthesized by taking an isomer of allyl glycoside 224 as starting compounds by employing a similar strategy (Scheme 33).

2.4. Natural Products-Based Terpenes Synthesis

Curcusones belonging to the group of diterpenes are complex natural products. They are extracted from Jatropha curcas and possess anti-cancerous activities. Cui et al. reported the first total synthesis of curcusone diterpenes in 2021 [74]. First of all, cyclohexenal 232 was converted to silyl enol ether, followed by a Mukaiyama aldol reaction and NaBH₄ reduction to give 233 in a 73% yield. Further, an organocatalytic Mitsunobu reaction was performed in the presence of diethyl azodicarboxylate and alcohol 234 at 0 °C to 50 °C to yield compound 235. The compound 235 was converted to the enone 236 over a few steps. Next, the enone 236 was methylated in the presence of KHMDS and methyl iodide to obtain two isomers (−)-S-curcusone A and (−)-R-curcusone B 238, which were converted to (−)-R-curcusone C and (−)-S-curcusone D 240 by α-hydroxylation in 1:1 diastereomeric ratio. The compound 238 was converted to (+)-spirocurcusone 238 in a 60% yield and (−)-pyrocurcusone 239 in a 21% yield. The compound 240 was also converted to (−)-dimericursone 241 over a few steps (Scheme 34). The synthesized compounds were further evaluated for anti-proliferative activity against MCF-7 cells by using a WST-1 assay. Curcusone D 240 exhibited the best cytotoxic activity among all.

Vibsanins are diterpenoids present in the leaves of Viburnum awabuki, which possess piscicidal activity. They consist of 7-membered, 11-membered, and rearranged vibsanes. The total synthesis of 11-membered vibsane is reported by Takao et al. in 2020 [75]. The synthesis commenced from the preparation of fragments 244 and 245 from commercially available substances 242 and 243 over a few steps. These fragments were coupled in the presence of tertiary butyl and THF to give the compound 246 in a 52% yield. The Mitsunobu reaction between 246 and acid 247 at −15 °C was performed to afford acylate and give ester 248 in a 72% yield. Further, deprotection and oxidation of ester 248 followed by a Nozaki–Hiyama–Takai–Kishi (NHTK) reaction gave diastereoselectively pure alcohol 249 in an 82% yield. The last step involved another Mitsunobu reaction with para-nitrobenzoic acid, diethyl azodicarboxylate, and triphenyl phosphine at 0 °C, followed by chemoselective methanolysis to give the final product 250 in a 91% yield (Scheme 35).

Pavidolide B belongs to the cembranoid family, which is a pervasive class of marine natural products. These are isolated from genera Sarcophyton and Sinularia. These exhibit biological activity against human probe myelocytic cell lines. In 2019, Zhang et al. proposed the total synthesis of (−)- pavidolide B by utilizing annulation reactions and ring closing metathesis reactions as key steps to achieve a 16% overall yield [76]. The total synthesis was commenced by the reaction of unsaturated aldehyde 251 and dimethyl-2-bromomalonate 252 in the presence of 2-(diphenyl((trimethylsilyl) ocy) methyl) pyrrolidine catalyst 253 with the subsequent protection of the aldehyde group in the presence of PTSA and CH(OEt)₃, which were selected after the screening of various conditions, followed by hydrolysis to give 80% of substrate 254 in a diastereomeric ratio of 1.5:1. In the later step, the Mitsunobu coupling with alcohol 255 was employed in the presence of diethoxyethyl azodicarboxylate (DEAD) to obtain 74% of the coupled product 256 in a similar diastereomeric ratio. After the screening of various conditions, the annulation reaction was performed in the presence of PhSH and AIBN to obtain the annulated product 257 in a 38% yield with a dr of 1.6:1. The compound 257 was converted to tetracyclic pavidolide 258 in a 95% yield over a few steps (Scheme 36).

(+)-ar-Macrocarpene is a naturally occurring sesquiterpenoid derived from Cupressus macrocarpa. This family covers a number of biologically active derivatives. In 2019, Khatua et al. reported the total synthesis of ar-Macrocarpene in a 42.1% overall yield from the commercially available compound 259, which was converted to alcohol 260 over a few steps [77]. It underwent the Mitsunobu reaction with o-nitrophenylsulfonyl hydrazide 261 at 0 °C for 2 h to furnish sulfonyl hydrazine 262, which was rearranged in the presence of methanol, and gave 65% of the diazene intermediate 263 in the presence of methanol. In the final step, the diazene intermediate was further hydrogenated to yield (+)-ar-Macrocarpene 264 in a 99% yield (Scheme 37).

Andrographolide is known as the king of bitters as it has a lot of applications in ayurvedic and local medicine [78]. Yang et al. proposed the total synthesis of andrographolide in 2020 [79]. Diene 265 was cyclized via Diels–Alder cycloaddition by using DMAD along with hydrolysis, followed by manganese-catalyzed HAT reduction, which gave trans-decalin 266 in a 63% yield. It was further treated with TIPSOTf and diisobutyl aluminum hydride (DIBAL-H) to produce ene-diol 267. The next step proceeded via a Mitsunobu reaction with 120 mol% of hydrazine derivatives in the presence of 120 mol% of diethyl azodicarboxylate and 130 mol% of triphenyl phosphine at −30 to 25 °C followed by the conversion to iodide 268 in the presence of imidazole and iodine in a 72% yield. In the next step, the treatment of iodide 268 with 2-thienyl copper lithium and vinyl bromide 269, along with carbonylative lactonization with Palladium-Xanthophos, gave andrographolide 270 in a 92% yield (Scheme 38).

