Cross-coupling reactions towards the synthesis of natural products

Abstract

Cross-coupling reactions are powerful synthetic tools for the formation of remarkable building blocks of many naturally occurring molecules, polymers and biologically active compounds. These reactions have brought potent transformations in chemical and pharmaceutical disciplines. In this review, we have focused on the use of cross-coupling reactions such as Suzuki, Negishi, Heck, Sonogashira and Stille in the total synthesis of some natural products of recent years (2016–2020). A short introduction of mentioned cross-coupling reactions along with highlighted aspects of natural products has been stated in separate sections. Additionally, few examples of natural products via incorporation of more than one type of cross-coupling reaction have also been added to demonstrate the importance of these reactions in organic synthesis.

Graphic abstract

Introduction

Reactions assembling the carbon–carbon bonds in organic compounds constitute a pillar of strength to organic synthesis. Particularly, the designing of natural products framework demands a rapid and selective construction of carbon skeleton [1, 2]. Cross-coupling reactions have gathered much attention of researchers from the past few decades because of simple, general and mild synthetic approaches involving the use of highly active ligands and transition metal complexes. These protocols are involved in the accomplishment of simple to complex carbon skeletons such as functional materials, synthetic fragments, bioactive compounds, natural products and agrochemicals [3, 4]. One of the prominent cross-coupling reactions is palladium catalyzed C–C bond forming reactions that give interesting properties to the final chains of molecules [5,6,7,8]. In 2010, Nobel Prize award for palladium-catalyzed cross-coupling reactions [4] had fastened its roots in chemical synthesis and their enabling characteristics make them a center of interest in multiple domains.

Tamura and Kochi [9] reported the first iron-catalyzed cross-coupling reaction and then as the time passed, many new strategies including Suzuki [10], Heck [11], Sonogashira [12], Negishi [13], Stille [14], Cadiot–Chodkiewicz [15], Castro–Stephens [16], Hiyama [17], Fukuyama [18], Liebeskind–Srogl [19] and Kumada reactions [20], etc., were developed for framing the structures of organic compounds and the scope of cross-coupling reactions became a key topic for the investigators. Keeping in view the recent advances and extensive applications of cross-coupling reactions, several reviews on novel synthetic methodologies have been reported [21,22,23].

Owing to unique chemical features and biological potential, many of the natural products are used as core part of valuable drugs [24]. Herein, we have emphasized the role of cross-coupling reactions in the total synthesis of some natural products. Natural products are briefly introduced and categorized into alkaloids, terpenoids, steroids, polyketides, macrolides, lignans, alkamides and lactones classes.

Review of literature

Suzuki cross-coupling reaction

Palladium-catalyzed Suzuki cross-coupling reaction (Suzuki–Miyaura coupling) is a widely known method to couple organoboranes/boronic acids with organic halides/triflates under basic conditions to form C–C bonds [25]. Non-toxicity and stability, accessibility of organoboron compounds/boronic acids, their incorporation into organometallic compounds and simple workup techniques add additional features to the armory of Suzuki cross-coupling. This cross-coupling endures many functional groups and the stereochemistry of coupling reagents is retained in the resulting biaryls [26]. It is one of the well-built tool to furnish biaryl moiety which displays vast applications in pharmaceuticals and material science [27]. The first natural product synthesis via Suzuki coupling was disclosed by Rossi [28] in 1981 which involved the preparation of sex pheromone 1 in 21.6% overall yield (Fig. 1).

Fig. 1

Structure of sex pheromone 1

Synthesis of alkaloids

Pentabromopseudilin 2 is a polyhalogenated bicyclic alkaloid [29] which was firstly isolated from Pseudomonas bromoutilis (1996) and later from Alteromonas luteoviolaceus, Chromobacteria and Pseudoalteromonas sp (Fig. 2). Biological activities such as antifungal, anti-tumour and antibiotic are associated with this polybrominated natural product. It acts as inhibitor against human lipoxygenases, myosin and exhibits the potential to act against MRSA with IC₅₀ value of 0.1 µM [30].

Fig. 2

Structure of pentabromopseudilin 2

Kum et al. [31] carried out the synthesis of an anti-MRSA and myosin-inhibiting natural product 2 with 38% overall yield through two steps by using Suzuki coupling protocol (Scheme 1). Synthesis was started from the coupling of phenol 3 with N-methyliminodiacetic acid (MIDA) boronate 4 and conditions were optimized to achieve the best results. The use of 10 mol% Buchwald 2nd generation precatalyst (Sphos Pd G2) along with 4 M KOH (base) in tetrahydrofuran (THF)/H₂O led to the formation of compound 5 which was treated with pyridinium tribromide 6 to shape the core of pentabromopseudilin 2 in 60% yield. The synthesized compounds 2 and 5 were evaluated for biological potential against Staphylococcus epidermidis; however among them, compound 2 showed clear zones of inhibition at 50 and 5 µM.

Scheme 1

Synthesis of pentabromopseudilin 2

Marine environment provides a number of valuable natural products with potential of anticancer, antibiotic and therapeutic activities. Among them, actinobacteria are of vital importance as these are the sources of market valued chemical substances. Lynamicin D 7 is a chlorinated bisindole pyrrole alkaloid which has been obtained from marine actinomycetes such as SCSIO 03,032 and NPS12745 (Fig. 3). This compound has the capability to act against drug-resistant pathogens (Staphylococcus aureus and Enterococcus faecium) [32, 33].

Fig. 3

Structure of lynamicin D 7

The first total synthesis of lynamicin D 7 was reported by Sigala et al. [34] which involved Suzuki coupling of dicarboxylate 9 with boronate 11 (Scheme 2). In this regard, pyrrole 8 was subjected to POCl₃ (63% yield) and CH₃COONa and resulting product was oxidized (using KMnO₄) followed by Fischer esterification (with CH₃OH, H₂SO₄) and bromination (using Br₂, 95%) provided indole-based dibromo dicarboxylate derivative 9. While boronate 11 was obtained from indole 10 by employing iodination followed by protection with Boc group (94% yield, 2 steps) and then treatment with pinacolborane in the presence of PdCl₂(dppf) (84% yield). Suzuki coupling of synthesized fragments 9 and 11 in the presence of Pd(OAc)₂, triphenylphosphine (PPh₃), Na₂CO₃ in THF/H₂O mixture at 60 °C produced bisindole pyrrole 12 in good yield (76%) which on treatment with trifluoroacetic acid (TFA) afforded the acquired product 7 in an excellent yield (97%). Biological activity of lynamicin D 7 was also studied which revealed that it had a minor effect on cell viability, but it could regulate splicing of pre-mRNAs as it alters the levels of kinase (SRPK1).

Scheme 2

Synthesis of lynamicin D 7

Carbazole alkaloids bearing pyrrole ring constitute a major class of natural products and their source of extraction includes various plant species including bacteria and fungi. From the last few decades, extensive work has been carried out on carbazole compounds due to their versatile chemical characteristics and biological potentials such as anti-HIV, anti-malarial, anti-tumour, anti-TB, etc. [35] Some of the biologically important carbazole alkaloids 13–24 are listed in Fig. 4.