For the synthesis of 14-hydroxy-collandonin, diene 265 was converted to diol 271 over a few steps. The diol 271 underwent acylation that gave allylic carbonate 272 in a 74% yield [79]. Further, allylic carbonate 272 was reacted with 250 mol% of umbelliferone 273 via a Mitsunobu reaction in the presence of 150 mol% of diethyl azodicarboxylate and 150 mol% of triphenyl phosphine at 25 °C followed by a Tsugi reduction in the presence of palladium acetate and formic acid along with the deprotection of silyl ethers to give 14-hydroxy-colladonin 274 in a 95% yield (Scheme 39).

2.5. Synthesis of Lactone-Based Natural Products

Lactones are naturally occurring compounds which possess various biological activities. Goniopypyrone and gonitriol are styryl lactones isolated from Goniothalamus giganteus. These lactones show cytotoxic activity against leukemic cells [80]. In 2019, Miyazawa et al. proposed the total synthesis of (+)-goniopypyrone and (+)-goniotriol by using key steps involving Pd-catalyzed carbonylation and diastereoselective reduction of ynone [81]. The total synthesis was commenced from D (−)-tartaric acid 275, which was converted to ynone 276 in a few steps. A number of reagents were screened out for diastereoselective reduction of ketonic group in ynone 276 and (S)-CBS catalyst and borane dimethyl sulfide catalyst were used to yield 12:88 ratio of diastereoselective alcohol 277 in a 12% yield and 278 in an 88% yield. Undesired diastereoisomer 277 was converted to 278 via the Mitsunobu reaction in the presence of para-nitrobenzoic acid (p-NBA) and diethyl azodicarboxylate (DEAD) in a 74% yield over two steps. The next step included the protection of the hydroxyl group of 278, followed by iodide introduction in the presence of NIS along with NsNHNH₂-mediated diimide reaction to give 96% of 279. The compound 279 underwent deprotection of acetonide followed by Pd-catalyzed carbonylation in the presence of 5 mol% of Cl₂Pd (PPh₃) and Et₃N, with subsequent deprotection of benzyl ether along with DBU treatment to furnish 73% of (+)-goniopypyrone 280 (Scheme 40).

Furthermore, the total synthesis of (+)-goniotriol was commenced from alcohol 281, which was subjected to the Mitsunobu reaction in the presence of para-nitrobenzoic acid (p-NBA) and diethyl azodicarboxylate (DEAD) to yield 91% of 282 [81]. In the next step, the iodide group was introduced in the presence of NIS in AgNO₃ with a subsequent diimide reaction in the presence of NsNHNH₂, followed by the deprotection of the acetonide group in acidic conditions to yield 91% of the cyclized precursor 283. In the last step, Pd-catalyzed carbonylation gave a 93% yield, followed by the deprotection of benzyl ether in the presence of TiCl₄ to give 66% of (+)-goniotriol 284 (Scheme 41).

Epi-zeaenol and zeaenol are lactones isolated from filamentous fungi. They are a biologically active natural product. Zeaenol expressed anti-cancerous activity against human cancer cell lines, with an IC₅₀ value of >50 µM and inhibition against NF-ĸB cells [82]. The total synthesis of epi-zeaenol and zeaenol was reported by Doda et al. in 2019 [83]. Mitsunobu inversion, Heck cross coupling reaction, De Brabander’s protocol for macrolactonisation, Ohira–Bestmann alkynylation, and alkyne aldehyde coupling are the key steps involved in the synthesis of zeaenol to obtain a 21% overall yield. The total synthesis of zeaenol was commenced from D-mannitol 285, which gave macrolactone 286 over a few steps. On treatment with TMSCl in methanol, macrolactone 286 was converted into allyl alcohol 287 in an 86% yield. The next step involved the Mitsunobu reaction in the presence of 4-nitrobenzoic acid, DEAD, and PPh₃ at room temperature for 12 h to invert the OH group followed by ester methanolysis to obtain alcohol 288 in an 81% yield over two steps. The alcohol 288 was treated with an excess of TiCl₄ to obtain zeaenol 289 in an 83% yield (Scheme 42).

Resorcyclic acid lactones, also called secondary polyketides, are extracted from fungal strains, i.e., Lasiodiplodia Theobromae, Penicillium sp., Syncephalastrum racemosum, etc. They exhibit a number of medicinal properties, such as anti-malarial, anti-microbial, and anti-cancerous, etc. [84]. Various research groups have reported the total synthesis of macrocyclic lactones except penicimenolide A. Das et al. reported the total synthesis of penicimenolide A, R-resorcyclide, and R-dihydroresorcyclide in 2021 by employing ring closing metathesis as key step [85]. The total synthesis was started from commercially available epoxide fragment 290, which gave the acid fragment 291 over a few steps that further coupled with hexenol fragment 292 via the Mitsunobu reaction in the presence of PPh₃, DIAD, and THF at 0 °C to room temperature to give compound 293. The oxidation of compound 293 by Grubb’s II oxidation method and deprotection with K₂CO₃ in methanol provided the cyclized product 294. Further, the OH group in 294 was oxidized by Dess–Martin periodinane and demethylated by using AlI₃ and phloroglucinol to give (R)-penicinomenolide 295 in a 34% yield. The cyclized compound 294 was converted to (R)-dihydroresorcyclide 296 in a 61% yield over a few steps (Scheme 43).

The synthesis of trans-resorcyclide 302 was commenced from a benzaldehyde derivative 297, which was converted to an acid 298 [85]. The next step involved the Mitsunobu reaction to couple compound 298 with 2-hydroxy heptene 299 to give a 62% yield of macrocycle 300. Further, Grubb’s II oxidation was performed followed by deprotection and Dess–Martin periodinane-mediated oxidation to give cyclized product 301 in a 60% yield. In the final series of steps, the OH group was first masked by selenium protection and then demethylated using AlI₃ and phloroglucinol. Selenide was demethylated and oxidized to obtain the final product (R)-trans- resorcyclide 302 in a 54% yield (Scheme 44).

Pyrenophorins are isolated from Pyrenophora avenae and exhibit anti-bacterial and anti-fungal properties, etc. Edukondalu et al. proposed the total synthesis of (−)-pyrenophorin in 2020 [86]. The synthesis commenced from epoxy bromide 303, which was alkylated with 2-vinyl-1,3-dithiane 304, followed by LAH-mediated epoxide opening and imidazole-mediated TBSCl protection of the obtained alcohol to provide 82% of olefin 305. The ozonolysis of olefin 305, accompanied by treatment with (methoxycarbonyl methylene) triphenyl phosphorane, and hydrolysis, along with desilylation, gave hydroxy acid 306 in an 86% yield. In the next step, dimerization of hydroxy acid 306 via the Mitsunobu reaction by employing diethyl azodicarboxylate, triphenyl phosphine, and a 10:1 ratio of toluene and THF provided a 61% of dimer 307. The deprotection of 1,3-dithiane group with CaCO₃ gave the desired product pyrenophorin 308 in a 73% yield (Scheme 45).

2.5.1. Synthesis of Glutamate Receptors

Glutamate is an excitory neurotransmitter in mammalian cells. It acts on a number of receptors and regulates important brain functions. The dysfunction of these receptors leads to many abnormalities. These receptors are activated by a number of positive allosteric modulators (PAMs). Yamada et al. reported the total synthesis of some positive allosteric modulators (PAMs) 313, 316, 319, and 322 for mGlu₂ and mGlu₃ receptors, in 2021 [87]. Starting with butanone derivative 309, alkylation was performed by employing either –R or S-oxirane derivative 310 to obtain 311 in a 97% yield. In the next step, the Mitsunobu reaction with methyl-4-methoxy-5-hydroxy benzoate 312 and di-tert-butyl azodicarboxylate at 120 °C for 45 min gave a 65% yield, which was further saponified under microwave irradiation at 100 °C for 30 min to give the final product 313 in an 87% yield (Scheme 46).

For synthesis of PAMs 316, 2-flouro-benzoate 314 was used as a starting material and reacted with methyl oxiranes under a microwave temperature of 350 °C for 3 h to provide compound 315 in a 97% yield [86]. Then, the Mitsunobu reaction with methyl-4-methoxy-5-hydroxy benzoates 312 at 120 °C for 45 min, along with saponification under microwave irradiation of 100 °C for 30 min, yielded 87% of the compound 316 (Scheme 47).

To obtain compound PAMs 319, butanone derivative 309 was alkylated with -R or -S-3-bromo-2-methoxy propan-1-ol 317 in the presence of K₂CO₃, KI, and ACN at 60 °C to give 69% of compound 318. Further, it underwent for the Mitsunobu reaction with methyl-3-methoxy-4-hydroxy benzoate 312 at 120 °C for 45 min, and was then saponified by microwave at 100 °C for 30 min, to obtain 319 in a 30–43% yield (Scheme 48).

The synthesis of PAMs 322 was commenced from 309, which was alkylated with bromo propanol 317 at 60 °C to obtain compound 320 in an 87% yield. A total of 20–55% of the final product 322 was obtained by employing the Mitsunobu reaction with phenol in the presence of di-tert-butyl azodicarboxylate and triphenyl phosphine at 120 °C for 45 min, followed by saponification at 100 °C for 30 min (Scheme 49).

The synthesized positive allosteric modulators were selected for the evaluation of their biological activities. These receptors were tested for their potential to act on human mGlu₂ and mGlu₃ cell lines. In the case of PAMs 322, the best activity is observed by substituting 4-hydroxy-2-methoxy benzoic acid that exhibited 0.028 µM against mGlu₂ cells, and 0.512 µM against mGlu₃ cells.

2.5.2. Synthesis of Steroid-Based Natural Products

Steroids are an important class of natural compounds possessing a number of biological activities. Dankasterones A and B and periconiastone A are steroids that are isolated from Gymnacella dankaliensis and Periconia sp., respectively, and exhibit anti-cancerous and anti-bacterial properties. Dankasterone A demonstrate anti-cancer potential against MG-MID-5.41. Dankasterone A and B exhibited marginal and significant growth inhibition against murine P388 cells. Furthermore, periconiastone A manifested significant anti-bacterial activity against Gram-positive E. faecalis and S. aureus with MIC values of 32 and 4 µg/mL [88]. In 2020, Chen et al. reported the total synthesis of dankasterones A and B and periconiastone A by employing metal-catalyzed hydrogen atom transfer and position selective C-H oxygenation as key steps [89]. The total synthesis was accomplished in 22–23 steps. The synthesis started with ketone 323, which, over a few steps, gave fragment 324. The compound 325 was converted to fragment 326 over a few steps, which, coupled with 324, in the presence of tert-BuLi followed by oxidation gave the coupled product 327 in 67% over two steps. The coupled product 327 was converted to compound 328 over a few steps, which underwent deprotection of ketal in the presence of p-TsOH, LAH-mediated reduction and a Mitsunobu reaction in the presence of di-tert-butyl-azodicarboxylate and triphenyl phosphine to yield olefin 329 in 82% over three steps. The oxidation of olefin 329 took place in the presence of CrO₃ using 3,5-DMP as promotor and HClO₄-supported C-H oxygenation to obtain spirocycle 330 in a 67% yield. Further, the rearrangement of 330 by deacetylation followed by oxidation with DMP and Julia–Kocienski olefination with 331 gave dankasterone B 332 in a 35% yield. Dehydrogenation of 332 in the presence of PhI(OH)(OTs) gave dankasterone A 333 in a 28% yield. The intramolecular aldol reaction of 332 by treatment with DBU in the presence of TBSOTf gave periconiastone A 334 in a 46% yield (Scheme 50).