Fig. 4

Structures of carbazole alkaloids 13–24

A convenient strategy for the total synthesis of carbazole alkaloids 13–24 was reported by Bhatthula et al. [36] with moderate to excellent yields (27–96%). The synthetic route involved Suzuki cross-coupling and Cadogan reductive cyclization as vital steps. Synthesis of mukonine 13 was started from benzoic acid 25 which underwent esterification (with CH₃I, Cs₂CO₃, 99%) followed by addition of bis(pinacolato diboron) to give compound 26 in 66% yield. Coupling of compound 26 with o-nitrobenzene 27 using Pd(PPh₃)₄ and K₂CO₃ in refluxing toluene in 5 h gave the coupled product 28 in 88% yield. Later, compound 28 in the presence of PPh₃ and o-dichlorobenzene (o-DCB) experienced Cadogan reductive cyclization to furnish the desired natural product 13 (66%) along with its regioisomer 13a (27%). Reduction of compound 13 with diisobutylaluminium hydride (DIBAL-H) and LiAlH₄ afforded koenoline 15 and murrayafoline A 17, respectively, while oxidation of compound 15 with MnO₂ gave murrayanine 16 in 81% yield. Saponification of compound 13 (using aq. KOH) produced mukoeic acid 14 in 96% yield. Carbazole 13a provided regioisomers 14a, 15a and 16a under saponification, reduction and oxidation conditions, respectively (Scheme 3). Synthesis of glycoborine 18 and clauszoline K 19 was achieved in 93% and 75% yield using compound 31/32 and 2-cholro-4-methyl-1-nitrobenzene 33 as Suzuki coupling partners (Scheme 4). Treatment of compound 41 (obtained from 4-bromotoluene 39) with o-nitrobenzene 27 in the presence of Pd(PPh₃)₄ gave biphenyl 43 in 86% yield which was cyclized (using PPh₃, o-DCB) to obtain 2-methyl-9H-carbazole 24 (94%). Moreover, the use of 3-bromophenol 37 as starting material and 2-cholro-4-methyl-1-nitrobenzene 33 (for Suzuki coupling) framed the structures of glycozolicine 20 (38%), glycozoline 21 (38%), mukolidine 22 (85%) and mokuline 23 (91%) (Scheme 5).

Scheme 3

Synthesis of carbazole alkaloids 13–17

Scheme 4

Synthesis of carbazole alkaloids 18 and 19

Scheme 5

Synthesis of carbazole alkaloids 20–24

Isocrytolepine 44 (obtained from Cryptolepis sanguinolenta) is an indoloquinoline alkaloid reported independently by Pousset et al. [37] and Sharaf et al. [38] in 1995 (Fig. 5). It consists of tetracyclic skeleton based on angularly fused indolo[3,2-c]quinoline ring with wide range of biological activities such as antiplasmodial, antimicotic, antihyperglycemic, antimuscarinic and antibacterial, etc. [39].

Fig. 5

Structure of isocrytolepine 44

Håheim et al. [40] presented the synthesis of tetracyclic core 48 of isocrytolepine 44 (Scheme 6). Suzuki coupling was employed between 3-bromoquinoline 45 and boronic acid 46 in the presence of PdCl₂(dppf) (5 mol%), K₂CO₃ in EtOH/H₂O at 60 °C for 20 h to give compound 47 in 84% yield. The latter compound 47 was cyclized using PdCl₂(dppf) (20 mol%) as catalyst and 1,3-bis(2,4,6-trimethylphenyl)-imidazolium (IMes) (5 mol%) as ligand to produce regiospecific compound 48 in good yield (73%).

Scheme 6

Synthesis of tetracyclic motif 48 of isocrytolepine 44

α-Cyclopiazonic acid 49 is a member of prenylated alkaloids possessing the potential to inhibit calcium-ATPase enzyme in sarcoendoplasmic reticulum due to its toxic nature (Fig. 6). For the first time, it was obtained from fungus Penicillium cyclopium [41].

Fig. 6

Structure of α-cyclopiazonic acid 49

A shortest synthetic pathway for the preparation of α-cyclopiazonic acid 49 involving seven steps was reported by Shi et al. [42] (Scheme 7). Synthesis was commenced from palladium-catalyzed coupling of 4-bromoindole 50 with t-prenylboronate 51 using Pd(PPh₃)₄, NaOH in toluene/H₂O at 90 °C to form regioisomer 52 in 91% yield. Vilsmeier–Haack formylation (with POCl₃, dimethylformamide (DMF), aq. KOH, 75%) and N-tosylation (with TsCl, 53%) produced aldehyde 53 which on reaction with compound 54 in the presence of LiHMDS yielded indole derivative 55 (78%). It was then subjected to [3 + 2] annulation by employing Tf₂NH (50% yield) to achieve diastereomeric mixture of three tetracycles. Only small amount of one diastereomer was separated and was treated with excess of Mg (50% yield) to give mixture of diastereomeric amines (56a:b:c = 1:0.3:0.7) from which the amine 56a was successfully separated. It was converted to the target product 49 in 59% yield on treatment with diketene 57 in dichloromethane (DCM) and t-BuOK.

Scheme 7

Synthesis of α-cyclopiazonic acid 49

Synthesis of polyketides

Anthracyclines account for a medically prime class of aromatic polyketides and demonstrate anti-cancer potential. Their structure contains aglycone chromophore attached with one or more deoxysugars. Nogalamycin 58 (extracted from Streptomyces nogalater) possesses antibacterial and anticancer potential, whereas its semisynthetic derivative, menogaril 59 exhibits anticancer properties. These compounds are naturally occurring polyketides (Fig. 7) [43].

Fig. 7

Structures of nogalamycin 58 and menogaril 59

The synthesis of anthracyclines 58 and 59 was achieved by Peng and VanNieuwenhze [44] via implementation of Suzuki cross-coupling protocol for the preparation of the DFT-ring system 65 (Scheme 8). In this regard, enol triflate 60 and D-ring precursor 61 in the presence of PdCl₂(dppf) and KOH in toluene at room temperature produced coupled product 62 in 69% yield. Then, compound 62 on subsequent primary alcoholic group protection (with TBSCl, 88%) followed by Staudinger reduction (using PPh₃, H₂O/THF) provided amine which was further protected with 2-naphthylsulfonyl group. In the following step, addition of formic acid selectively cleaved the primary TBS group to produce compound 63 (88% over 3 steps) which on treatment with PySO₃ followed by the addition of HC(OCH₃)₃ accomplished dimethyl acetal 64 in an excellent yield (95% over 2 steps). Epoxidation of alkene 64 was carried out with m-chloroperoxybenzoic acid (m-CPBA, 57%) which was reduced (using LiAlH₄, 59%) and cyclized in acidic conditions (3 M HCl, acetic acid) to afford DFT-ring system 65 in 77% yield.

Scheme 8

Synthesis of DFT- ring 65 of nogalamycin 58 and menogaril 59

Synthesis of terpenoids

The presence of tricarbocyclic core is a peculiarity of naturally occurring diterpenoid hamigerans. Furthermore, hamigerans possess three or four stereogenic centers arranged in adjacent positions around cis bicyclic core [45]. (−)-Hamigeran B 66 with magnificent anti-viral property was first isolated from Hamigera tarangaensis (a sponge) in 2000 (Fig. 8) [46].

Fig. 8

Structure of (−)-hamigeran B 66

Total synthesis of (−)-hamigeran B 66 was disclosed by Kuwata et al. [47] over 17 steps via Suzuki cross-coupling of (R)-triflate 68 (obtained from a cyclic ketone 67) with compound 69 using PdCl₂(dppf)·DCM, K₂CO₃ in dimethyl sulfoxide (DMSO) at 80 °C (Scheme 9). The coupling product (R)-70 (68%) was obtained as a mixture of two rotamers which was divulged through ¹H NMR interpretations. Further, the treatment of (R)-70 with SmI₂ for reductive coupling of two aldehydes resulted in two diastereomers 71a (51%) and 71b (49%). The stereochemistry of the target product 66 was maintained during the synthetic route and was obtained over several steps from diastereomer 71a.

Scheme 9

Synthesis of (−)-hamigeran B 66

Magnolia officinalis var. biloba is a commonly used Chinese medicine. Its active ingredient known as terpenoid quinone is also named as magterpenoid C 72. It is famous for the remedy of phlegm, dyspepsia and abdominal distension (Fig. 9) [48].

Fig. 9

Structure of magterpenoid C 72

The first total synthesis of magterpenoid C 72 by using Suzuki coupling and silica-gel accelerated [4 + 2] cycloaddition protocols was explained by Kumar et al. [49] (Scheme 10). Hydroquinone and 4-allyl anisole gave 2-bromo-1,4-dimethoxy-benzene 73 and compound 74, respectively, which were subjected to Suzuki coupling in the presence of Pd(PPh₃)₄, Na₂CO₃ in refluxing dimethoxyethane (DME)/H₂O for 6 h to give intermediate 75 in 60% yield. In the next step, oxidative demethylation of compound 75 was done using phenyliodine bis(trifluoroacetate) (PIFA) in acetonitrile/water mixture to access quinone 76 (62%). Quinone 76 was subjected to reduction (with NaBH₄, 99%) followed by the addition of AlCl₃ for demethylation (50% yield) and NaIO₄ to furnish the desired quinone 77 in 95% yield. Final framework of terpenoid 72 (67% over 2 steps) was achieved in a regioselective manner by the combination of quinone 77 with β-myrcene 78 in the presence of SiO₂-gel and MnO₂ for [4 + 2] cycloaddition and subsequent aromatization.

Scheme 10

Synthesis of magterpenoid C 72

Miscellaneous

Insects constitute a major portion of animals on earth. Although a number of peptides and proteins have been isolated from various insect species from past few years however, their biologically activity has been less investigated. Aspongopus chinensis Dallas, found in China, is used as traditional medicine as well as food. Investigation revealed that it exhibits pronounced biological activities such as anticancer, analgesic and angiogenesis, etc. Proliferation of neural stem cells is also associated with this insect species. Aspongpyrazine A 79 is a pyrazine obtained from insect A. chinensis (Fig. 10) [50].

Fig. 10

Structure of aspongpyrazine A 79

Bendre et al. [51] reported an efficient, simple and environmental friendly biological route for the preparation of palladium nanoparticles (PdNPs) using palladium chloride and oxytoxin (a harmone). These PdNPs were then applied in the Suzuki cross-coupling for the synthesis of aspongpyrazine A 79 with 86.4% overall yield (Scheme 11). Readily available 2-bromo-6-methylpyrazine 80 was subjected to Suzuki coupling with boronic acid 81 over PdNPs and K₂CO₃ in DMF/H₂O at 100 °C to obtain compound 82 in 90% yield. The latter compound 82 underwent deprotection with 47% HBr and aliquat© 336 (catalyst) to afford final skeleton of aspongpyrazine A 79 in 96% yield.

Scheme 11

Synthesis of aspongpyrazine A 79

Kehokorin A 83 and kehokorin B 84 contain dibenzofuran core in their structures and have been extracted from field-collected sample of fruit bodies of Trichiaceae (Trichia favoginea var. persimilis) (Fig. 11). Biological evaluation of these compounds showed that kehokorin A 83 possesses cytotoxicity potential against HeLa cell line which was attributed to the presence of rhamnose unit [52].

Fig. 11

Structures of kehokorin A 83 and kehokorin B 84

Fujiwara et al. [53] implemented Suzuki cross-coupling approach twice in the total synthesis of kehokorin A 83 and kehokorin B 84. In their work, phenol 85 was transformed into bromo-phenol derivative 86 (95%) on treatment with N-bromosuccinimide (NBS) in the presence diisopropylamine (i-Pr₂NH) followed by the addition of TMSCHN₂ (trimethylsilyldiazomethane) for methylation of phenolic hydroxyl group. In the next step, compound 86 was coupled with boronic acid 87 to access biaryl compound 88 in 94% yield under the conditions of Pd₂(dba)₃, SPhos and K₃PO₄ in toluene at 105 °C which over three steps provided dibenzofuran core 89. Compound 89 produced was further transformed into compound 90 which again underwent Suzuki coupling with boronic acid 91 under similar conditions to give p-terphenyl dibenzofuran 92 in 55% yield (Scheme 12). The benzyl group of the dibenzofuran 92 was cleaved by using H₂, Pd/C to obtain compound 93 which on treatment (with K₂CO₃, BuOH, 1,4-dioxane) furnished kehokorin B 84 (70%), whereas on incorporation of imidate 94 (using TMSOTf) followed by the addition of K₂CO₃, BuOH, 1,4-dioxane and H₂, Pd/C for hydrogenolysis produced kehokorin A 83 (48%) (Scheme 13).

Scheme 12

Synthesis of p-terphenyl dibenzofuran 92

Scheme 13

Completion of the total synthesis of kehokorin A 83 and kehokorin B 84

11,12-Dihydro-3-hydroxyretinol 95 has been collected from Laurencia nipponica (red alga) at Muroran, Hokkaido in Japan. It possesses moderate antifouling property in 5–10 µg/cm² against the larvae of Amphibalanus amphitrite (Fig. 12) [54].

Fig. 12

Structure of (R)-11,12-dihydro-3-hydroxyretinol 95

Rivas et al. [55] reported the stereocontrolled synthesis of (R)-11,12-dihydro-3-hydroxyretinol 95 with 73% yield via Suzuki cross-coupling of enantiopure alkenyl iodide 99 with pinacolboranedienoate 98 (Scheme 14). Compound 98 was obtained when methyl geranoate 96 with 2-propenylboronate 97 was coupled with second generation Grubbsˈ catalyst in 48% yield. In the following step, Suzuki coupling in the presence of 7 mol% Pd(PPh₃)₄ and 10% aq. TlOH in THF at 25 °C in 2 h gave all-trans-tetraenoate 100 (71%) which on reduction with DIBAL-H yielded the desired product 95.

Scheme 14

Synthesis of (R)-11,12-dihydro-3-hydroxyretinol 95

Bradykinin binding inhibitor, a metabolite termed as L-755,807 101 (non-peptide natural product) was isolated from Microsphaeropsis sp. It acted as ³H-bradykinin binding inhibitor with IC₅₀ of 71 µM (Fig. 13) [56].

Fig. 13

Structure of L-755,807 101

A convergent synthetic route for the total synthesis of L-755–807 101 and its stereoisomers via Suzuki coupling and E-selective HWE (Horner-Wadsworth-Emmons) protocol was presented by Tanaka et al. [57]. (R)(−)-3-Hydroxy-2-methylpropionate 102 gave (R,R)-vinyl bromide 103 over several steps. Then, (R,R)-103 was treated with boronic acid 104 by loading Pd(PPh₃)₄, TlOEt in THF/H₂O to accomplish (R,R)-triene alcohol 105 in 65% yield which on oxidation (with MnO₂) provided (R,R)-triene aldehyde 106 in 79% yield (Scheme 15). Moreover, amide 107 was converted to phosphonate 108 on treatment with n-BuLi and dimethoxy methyl phosphonate which was further assembled with already synthesized fragment 106 under HWE reaction conditions (t-BuOK in 1 M THF) to form compound 109 in 65% yield. Deprotection of TES group of compound 109 using 3HF·TEA followed by the addition of AZADOL for oxidation afforded the target skeleton of L-755,807 101 in 63% yield (Scheme 16). Additionally, structure–activity relationship (SAR) for L- 755,807 101 and its isomers was studied for the first time and it was observed that the prepared compounds showed potent Aβ aggregation inhibitory activity (IC₅₀ values 5–21 µM).