2.5.3. Synthesis of Chromone-Based Natural Products

Preussochromone belongs to a family of chromone natural products which have a tricyclic skeleton and a chromenone core with a dihydrothiopyran ring. It shows biological activity against human cancer cell lines with an IC₅₀ value of 25.5 µM against HeLa and an IC₅₀ value of 8.34 µM against A549 cells [90]. Beller et al. reported the total synthesis of preussochromone A in 2020 [91]. The significant steps employed for the synthesis of (−)-preussochromone are Lewis-acid-mediated cycloisomerization and thia-Michael-retro-Michael addition reaction that provided the target compound in an 8% overall yield in 11 steps. The synthesis started from a primary alcohol 335, which was converted to a 71% yield of thiobenzoate 336 by employing the Mitsunobu reaction in the presence of 2 eq. of BzSH, 1.5 eq. of diazo dicarboxylate, and 1.5 eq. of triphenyl phosphine at 0 °C to room temperature. Dihydroxylation of thiobenzoate 336 along with thioester cleavage in the presence of sodium methoxide gave diol 337. It was further coupled with 2-sulfonyl chromenone 338 via thia-Michael-retro-Michael addition in the presence of K₂CO₃ to furnish diol 339 in a 94% yield. The diol 339 was converted to the target compound preussochromone A 340 over a few steps providing a final yield of 61% (Scheme 51).

2.5.4. Synthesis of Acetylenic-Based Natural Products

Asparenydiol consists of acetylene in its structure and is isolated from Asparagus Officinalis. It possesses many biological properties, such as anti-cancer, anti-pyretic, anti-diabetic, and immunomodulators. It exhibits anti-proliferative activity against Col-2, KB, LNCap, HU-VEC, and Lu-1 cell lines in the range of 4–20 µg/mL [92]. Casotti et al. reported the total synthesis of asparenydiol in 2020 by employing the Mitsunobu reaction and Sonogashira cross-coupling reaction as key steps to furnish it with a 30% overall yield [93]. The synthesis commenced with iodophenol 341, which was converted to terminal alkyne 342 over a few steps. It was coupled with methyl (E)-3- methyl bromo acrylate 343 via Sonogashira coupling by taking Pd-Cu/PVPy as catalyst and 2,2,6,6-tetramethylpiperidine as base to give a 57% yield of 344. The terminal acetate group underwent DIBAL-mediated reduction at a low temperature to give 90% of primary alcohol 345. A Mitsunobu reaction for the etherification of 345 with phenol derivative 346 in the presence of diethyl azodicarboxylate and triphenyl phosphine at 0 °C to 20 °C for 6 h provided an isolated yield of 84% followed by the deprotection of the hydroxyl groups by treatment with TBAF to give the target compound asparenydiol 347 in a 30% yield (Scheme 52).

2.5.5. Synthesis of Piperidinones-Based Natural Products

Pipermethystine is a secondary alkaloid present in Piper Methysticum, which possess many biological properties [94]. Vázquez-Amaya et al. reported the total synthesis of pipermethystine by employing the Mitsunobu reaction in 2020 [95]. Starting from hydroxy (R)-hydroxypiperidine 348, triple C-H functionalization gave piperidone derivative (R)-349 in a 54% yield. In the next step, the Mitsunobu reaction with AcOH in the presence of diethyl azodicarboxylate (DIAD) and triphenyl phosphine (PPh₃) followed by deprotection with ceric ammonium nitrate (CAN) gave 70% of ester (S)-350. The acylation of ester (S)-350 with cinnamoyl chloride provided (S)-pipermethystine 351 in a 72% yield. The configuration of the synthesized compound was opposite to the naturally occurring isomer. For that reason, piperidone derivative 349 was O-acetylated in a basic condition followed by oxidative debenzylation and treatment with cinnamoyl chloride for N-acylation to get (R)-pipermethystine 352 in a 70% yield (Scheme 53).

2.5.6. Synthesis of Peptide-Based Natural Products

Asperipin is a biologically important compound. It is extracted from Aspergillus flavus. Shabani et al. reported the total synthesis of aspirin in 2020 [96]. In the first step, (R)-glyceraldehyde acetonide 353 was treated with phenyl magnesium bromide to give alcohol 354 in an 85% yield with 99:1 diastereomeric ratio. It was further treated with tyrosine derivative 355 via Mitsunobu reaction in the presence of DIAD and PPh₃ under sonication to obtain ether adduct 356 in a 45% yield. The nosylation of adduct 356 in the presence of KHMDS at −78 °C, along with the hydrolysis of the ester and oxazolidine groups, in the presence of Cs₂CO₃ and LiOH yield 85% of the β-hydroxy tyrosine derivative 357. The β-hydroxy derivative 357 was coupled with Thr(Bn)-Gly-OtBu followed by a Mitsunobu reaction in the presence of DIAD and PPh₃ to give aziridine 358 in a 90% yield. Over a few steps, the aziridine 358 was converted to the desired product asperipin-2a 359 (Scheme 54).