Scheme 15

Synthesis of (R,R)-triene aldehyde 106

Scheme 16

Completion of synthesis of L-755,807 101

Anithiactins A-C (110–112) are modified phenylthiazole derivatives and have been extracted from Streptomyces sp. These compounds displayed moderate acetylcholinesterase inhibitory activity with no cytotoxicity [58]. Later on, thiasporine A 113 was extracted from Actinomycetospora chlora in addition to anithiactins A and C (Fig. 14) [59].

Fig. 14

Structures of anithiactin A 110, anithiactin B 111, anithiactin C 112 and thiasporine A 113

Vaaland et al. [60] designed the synthetic route for four title natural products 110–113 by employing Suzuki coupling as main step (Scheme 17). The starting substrates i.e. boronic acid hydrochloride 46 and thiazole bearing carboxylate 114 were coupled in the presence of 15 mol% Pd₂dba₃, 43 mol% XPhos and CsF in refluxing dioxane for 17 h to form a common intermediate 115 in 64% yield. Furthermore, protocols such as hydrolysis (using aq. NaOH, CH₃OH) and aminolysis (using 4 M NH₃, CH₃OH) were implemented to obtain the structures of desired naturally occurring thiazole derivatives 110–113 in moderate to excellent yields (57–95%).

Scheme 17

Synthesis of thiazole derivatives 110–113

Fumimycin 116 (obtained from Aspergillus fumisynnematus) is an unusual metabolite bearing interesting alanine motif connected to a phenyl moiety at the α-carbon (Fig. 15). It showed peptide deformylase inhibitory potential with IC₅₀ of 4.1 µM in addition to antibacterial activity [61].

Fig. 15

Structure of (±)-fumimycin 116

Zaghouani et al. [62] gave a concise total synthesis of (±)-fumimycin 116 in 11.6% overall yield based on 7 steps by employing Suzuki coupling approach (Scheme 18). For this purpose, pyruvic acid 117 and phenol 118 underwent esterification using N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) followed by intramolecular aza-Friedel–Crafts cyclization (using Cbz-NH₂, 15 mol% TfOH) and regioselective chlorination (with N-chlorosuccinimide (NCS), 5 mol% PalauˈChlor) to give chlorobenzofuranone 119 in 76% yield. Decorated styrene 121 with complete E-selectivity in 73% yield was obtained by coupling of chlorobenzofuranone 119 with boronate 120 by using Pd(OAc)₂ (catalyst), SPhos (ligand), K₃PO₄ (base) in THF/H₂O at 60 °C. The synthesis of natural product 116 was achieved in 42% yield (over 3 steps) when styrene derivative 121 underwent Cbz-deprotection (with Pd(OAc)₂/Et₃SiH, trimethylamine (TEA)) followed by fumaryl coupling (using fumaryl chloride) and hydrolysis (with silica/H₂O).

Scheme 18

Synthesis of (±)-fumimycin 116

Sonogashira cross-coupling reaction

Numerous natural products contain alkynes as a fundamental component in their structure and Sonogashira cross-coupling is a vital approach to incorporate alkynes in the skeleton of a wide range of natural products [63]. This reaction includes coupling of a terminal alkyne with vinyl/aryl halide in the presence of palladium catalyst and copper additive as a co-catalyst. Under certain circumstances, copper additives may be harmful to reaction results for some substrates. To solve such kind of problems, copper-free Sonogashira coupling has also been discovered [64, 65]. Furthermore, Sonogahira coupling is employed for the building of bioactive compounds and electronic materials [66].

Synthesis of alkaloids

(±)-Aspergilline A 122 (extracted from Aspergillus versicolor) is a cyclopiazonic acid derived alkaloid with a rigid and highly oxygenated hexacyclic skeleton which is based on indole, tetrahydrofuran and tetramic acid moieties (Fig. 16). This natural product shows inhibitory activity against tobacco mosaic virus and moderate cytotoxicity in various human cell lines [67].

Fig. 16

Structure of (±)-aspergilline A 122

Nakhla and Wood [68] described the total synthesis of (±)-aspergilline A 122 in 16 steps by employing Sonogashira coupling in addition to various protocols such as oxidation, cyclization, [3 + 2] cycloaddition and Aldol reaction (Scheme 19). The synthesis was commenced from N-methylation of readily available bromoisatin 123 to obtain N-methylated product 124 (using CH₃I and K₂CO₃) in good yield (94%) which on coupling with propargyl amine 125 in the presence of 4 mol% Pd(PPh₃)₄, 8 mol% CuI, Cs₂CO₃ and i-Pr₂NEt (Hünig’s base) in toluene at 85 °C gave isatin 126 in 72% yield. Aldol substrate 128 was prepared in 69% yield from acid chloride 127 by premixing it with i-Pr₂NEt followed by the addition of isatin 126, Raney Ni and DMP. The compound 128 was further converted into (±)-aspergilline A 122 over several steps.

Scheme 19

Synthesis of (±)-aspergilline A 122

Cyclopiamide A 129 (obtained from Penicillium cyclopium) and speradine E 130 (obtained from Aspergillus oryzae) are N-methyl-2-oxindoles [69] having structural resemblance to alkaloid 122. However, speradine E 130 consists of an additional β-dicarbonyl motif than cyclopiamide A 129 (Fig. 17).

Fig. 17

Structures of cyclopiamide A 129 and speradine E 130

The preparation of cyclopiamide A 129 and speradine E 130 was described by Nakhla et al. [70] via a unified approach (Scheme 20). Isatin 126 (obtained from Sonogashira coupling) was advanced to pyrrolinone 132 (45%) by treating allyl malonyl chloride 131 with i-Pr₂NEt followed by the addition of isatin 126. The compound 132 was treated with sodium hydride to get tetracycle 133 in 25% yield which in the presence of 1.2 mol% Pd(PPh₃)₄ and morpholine underwent decarboalkoxylation and dehydrative aromatization and the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) furnished cyclopiamide A 129 in 93% yield. The framework of speradine E 130 was obtained in 54% yield from the reaction of methyl malonyl fluoride 134 with alkaloid 129.

Scheme 20

Synthesis of cyclopiamide A 129 and speradine E 130

(+)-Anatoxin-a 135 and (+)-homoanatoxin-a 136 are natural alkaloids possessing distinctive structural features and strong biological properties that have made them a theme of considerable research work in synthetic and pharmacological studies (Fig. 18). These are extremely neurotoxic compounds generated during surface-water blooms by benthic and planktonic cyanobacteria. These compounds may prompt asphyxiation, respiratory paralysis and ultimately death as they function as neuromuscular blocking agents [71,72,73,74].

Fig. 18

Structures of (+)-anatoxin-a 135 and (+)-homoanatoxin-a 136

Addante-Moya et al. [75] reported an easy and systematic synthetic methodology for the construction of natural and unnatural enantiomers of anatoxin-a 135 and homoanatoxin-a 136 by utilizing ring opening reaction, cyclization, Sonogashira coupling and chemo- and regioselective hydration as key steps. 9-Oxabicyclo[6.1.0]non-4-ene 137 and chiral α-methylbenzylamine 138 reacted under microwave irradiation in methanol to give a mixture of diastereoisomeric amino-alcohols (-)-139 and (+)-140 in 34% and 34.2% yields, respectively (Scheme 21). Azabicyclo ketone (-)-141 required for the accomplishment of natural enantiomers (+)-anatoxin-a 135 and (+)-homoanatoxin-a 136 was prepared from (-)-139 over several steps. Enol triflate (+)-142 produced from azabicyclo ketone (-)-141 (using potassium bis(trimethylsilyl)amide (KHMDS) and Cominsˈ reagent) was coupled with trimethylsilyl enyne (for anatoxin-a) and propyne (for homoanatoxin-a) by loading PdCl₂(PPh₂)₂, CuI, TEA in DMF at room temperature to give corresponding compounds (-)-143 (86%) and (-)-144 (75%), respectively. Next, trimethylsilyl group of compound (-)-143 was unmasked using K₂CO₃ in methanol followed by triple bond hydration (using HgO, boron trifluoride etherate, trichloroacetic acid). The addition of trifluoroacetic acid cleaved Boc group and afforded trifluoroacetate salt of (+)-135 in 99% yield. The final structure of homoanatoxin-a (+)-136 was also achieved in 99% yield by using the similar conditions for the triple bond hydration and Boc deprotection (Scheme 22).

Scheme 21

Preparation of enol triflate (+)-142

Scheme 22

Synthesis of (+)-anatoxin-a 135 and (+)-homoanatoxin-a 136

Synthesis of terpenoids

Cleviolide 145 is a first monoterpene isolated from Senecio clevelandii by Bohlmann et al. [76] It is reported as a precursor of two monoterpenes named cis-dihydrocleviolide (obtained from S. clevelandii) and trans-dihydrocleviolide (obtained from Psathyrella scobinacea) (Fig. 19) [77].

Fig. 19

Structure of cleviolide 145

The three-step preparation of natural acetylenic monoterpene cleviolide 145 was described by Cheval et al. [78] in 40% overall yield via Sonogashira coupling (Scheme 23). Nosylate 146 bearing 2,5-dihydrofuran-2-one is a component of various natural products and has been utilized for the synthesis of cleviolide 145. Nosylate 146 and 4-methylpent-yn-3-ol 147 were reacted in the presence of PdCl₂(PPh₃)₂ as catalyst, CuI as co-catalyst and i-Pr₂NEt as base in acetonitrile to produce compound 148 in 67% yield. Treatment of compound 148 with diphosphorous pentaoxide in benzene gave the desired natural product cleviolide 145 in good yield (81%). Vinyl nosylates could be efficient coupling partners for Sonogashira coupling approach either in the presence of Cu or Ag salts and p-nitro substituted nosylate allowed this cross-coupling to be done at room temperature.

Scheme 23

Synthesis of cleviolide 145

Over the years, natural products have been considered as valuable compounds in synthetic as well as therapeutic industry owing to the diversity in their chemical structures and biological capabilities. They are obtained from various species. In this regard, daphnane 149 and tigliane 150 have been extracted from thymelaeaceae and euphorbiaceae (Fig. 20). Daphnane and tigliane are structurally complex naturally occurring diterpenes comprising of [5–7-6] tri-cyclic carbon framework and these natural compounds are of great importance due to their antimalarial, antimicrobial, anti-HIV and neurotrophic properties [79, 80].

Fig. 20

Structures of daphnane 149 and tigliane 150

Dai et al. [81] reported a concise synthesis of common tricyclic carbon core 151 (Fig. 21) of daphnane and tigliane via Sonogashira coupling followed by gold catalyzed furan preparation and furan/allene [4 + 3] cycloaddition (Scheme 24). Synthesis was commenced from the reaction of aldehyde 153 with compound 152 in the presence of CuI and i-Pr₂NH followed by the addition of bromo moiety 154 and sodium hydride to produce fragment 155 in 70% yield. In the following step, allene 157 was obtained by the combination of compound 155 with fragment 156 (obtained from cyclopentanone) in the presence of palladium catalyst [PdCl₂(PPh₃)₂], CuI and i-Pr₂NH at 70 °C. The gold catalysis (with 10% PPh₃AuCl/AgOTf) followed by [4 + 3] cycloaddition (with 13% ^tBuXPhosAuCl/AgSbF₆) of substrate 157 produced the target skeleton of diterpenes 158a and 158b in acceptable ratio (1.8:1). It was concluded that gold-catalyzed [4 + 3] cycloaddition could be used for the accomplishment of complex oxa-bridged polycyclic frameworks of natural products in a stereoselective way.

Fig. 21

Common tricyclic core 151 of daphnane 149 and tigliane 150

Scheme 24

Synthesis of common tricyclic carbon core of daphnane and tigliane

Fenical and co-workers in 2010 isolated secondary metabolites, nitropyrrolins A-E from CNQ-509 strain. Nitropyrrolin A 159, nitropyrrolin B 160 and nitropyrrolin D 161 (hybrid isoprenoid natural products) showed cytotoxic activity toward human colon cancer cells with IC₅₀ values 31.1 µM, 31.0 µM and 5.7 µM, respectively (Fig. 22) [82, 83].

Fig. 22

Structures of nitropyrrolins A, B, D (159–161)

Ding et al. [84] outlined a synthetic methodology for the synthesis of nitropyrrolins A, B, D via Sonogashira coupling approach for substituted pyrrole formation. This approach further involves carboxylative cyclization, sulfonylcarbamate preparation and deprotection protocol for the formation of hydroxyl ketone. The synthesis was commenced with the coupling of N-Boc protected iodide 162 with alkyne 163 using PdCl₂(PPh₃)₂, CuI, TEA in DMF to furnish pyrrole substrate 164 in 90% yield. Pyrrole 164 was subjected to carboxylative cyclization by using silver carbonate, PPh₃ in DCM to afford desired carbonate which was then treated with p-TsNH₂ and K₂CO₃ in DMF followed by refluxing in pyridine/CH₃OH afforded the required hydroxyl ketone 165 (60% yield). Next step involved the diastereoselective reduction of ketone 165 through Corey–Bakshi–Shibata reduction approach (using (R)-Me-CBS and BH₃·DMS) to give diols 166a and 166b with good diastereoselectivity (6:1). The final structure of natural product 159 was achieved in 92% yield by deprotection of Boz group of diol 166a with aqueous K₂CO₃ in methanol (Scheme 25). Similarly, the skeleton of nitropyrrolin B 160 was constructed in 60% overall yield from N-Boz protected iodide 162 by employing Sonogashira coupling with ent-163 in the presence of PdCl₂(PPh₃)₂ and diastereoselective reduction (with CBS) of ent-165 to furnish ent-166a which was subjected to one-pot epoxidation and mesylation (using MsCl, TEA) followed by deprotection of N-Boz group under mild conditions yielded nitropyrrolin B 160 in 92% yield. It was further transformed to nitropyrrolin D 161 as previously reported by Morimoto and coworkers [82] (Scheme 26).

Scheme 25

Synthesis of nitropyrrolin A 159

Scheme 26

Synthesis of nitropyrrolin B and D (160, 161)

Heronapyrrole B 167 is a secondary metabolite obtained from CMB-M0423 strain of Streptomyces sp. by Capon research group [85, 86]. This natural product shows antibacterial activity against Gram-positive bacteria (S. aureus, B. subtilis) (Fig. 23) [87].

Fig. 23

Structure of heronapyrrole B 167

The synthesis of nitropyrrolin A 159 and heronapyrrole B 167 through Sonogashira coupling was reported by Ding et al. [88] (Scheme 27). Heronapyrrole B 167 was accomplished in 90% yield by treating compound 166 (prepared from iodide 162) with AD-mix-α, MeSO₂NH₂ in tert-butanol/water mixture followed by deprotection of Boz group with aq. K₂CO₃ in methanol.