2.5.7. Synthesis of Amino Acids-Based Natural Products

The natural compounds containing 1,3-diols are among the most important organic compounds, which possess many biological and medicinal properties. Galantinic acids are natural amino acids containing 1,3-diols and act as the back-bone of galantin, an antibiotic. 1-Deoxy-5-hydroxy-sphingolipid also belongs to this class of compounds and acts as anti-prostate cancer substances [97]. Rehman et al. reported the total synthesis of (−)-galantinic acid and hydroxy-sphingolipids in 2020 [98]. The total synthesis of (−)-galantinic acid commenced from (±)-glysidyl benzyl ether 360, which was converted to intermediate compound 361 over a few steps. In the next step, regioselective epoxide ring opening was performed in the presence of benzyl alcohol and catalytic amount of BF₃.OEt₂ to obtain compound 362 in a 93% yield. Further, the Mitsunobu reaction was employed for the conversion of the secondary hydroxyl group to azide 363 with mesylate chloride and sodium azide at 80 °C for 7 h in an 88% yield. The last step included the introduction of carboxylic group in the presence of sodium periodate with RuCl₃.6H₂O as a catalyst followed by Pd-catalyzed hydrogenation in MeOH to furnish (−)-galantinic acid 364 in an 89% yield (Scheme 55).

The synthesis of 1-deoxy-5-hydroxysphingolipid 367 started from an epoxide intermediate 361, which was reduced in the presence of DIBAL-H, followed by oxidation in the presence of 1-dodecene with 5 mol% of Grubb’s catalyst to give 365 in a 72% yield [98]. The next step was performed via the Mitsunobu reaction in the presence of mesylate chloride and triethyl amine with sodium azide at 80 °C for the conversion of the secondary hydroxyl group to azide 366 in an 85% yield. Lastly, azide 366 was reduced in the presence of 10% Pd on C and hydrogen to yield target compound 1-deoxy-5-hydroxysphingolipid 367 in a 91% yield (Scheme 56).

Jomthonic acid A is an amino acid derivative isolated from the genus Streptomyces of the soil-derived actinomycete. It expresses anti-atherogenic and anti-diabetic activity against S-13 preadipocytes of mice. It also acts as an inhibitor of preadipocytes differentiation into mature adipocytes in the 2–50 µM range [99]. It has many structural features that were built by employing the Mitsunobu reaction, Gilman reaction, Yamaguchi esterification, and amide coupling. Dumpala et al. reported the total synthesis of jomthonic acid A in 2019 [100]. The synthesis was initiated from trans-cinnamyl alcohol 368, which was epoxidized by employing sharpless asymmetric epoxidation in the presence of (+)-DIPT and Ti(OⁱPr)₄ followed by regioselective ring cleavage with Gilman reagent to give diol 369 in a 68% yield. The diol 369 was subjected to selective hydroxyl protection in the presence of TBSCl/Bu₂SnO/CH₂Cl₂ in imidazole providing a 93% yield of silyl ether 370, leading towards the Mitsunobu reaction with diphenyl phosphorazidate (DPPA) and DIAD at 0 °C to rt to obtain azide 371 in an 85% yield. Deprotection of azide 371 was performed in the presence of TBAF, followed by oxidation in the presence of TEMPO and PhI(OAc)₂ in CH₃CN/H₂O, to give acid fragment 372 in a 93% yield. The fragment (R)-374 was synthesized from (3R)-3-hydroxybutanoate 373 over a few steps. In the next step, acid fragment 372 and silyl ether 374 were coupled via Yamaguchi esterification in the presence of 2,4,6-trichlorobenzoyl chloride to give 68% of azide 375. The jomthonic acid 376 was obtained from azide 375 in an 80% yield over a few steps (Scheme 57).

2.5.8. Synthesis of Natural Products Containing Carbohydrate Derivatives

Ampelomycins are polyhydroxylated cycloalkane-type compounds, also known as “carbohydrate mimetics”, and are isolated from a fungal strain Ampelomyces sp. [101]. They can act as important scaffolds for the synthesis of drugs and analogues. In 2019, Brindisi et al. reported the total synthesis of ampelomins [102]. The main steps employed for the synthesis of ampelomins were the Mitsunobu reaction, stereoselective hydrogenation, and a regioselective and stereoselective nucleophilic ring opening. The synthesis of ampelomin B was initiated from diol 377, which underwent diol protection with DMP, followed by halohydrin formation in the presence of iodine and AcOAg, along with deprotection of diol at 40 °C and ring closure with DBU at room temperature to give β-epoxide 378 in a 99% yield. The homogenous hydrogenation of epoxide 378 with 10 mol% of Crabtree’s catalyst at room temperature gave 99% of alcohol 379. Further, the Mitsunobu reaction was performed in the presence of para-nitrobenzoic acid, diethyl azodicarboxylate, and benzene for 8 h to obtain 47% of the substituted product 380. Methanolysis of 380 gave the desired (−)-ampelomin B 381 in an 83% yield (Scheme 58).