Scheme 27

Synthesis of heronapyrrole B 167

Synthesis of steroids

Among all the categories of natural products, steroids have played a vital role in evoking latest ideas in total synthesis. A significant amount of knowledge has been added to organic chemistry in the context of tracking suggestions for the assembly of fragments to form steroids. Evidently, this curiosity continues to present day. Aplykurodine obtained from mollusks represents a class of most degraded steroids and (±)-aplykurodinone-1 169 (extracted from Synphonota geographica) belongs to this family of natural products. Its skeleton consists of a cis-fused ring with epimeric C₈, an unsaturated side chain [89] and six contiguous stereocenters (Fig. 24) [90].

Fig. 24

Structure of (±)-aplykurodinone-1 169

Tao et al. [91] reported a highly efficient formal synthesis of (±)-aplykurodinone-1 169 via one pot hetero-Pauson–Khand reaction (h-PKR), desilylation and Sonogashira coupling as key steps (Scheme 28). h-PKR has rare applications in the formation of natural products; however it is known as a convenient method to shape butenolides and α,β-unsaturated lactams. The synthesis was commenced with the iodination of enone 170 (using iodine, pyridine in DCM) to afford vinyl halide 171 in good yield (85%). Then, vinyl iodide 171 underwent Sonogashira coupling with TMS-acetylene in the presence of PdCl₂(PPh₃)₂, CuI, TEA as base in THF at room temperature to give 2-alkynyl-2-cyclopentanone 172 (90% yield). The compound 172 was treated with 2-iodobenzoic acid (IBX) in DMSO/THF for TBS deprotection followed by the addition of Mo(CO)₆, CO in toluene/DMF to perform one pot cycloaddition and desilylation to produce tricyclic compound 173 in 60% yield. The formal synthesis of (±)-aplykurodinone-1 169 was achieved by converting tricyclic compound into required enone 174 (20% overall yield) over several steps. The final framework of natural product 169 with high stereoselectivity was established through Micheal addition [92] of enone 174.

Scheme 28

Synthesis of aplykurodinone-1 169

Synthesis of polyketides

Bysspectin A 175 is a polyketide-derived octaketide dimer isolated from endophytic fungus (Byssochlamys spectabilis) and consists of a unique carbon skeleton based on two hydrophobic ketone chains and 2-phenylbenzofuran motif (Fig. 25). It acts as an inhibitor against hCE2 (human carboxylesterase) owing to its hydrophobic nature [93].

Fig. 25

Structure of bysspectin A 175

Yang et al. [94] designed the synthetic strategy for bysspectin A 175 for the first time and utilized copper catalyzed domino Sonogashira cyclization to obtain the targeted product with 7.7% overall yield (Scheme 29). In order to complete the synthesis, compound 177 was obtained from 176 [95] and was further converted into compound 178 in 92% yield via Sonogashira coupling using trimethylsilyl acetylene, PdCl₂(PPh₃)₂, CuI, TEA in THF at 50 °C. Phenolic hydroxyl group of compound 178 was protected (using SEMCl, i-Pr₂NEt) followed by the addition of octylmagnesium bromide, Dess–Martin periodinane (DMP) and potassium carbonate to form terminal alkyne 179 in good yield (89%). Then, domino Sonogashira cyclization was done between terminal alkyne 179 and fragment 180 in the presence of [Cu(phen)(PPh₃)₂]NO₃, Cs₂CO₃ in toluene to obtain benzofuran ring in 83% yield. Deprotection of SEM group with tetra-n-butylammonium fluoride (TBAF) afforded the required product 175 in 65% yield.

Scheme 29

Synthesis of bysspectin A 175

Synthesis of macrolides

Salarins are marine macrolides extracted from Madagascan sponge (Facaplysinopsis sp.) comprising of 17-membered lactone set with a trisubstituted oxazole or a trisacylamine core. Salarin C 181 (a nitrogenous macrolide) isolated by Kashman and coworkers belongs to this class and acts as antiproliferative agent (Fig. 26) [96, 97].

Fig. 26

Structure of salarin C 181

Schӓckermann and Lindel [98] reported the synthesis of eastern portion 189 of salarin C 181 by employing halogen dance reaction to join the trisubstituted oxazole ring. In the first step, methylation of oxazole 182 was done with CH₃I to furnish trisubstituted oxazole 183 in 90% yield which in the next step was coupled with propargyl alcohol in the presence of PdCl₂(PPh₃)₂, CuI, TEA in acetonitrile to give compound 184 in 83% yield. Hydrosilylation of compound 184 with Et₃SiH [Cp*Ru(MeCN)₃]PF₆] and desilylation with TBAF was performed to get allylic alcohol. Trisubstituted n-butanesulfonyloxazole 185 was prepared from allylic alcohol by O-silylation (TBSCl, imidazole) followed by oxidation (H₂O₂, (NH₄)₆Mo₇O₂₄·4H₂O) (Scheme 30). Then, trisubstituted n-butanesulfonyloxazole 185 was coupled with (Z)-iodoalkene 187 (prepared from TMS-protected alkyne 186) in the presence of n-BuLi followed by the addition of p-TsOH in methanol and DMP in DCM to form unsaturated aldehyde in good yield (93%). Phosphonate 188 was used for the Still Gennari olefination of aldehyde (using KHMDS in THF) to accomplish the partial segment 189 (bisalkenyloxazole) of salarin C 181 in 88% yield (Scheme 31). Additionally, photooxidation of bisalkenyloxazole was carried out by using singlet oxygen which supported Kashman’s hypothesis of conversion of salarin C to salarin A.

Scheme 30

Synthesis of trisubstituted n-butanesulfonyloxazole 185

Scheme 31

Synthesis of partial section 189 of salarin C

Synthesis of alkamides

Alkamides are secondary metabolites obtained from various plant families and constitute a well-defined class of natural compounds in which peptide bonding connects unsaturated fatty acids with different amino acids. Tingling and pungent effects are the characteristic features of this class. Spilanthol (affinin) 190 is a familiar bioactive alkamide which has been extracted from plants of Asteraceae family and it also produces numbing, tingling, pungency and mouth-watering effects. According to scientific research, it exhibits a variety of biological activities such as antimicrobial, antimutagenic and insecticidal, etc. (Fig. 27) [99].

Fig. 27

Structure of spilanthol 190

Alonso et al. [100] reported the synthesis of spilanthol 190 in five steps via Sonogashira coupling, Z-selective alkyne semi-reduction and HWE as main steps (Scheme 32). During the connection of double bonds, control of alkene geometry was maintained in the synthetic route. The first step in synthetic strategy involved the Sonogashira coupling of alcohol 191 with 1-bromo-1-propene in the presence of Pd(PPh₃)₄, PPh₃, CuI, diisopropanolamine (DIPA) in DMF to afford the compound 192 (53%) which was further transformed to a diene 193 (59% yield) by using Zn/Cu/Ag in the presence of TMSCl through Z-selective alkyne semi-reduction. Later, alcohol 193 underwent Swern oxidation followed by the addition of phosphonoacetamide 194 to crude aldehyde to accomplish the synthesis of 190 in 63% yield. Moreover, it was found that spilanthol could be an advantageous contemporary anesthetic in medical field.

Scheme 32

Synthesis of spilanthol 190

Negishi cross-coupling reaction

After the revelation of palladium catalyzed Negishi coupling of aryl/vinyl chlorides by Fu and co-workers [101], a significant success has been made in developing new catalytic methodologies related to this approach. It involves the use of organozinc reagent as a coupling partner and immensely utilized to compose natural products [102]. It implies mild reaction conditions with advantage of low toxicity of readily available organozinc substrates and their fast transmetalation to palladium. In some cases, other metal catalyst systems containing nickel, iron, copper or cobalt are also used instead of palladium-based catalyst [103, 104].

Synthesis of macrocycles

Argyrins are macrocyclic natural products which have been isolated from myxobacteria in 2002 by Sasse et al. These are known as heptapeptides based on thiazole heterocycle and tryptophan amino acid. Biological interpretation showed that these compounds act as cytotoxic and immunosuppressant agents, etc. (Fig. 28) [105, 106].

Fig. 28

Structure of argyrin C 195

For the first time, Stempel et al. [107] carried out an efficient and short synthesis of AzuAla¹ argyrin C 204 in a stereocontrolled manner by incorporating Negishi coupling reaction (Scheme 33). By keeping in consideration to track and detect bioactive compounds by using non-invasive probes, β-(1-azulenyl)-ʟ alanine (termed as AzuAla¹, unnatural deep blue amino acid) was prepared with fluorescent/photophysical features and then utilized it for the preparation of natural product 204. Iodoalanine 197 (obtained from alanine 196) was converted into organozinc reagent by using zinc and 20 mol% iodine that underwent Negishi coupling with C3-iodinated compound 199 (prepared from indole 198) in the presence of 2.5 mol% Pd₂(dba)₃ as catalyst and 5 mol% SPhos as ligand at 35 °C to give compound 200 in 88% yield. Compound 200 was saponified (sodium hydroxide, methanol) with subsequent benzenesulfonyl group cleavage and addition of glycine methyl ester to produce dipeptide 201 in good yield (79%). Next, the dipeptide 201 was fused with fragment 202 to give tripeptide unit 203 (81% yield) which over several steps gave Azuala¹ argyrin C 204. Nevertheless, it was the first synthetic approach to introduce fluorophore group such as AzuAla¹ in complex natural product.

Scheme 33

Synthesis of AzuAla¹ argyrin C 204

Synthesis of lignans

Lignan natural products; (±)-dimethylretrodendrin 205, (±)-dimethylmetairesinol 206, (±)-kusunokinin 207, (±)-bursehernin 208, (±)-yatein 209, (±)-collinusin 210 bearing dibenzylbutyrolactone and aryltetralin cores are associated with anti-tumour, anti-viral, fungicidal, antibiotic and anti-HIV activities (Fig. 29) [108, 109].

Fig. 29

Structures of lignan natural products (205–210)

KC et al. [110] reported regioselective dicarbofunctionalization of unactivated olefins via Ni-catalyzed tandem cyclization/Negishi cross-coupling and implemented this methodology to construct the skeletons of six lignan natural products (205–210) in good yields (65–86%) and diastereoselectivities (dr, 19:1–40:1). For this purpose, organozinc reagent 213 and substrate 211 were coupled in the presence of NiBr₂, terpy 212 in N-methyl-2-pyrrolidone (NMP) at 50 °C followed by Jones oxidation to produce lactone 214 in 62% yield. Lactone 214 on treatment with fragments 215, 216 and 217 after subjection to lithium diisopropylamide (LDA) gave natural products 205 (73%), 206 (71%) and 207 (86%), respectively (Scheme 34). The same procedure was repeated for the accomplishment of remaining lignans 208–210 by employing different organozinc reagents 218 and 222 (Scheme 35).

Scheme 34

Synthesis of (±)-dimethylretrodendrin 205, (±)-dimethylmetairesinol 206, (±)-kusunokinin 207

Scheme 35

Synthesis of (±)-bursehernin 208, (±)-yatein 209, (±)-collinusin 210

Synthesis of polyketides

Seragamide A 224 was isolated from Suberites japonicas (Okinawan sponge) as a cytotoxic metabolite having peptide motif. It plays a vital role in the polymerization of G-actin and stabilizes F-actin filaments (Fig. 30) [111].

Fig. 30

Structure of seragamide A 224

Lang and Lindel [112] disclosed the synthesis of polyketide Sect. 230 of seragamide A 224 via Negishi coupling reaction. tert-Butyl ester 225 (obtained from enantiomerically pure (R)-propylene oxide) was subjected to reduction (DIBAL-H) followed by oxidation and Corey-Fuchs reaction (CBr₄, PPh₃, TEA) to access dibromoalkene 226 (81%). Then, the compound 226 was treated with LDA followed by methylation (using CH₃I) and hydrozirconation/iodination (with Cp₂ZrHCl and I₂) to get (E)-olefin 227 in 84% yield with perfect stereo- and regioselectivity. Olefin 227 was coupled with organozinc homoenolate 228 (prepared from β-bromopropionic acid ester) in the presence of PdCl₂(dppf) x DCM at room temperature to produce compound 229 in 75% yield which on subjection with ceric ammonium nitrate (CAN) afforded polyketide portion 230 (82%) (Scheme 36). Further, tripeptide Sect. 231 of seragamide 224 was synthesized by using D-tyrosine as starting material that was converted to tripeptide 231 over several steps which in the presence of TFA/DCM followed by the addition of BEP, i-Pr₂NEt in DCM was fused with polyketide unit 232 (from 230) to give pepetide-polyketide 233 (60%) with higher diastereoselectivity (dr, 9:1) than tripeptide fragment 231 (dr, 4:1) (Scheme 37).

Scheme 36

Synthesis of polyketide section 230 of seragamide A 224

Scheme 37

Synthesis of tripeptide-polyketide 233 of seragamide A 224

Synthesis of terpenoids

Stachyflin 234 possessing cis-fused rings and an ethereal bond is a terpenoid and shows anti-influenza A virus activity with EC₅₀ value of 0.003 µM. Its biological potential and structural features have made it a fascinating molecule in synthetic chemistry (Fig. 31) [113].

Fig. 31

Structure of stachyflin 234

Haut et al. [114] and Wildermuth et al. [115] independently reported a total synthesis of (+)-stachyflin 234 through sp²-sp³ Negishi cross-coupling reaction of isoindolinone 236 with dehydrodecalin 237 in the presence of Pd-SPhos G2 catalyst, SPhos ligand and dimethylacetamide (DMA) base in THF to furnish compound 238 in 56% yield (Scheme 38). Cleavage of MOM-ether group (with HCl), cationic cyclization (with BF₃·OEt₂) and hydrogenation (with H₂, Pd/C) gave cis-fused decalin 239 (62% over 3 steps) which on treatment with PIFA in benzene and demethylation by potassium n-dodecanthiolate provided required (+)-stachyflin 234 (43% over 2 steps).

Scheme 38

Synthesis of stachyflin 234

Miscellaneous

In 1990, first naturally occurring paracyclophanes were extracted from blue-green algae and contained 22-membered cyclic infrastructure exhibiting cytotoxic potential against tumor cell lines (KB and LoVo) with IC₅₀ value 2–10 µg/mL. (−)-Cylindrocyclophane F 240 belongs to these types of natural products (Fig. 32) [116,117,118].

Fig. 32

Structure of (−)-cylindrocyclophane F 240

Berthold and Breit [119] reported a short and convergent route for the preparation of (−)-cylindrocyclophane F 240 using Pd-catalyzed Negishi coupling and cross olefin metathesis protocol (Scheme 39). Compound 241 (obtained from ʟ-(+)-lactic acid precursor) underwent iodine lithium exchange (t-BuLi, Et₂O) followed by transmetalation (ZnCl₂, THF) and Negishi cross-coupling reaction with triflate 242. As a result, diene 243 was obtained in 96% yield with 5 mol% PdCl₂(dppf) loading in THF. Next step involved olefin cross metathesis using Grubbs II followed by hydrogenation (H₂, Pd/C, AcOEt) and deprotection (BBr₃, DCM) to obtain targeted (−)-cylindrocyclophane F 240.