The synthesis of ampelomin D started from diol 377, which was converted to substituted diol 382 over a few steps [102]. The next step involved the inversion of the configuration via the Mitsunobu reaction in the presence of p-nitrobenzoic acid, diethyl azodicarboxylate, triphenyl phosphine, and benzene under reflux to afford 383 in a 39% yield. Further, the hydrolysis of 383 at room temperature gave the final product (+)-ampelomin D 384 in a 96% yield with an overall yield of 14% (Scheme 59).

2.5.9. Synthesis of Natural Products-Based Fatty Acid Amides

Serinolamine A and columbamide D are endocannabinoids, which are extracted from a cyanobacteria, Lyngbya majuscula. These exhibit many biological properties as they act as anti-proliferatives against lung cancer and breast cancer cells [103,104]. Ghotekar et al. reported a concise and efficient total synthesis of serinolamides and columbamides in 2019 [105]. The total synthesis commenced from the preparation of two fragments, 386 and 388. The fragment 386 was synthesized from tetradecanol 385 over a few steps. 9-Decen-1-ol 387 was converted to fragment 388 over a few steps. Next, (R)-benzyl glycidyl ether 389 underwent regioselective opening under basic conditions to give (R)-triol 390 in a 98% yield. In the next step, the Mitsunobu reaction was performed for amine linkage formation in the presence of diethyl azodicarboxylate, triphenyl phosphine, and DMF at 0 °C for 6 h to obtain (S)-amino alcohol 392 in a 95% yield. Further, nosyl deprotection in the presence of thiophenol in acetonitrile, followed by hydrogenation with H₂/Pd(OH)₂, gave enantiopure alcohol (R)-393 in a 97% yield. The alcohol (R)-393 was used as a precursor to couple the fragment 388 for the synthesis of columbamide D 394 in a 71% yield. Similarly, alcohol (R)-393 was coupled with fragment 386 to furnish serinolamide-A 395 in a 75% yield (Scheme 60).

2.5.10. Synthesis of Chlorosulpholipids-Based Natural Products

Chlorosulfolipids are complex marine natural products extracted from Ochromonas danica, a freshwater algae [106]. These natural products possess antimicrobial and antiviral properties and are integral parts of membranes. Sondermann et al. proposed the total synthesis of mytilipin B in 2019 [107]. The total synthesis was achieved after solving many problems regarding deviations of the spectrum of naturally occurring and laboratory synthesized mytilipin. The total synthesis was commenced from epoxide 396, which was converted to 1,2-diol 397 over a few steps. The 1,2-diol 397 underwent 1,4-dioxolane formation in the presence of copper sulfate and p-toluene sulfonic acid, followed by hydrogenolysis with Pd/C and ethyl acetate, leading to the Mitsunobu reaction with 1-phenyl-1H-tetrazole-5-thiol, triphenyl phosphine, and THF at 0 °C to 23 °C to get a quantitative yield of 398. The compound 398 was converted to sulfone 399 in an 84% yield by oxidation in the presence of (NH₄)₆Mo₇O₂₄.4H₂O and hydrogen peroxide. The sulfone 399 was converted to 4a diastereomer 400 of mytilipin B in a 72% yield. The sulfone 399 was also converted to 4b diastereomer of mytilipin B 401 in a 72% yield by adopting a different route over a few steps (Scheme 61).

2.5.11. Synthesis of Dihydropyran-Based Natural Products

Marine organisms are a source of many natural products. Eurotiumide F and G are marine fungi-derived natural products, which possess many biological properties, i.e., antimicrobial and antifouling. Nakayama et al. reported the total synthesis of eurotiumide F and G in 2019 [108]. Aldehyde 402 and 1-phenyl-1H-tetrazole-5-yl (PT)-sulfone 403 were reacted together to give ketone 404 over a few steps. It underwent hydrolysis in the presence of KOH in ethanol under reflux, followed by an intramolecular Mitsunobu reaction in the presence of diethyl azodicarboxylate and triphenyl phosphine in THF to obtain trans-4-methoxyisochroman-1-one 405 in an 80% yield over two steps. The last step involved the reduction with DIBAL to obtain lactol with the subsequent removal of the MOM group to obtain the final compound (−)-eurotiumide G 406 in a 40% yield. The compound trans-4-methoxyiso-chroman-1-one 405 was converted to (+)-eurotiumide F 407 in a 46% yield over a few steps. (+)-Eurotiumide G 408 was synthesized from ketone 404 by DIBAL-mediated reduction and MOM deprotection by treatment with 6 M HCl in methanol in a 55% yield (Scheme 62).

2.5.12. Synthesis of Enediynes-Based Natural Products

Kedarcidin chromophore is an important natural product with biological properties, such as antitumor and antibacterial, etc. It exhibits selective in vivo antitumor activity against B16 melanoma cells and P388 leukemia [109]. It was discovered for the first time in 1990. The first total synthesis of kedarcidin chromophore, comprised of 17 steps, was proposed by Lear et al. in 2019 by employing a stereoselective allenyl zinc keto addition, Mitsunobu etherification, α-selective glycosylations, atropselective Sonogashira and Shiina cyclization sequence, Ce-mediated enediyne cyclization, and Ohfune-based amidation [110]. The total synthesis was commenced from ketone 409, which was converted to compound 410 over a few steps. A total of 1.1 Eq. of β-amino-2-chloroazatyrosine 411 was utilized for the inversion of allylic C 11-β alcohol via Mitsunobu reaction in the presence of di-2-methoxyethyl azodicarboxylate, triphenyl phosphine, and toluene at 0 °C to deliver compound 412 in a 73% yield. The compound 412 was converted to kedarcidin chromophore 413 over a few steps. (Scheme 63).

2.6. Synthesis of Epidithiodiketopiprazine-Based Natural Products

The importance of the Mitsunobu reaction is evident from its role in the total synthesis of natural products. Scabrosins are ETPs (epidithiodiketopiperazine) which are fungal metabolites with a diverse structure and biological significance as antineoplastic and cytotoxic substances. They express in vitro cytotoxic activity against human breast cancer cells (MCF-7) with an IC₅₀ value of 1 nM, and murine leukemia P388 with an IC₅₀ value of 16 nM. Scabrosins also exhibit appreciable in vivo antineoplastic activity [111]. These factors make scabrosins an important scaffold for carrying out total synthesis. Due to their complex bonding, the total synthesis of these natural products has not been reported yet. In 2019, Liu et al. reported the synthesis of the desulfur-scabrosin skeleton, common to most ETPs, by using the Mitsunobu reaction, pyrrolidine ring construction, asymmetric nucleophilic epoxidation, and base-induced keto-enol isomerization as key steps [112]. The synthesis was started from phenol 414, which was converted to epoxycyclohexene alcohol 415 over a few steps. The epoxycyclohexene alcohol 415 was subjected to Mitsunobu coupling with compound 416 in the presence of diethyl azodicarboxylate and triphenyl phosphine to afford compound 417 in a 91% yield. The compound 417 was converted to ester 418 over a few steps, which underwent saponification with lithium hydroxide followed by dimerization in the presence of HATU/DIPEA and deprotection with TBAF to yield a quantitative amount of diastereomer b` of the desulfur-scabrosin skeleton 419. The diastereomer b` was converted to diastereomer c` of the desulfur-scabrosin skeleton 420 in an 80% yield by base-mediated keto-enol isomerization in the presence of NaOMe in MeOH, followed by desilylation with TBAF (Scheme 64).

2.7. Liponucleoside-Based Natural Product Synthesis

Caprazamycins are liponucleoside-based natural products consisting of uridine attached to some amino acids. It has a diazepanone ring in its structure, which is a common structure in liponucleosides. These are obtained from Streptomyces sp. MK730-62F2. Caprazamycins exhibit biological activity as antimicrobial agents and provide a powerful ingredient for the synthesis of synthetic derivatives and drugs [113]. Nakamura et al. proposed the total synthesis of caprazol and caprazamycin A by utilizing an intramolecular Mitsunobu reaction as a key step in 2019 [114]. The total synthesis commenced from the preparation of 59% of diethyl isocyanomalonate 422 from diethylaminomalonate 421 in the presence of triphosgene and activated charcoal in 1,4-dioxane. In the next step, the aldol reaction between aldehyde 423 and diethyl isomalonate 422 was conducted in the presence of (S, S)-thiourea catalyst 424 to furnish oxazolidine 425 in a 42% yield. Further, oxazolidine 425 was converted to compound 426 over a few steps, which underwent the Mitsunobu reaction in the presence of di-tert-butyl azodicarboxylate, triphenyl phosphine, and toluene to afford 75% of 427. The compound 427 was converted to protected caprazol 428 over a few steps, which underwent Troc group removal and reductive amination followed by Pd black treatment in methanol to furnish caprazol 429 in a 46% yield. The caprazamycin A 430 was obtained from protected caprazol 428 in a 90% yield over a few steps (Scheme 65).

Miscellaneous

Aspongodopamine A and B are heterocyclic natural products extracted from Aspongopus chinensis. They have many applications in the field of science and are used as pain-killers and also as food. The total synthesis of aspongodopamine has been reported by Ding et al. in 2020 [115]. A known alcohol 431 was converted to a secondary alcohol 432 over a few steps. In the next step, the secondary alcohol 432 was subjected to nucleophilic substitution with ester 433 followed by the addition of sodium azide in TBAI to provide azide 434 in a 92% yield. Further, the Mitsunobu reaction was performed with bis-boc adenine 435 in the presence of diisopropyl azodicarboxylate in THF to afford 436 in a 70% yield. Finally, 56% of aspongodopamine B 437 was furnished from compound 436 over a few steps (Scheme 66).

The process of synthesis of natural products is very complicated and involves a number of strategies to achieve final compounds. In that regard, the Mitsunobu reaction plays an important part. Tetrodotoxin is a marine natural product with a wide range of origins. It is a highly complex natural product whose total synthesis is still unknown, but the synthesis of its naturally occurring intermediates Cep-212 and Cep-210 were reported by Adachi et al. in 2019 [116]. The synthesis of Cep-212 443 started from geraniol 438, which was converted to alcohol 439 over a few steps. In the next step, the azide group of 439 was reduced, followed by guanidinylation with N, N`-bis-boc-S-methylisothiourea 440 in the presence of mercuric chloride and triethyl amine to afford di-Boc guanidine 441 in a 58% yield. The next step involved the Mitsunobu reaction in the presence of DIAD and PPh₃ to give cyclic guanidine 442 in a 59% yield. Finally, the deprotection of protecting groups was performed in the presence of K₂CO₃ in MeOH, followed by treatment with TFA, to yield 60% of the final product 443 Cep-212 (Scheme 67).

The synthesis of Cep-210 commenced from intermediate 439, which was converted to allylic alcohol 444 over a few steps. In the following series of steps, allylic alcohol was protected in the presence of TBSOTf, followed by azide hydrolysis with lithium aluminium hydride and gunidinylation with N, N`-bis-boc-S-methylisothiourea 440 of subsequent amine, to give di-Boc guanidine 445 in an 88% yield over two steps. Further, the Mitsunobu reaction was performed under classical conditions of DIAD and PPh₃ to obtain cyclic guanidine 446 in an 87% yield. The deprotection of the TBS and Boc group was performed in the presence of TFA in CH₂Cl₂, along with treatment with silica gel, to yield the final product Cep-210 447 in a quantitative yield (Scheme 68).

Cladosporin is a secondary metabolite that is isolated from various fungi, i.e., Aspergillus flavus and Cladosporium cladosporioides. It possesses many biological properties, such as antifungal, antibacterial, insecticidal, and plant growth inhibitory, etc. It was found to exhibit potent antiparasitic activity with an IC₅₀ value of 40 nM against liver and blood stage proliferation of pathogens. In addition, cladosporin was found to be >100 times more selective against parasitic KRS. It is found to inhibit KRSs from Loa Loa and Schistosomamansoni species [117]. Das et al. reported the total synthesis of cladosporin in 2019 [118]. The total synthesis commenced from (S)-propylene oxide 448, which was converted to intermediate 449 over a few steps. The intermediate 449 was epoxidized in the presence of m-CPBA to yield epoxide 448 in an 88% yield. Next, the Grignard reaction was performed in the presence of 1-bromo-3,5-dimethoxy benzene 449 to give two diastereomers 452 and 453 in 1:1 diastereomeric ratio with an 86% overall yield. The diastereomer 452 was converted to 453 via the Mitsunobu inversion in the presence of p-nitrobenzoic acid, diisopropyl azodicarboxylate, and triphenyl phosphine in THF, followed by ester hydrolysis with K₂CO₃ in MeOH, to give alcohol 453 in an 83% yield over two steps. The alcohol 453 was iodized with NIS in CH₂Cl₂, followed by treatment with Pd(PPh₃)Cl₂ and 1,10-phenanthroline along with demethylation, to obtain the final product cladosporin 454 in a 61% yield (Scheme 69).

The structure determination along with total synthesis of rarely occurring natural products is a complex and tedious process. Chloroenyne and related natural products are obtained from Laurencia majuscule [119]. Its structure has been determined by computational methods and NMR analysis of its diastereomers. Shepherd et al. proposed the total synthesis of four different diastereomers of chloroenyne and the total synthesis of notoryne in 2019 [120]. The total synthesis was commenced from epoxy alkene 455, which was subjected to ozonolysis in the presence of ozone, PPh₃, and NaBH₄, followed by the Mitsunobu reaction with 1-phenyl-1H-tetrazole-5-thiol 456, DIAD, and PPh₃, followed by treatment with 3-chloroperbenzoic acid 457, to furnish tetrazole sulfone 458 in a 60% yield. Epoxide 459 was converted to aldehyde 460 over a few steps. Next, tetrazole sulfone 458 and aldehyde 460 were coupled together in the presence of NaHMDS and DME to give 461 in a 80% yield. The 461 was converted to alkene 462 over a few steps. The alkene 462 was reacted with crotonaldehyde in the presence of Grubb’s second-generation catalyst for a cross-metathesis reaction, followed by treatment with trimethylsilyl diazomethane and the deprotection of the p-methoxy benzyl group, to give diastereomer c 463 of chloroenyne in an 84% yield. The diastereomer c 463 underwent the Mitsunobu inversion with para-nitrobenzoic acid 464, DIAD, and PPh₃, along with ester methanolysis to give diastereomer a 465 in a 25% yield over two steps (Scheme 70).

Furthermore, alcohol 466 underwent the Mitsunobu inversion in the presence of DIAD, PPh₃, and para-nitrobenzoic acid 464 followed by ester methanolysis to afford inverted alcohol 467 in a 79% yield over two steps. In the next step, enyne introduction was performed by the reaction of alcohol 467 with crotonaldehyde in the presence of Grubb’s II catalyst to give diastereomer b 468 in a 39% yield over three steps. Diastereomer d 469 was prepared from 468 by the Mitsunobu inversion in the presence of DIAD, PPh₃, and p-nitrobenzoic acid 464 followed by ester methanolysis (Scheme 71).

Further, synthesis of notoryne 472 was commenced from chloride 462, which was deprotected by BCl₃.SMe₂, followed by the Mitsunobu inversion in the presence of DIAD, PPh₃, and para-nitrobenzoic acid 464 to give alcohol 470 in a 91% yield. Terminal alkene in 470 was subjected to ozonolysis followed by the Yamamoto–Petersen reaction to give (Z)-enyne 471 in a 32% yield with high diastereoselectivity. The final step involved the deprotection of (Z)-enyne 471 to give diastereoselective (Z)-notoryne 472 in a 95% yield (Scheme 72).

3. Conclusions

To conclude, the Mitsunobu reaction has been in use for the past few decades. Throughout this review, the significance of the Mitsunobu reaction in the total synthesis of natural products from recent years has been mentioned and explained. The smooth inversion of configuration, short reaction time, mild reaction conditions, easy separation, and purification techniques are some of the salient features achieved by employing the Mitsunobu reaction. It has adopted a wide range of pronucleophiles that expand from alcohols, carboxylic acids, imides, and sulfonamides to β-ketoesters, purines, and oximes, allowing the formation of C-C, C-N, and C-O bonds. As a lot of research has been done regarding the Mitsunobu reaction, there is still space present in this area to improve the efficacy of this reaction. With the progress of time, innovative methods should be investigated and utilized for large scale synthesis of new classes of products.