Scheme 39

Synthesis of (−)-cylindrocyclophane F 240

Heck cross-coupling reaction

Heck cross-coupling reaction includes the coupling of aryl iodide/bromide/chloride, triflates, mesylates, tosylates and diazonium salts with olefins to accomplish aryl-substituted alkenes. This methodology has been extended to the coupling of alkenyl compounds with olefins [120]. This interesting strategy finds its applications in the formation of medicinally important analogues, polymers and natural products. Some known examples are the synthesis of retinoid x receptor antagonist and diazepinylbenzoic acid via Heck coupling [121].

Synthesis of alkaloids

Ergot alkaloids are a source of indole alkaloids exhibiting a wide spectrum of biological activities such as antiprolactin and anti-Parkinson’s activity. These are obtained from Claviceps pupurea (fungus) which grows on rye and other grains. (+)-Lysergol 244 is an indole alkaloid belonging to this attractive family of natural products (Fig. 33) [122].

Fig. 33

Structure of (+)-lysergol 244

Milde et al. [123] used anti-carbopalladation/Heck reaction to achieve the enantioselective synthesis of (+)-lysergol 244 in 12 steps and with 13% overall yield (Scheme 40). 2-Bromoindole 245 was used as starting precursor to obtain alcohol 246 over several steps. Racemic alcohol 246 was converted to required domino precursor 249 on treatment with DMP followed by enantioselective reduction (using Noyori’s catalyst 247) and Mitsunobu reaction (using sulfonamide 248). Next step involved anti-carbopalladation/Heck reaction by the addition of 10 mol% [PdCl₂(PhCN)₂] as catalyst, 20 mol% XPhos as ligand in DMA at 120 °C for 2 h to form two rings of target product 250 in a stereospecific manner in 80% yield along with side product 251 (17%). Proceeding from compound 250, the final structure of (+)-lysergol 244 was accomplished over several steps.

Scheme 40

Synthesis of (+)-lysergol 244

Lycorine-type alkaloids are derived from plants and show antimitotic, antiviral and antineoplastic activities, etc. (±)-γ-Lycorane 252 is not associated with any significant pharmaceutical property; however, it has become a popular molecule in the aspect of describing the potential of new synthetic techniques for the combination of fragments in lycorine-type alkaloids (Fig. 34) [124].

Fig. 34

Structure of (±)-γ-lycorane 252

Monaco et al. [125] reported the synthesis of (±)-γ-lycorane 252 via Heck cyclization reaction (Scheme 41). Firstly, compound 254 was prepared in 87% yield by treating piperonylamine 253 with bromine in acetic acid followed by the addition of cyclohexanone, diacetoxyacetyl chloride and boron trifluoride diethyl etherate. Next, compound 254 was cyclized in the presence of PdCl₂(PPh₃)₂ in DMF to afford pentacyclic motif 255 in 74% yield. The required product 252 (85%) was formed by the hydrogenation of double bonds of compound 255 by using H-Cube hydrogenation flow reactor, 10% palladium on charcoal in ethanol/ethyl acetate mixture and then followed by its reduction with LiAlH₄.

Scheme 41

Synthesis of (±)-γ-lycorane 252

Tuberculosis (TB) is an infectious disease and needs to be treated with effective drugs. Advent of new drugs with low toxicity, high potency, good interaction and novel mechanism of action remains a challenge for the cure of tuberculosis. However, natural resources serve best in producing molecules with unique chemical and biological attributes. 3,4-Diarylpyrrole alkaloids are suitable example of captivating bioactive metabolites obtained from marine species. Denigrin A 256 and denigrin B 257 (extracted from Dendrilla nigra) with potent antitubercular activity belongs to this category of natural products (Fig. 35) [126].

Fig. 35

Structures of denigrin A 256 and denigrin B 257

Karak et al. [127] reported the first synthesis of denigrin A and B (256, 257) with 62% and 31% overall yields based on three and five steps, respectively, via Heck reaction as a key step (Scheme 42). The starting substrates; maleic anhydride 258 and diaryliodonium tosylate 259 were coupled through Heck reaction (Pd(OAc)₂, sodium acetate in acetonitrile) to produce monoarylated 260 and diarylated compound 261 (69%, 4:96). To obtain denigrin A 256 (97%), compound 261 was reacted with p-methoxyphenethylamine 263 in acetic acid followed by the addition of BBr₃ in DCM. On the other hand, treatment of diarylated compound 261 with LiAlH₄ and p-methoxybenzaldehyde provided Z-isomer 262 as sole product in 89% yield. Later, compound 262 was reacted with fragment 263 in acetic acid to yield Z-benzylidene-diarylpyrrol-2(5H)-one 264Z and 264E through one-pot reaction. The cleavage of methyl ether groups of 264Z with BBr₃ afforded denigrin B 257 in 89% yield.

Scheme 42

Synthesis of denigrin A and B (256, 257)

Synthesis of lactones

Zeaenol 265 and 7-epi-zeaenol 266 extracted from a filamentous fungi belongs to resorcyclic acid lactones. Such compounds are known for cytotoxic potential having anticancer potential against human tumor cell line with same IC₅₀ act as NF-ҡB inhibitor. (Fig. 36) [128].

Fig. 36

Structures of zeaenol 265 and 7-epi-zeaenol 266

Doda et al. [129] disclosed the asymmetric synthesis of zeaenol 265 and 7-epi-zeaenol 266 in 7 and 9 steps with 32% and 21% overall yield, respectively, by employing Heck reaction as fundamental step (Scheme 43). In this regard, trans allyl alcohol 267 obtained from D-mannitol was protected with MOM group to give compound 268 which underwent coupling with aromatic triflate 269 in the presence of Pd(OAc)₂, PPh₃, Bu₄NBr, K₂CO₃ in DMF at 80 °C for 5 h to provide trans olefin 270 in 88% yield over 2 steps. Deprotection of compound 270 with camphorsulfonic acid (CSA) and macrolactonization (using sodium hydride) gave macrolactone 271 in good yield (85%) which on treatment with TiCl₄ produced desired 7-epi-zeaenol 266 in 88% yield. Moreover, subjection of macrolactone 271 with TMSCl, 4-nitrobenzoic acid, potassium carbonate and TiCl₄ furnished zeaenol 265 in 83% yield.

Scheme 43

Synthesis of resorcyclic acid lactones 265 and 266

Miscellaneous

Abscisic acid 272 isolated in 1960s is a plant hormone. It plays an important role in growth of plants from different aspects including seed development, germination and alteration to abiotic environmental stress (Fig. 37) [130].

Fig. 37

Structure of abscisic acid 272

Dumonteil et al. [131] reported an environment friendly synthesis of abscisic acid 272 via Heck reaction in ligand and solvent free conditions with 54% yield (Scheme 44). In order to proceed, diketone 273 was reacted with (S,S)-hydrobenzoin and pyridinium p-toluenesulfonate (PPTS) in cyclohexane followed by the loading of vinylmagnesium bromide in THF to give compound 274 in quantitative yield. Heck coupling of compound 274 with Z-enoate 275 in the presence of 5 mol% Pd(OAc)₂ and silver carbonate at 50 °C for 17 h delivered (E/Z)-diene 276 in 96% yield which on saponification using NaOH and TBACl followed by acidic treatment (with HCl) yielded the S-enantiomeric enriched 272 (59% over 2 steps).

Scheme 44

Synthesis of abscisic acid 272

Stille cross-coupling reaction

Stille cross-coupling reaction represents the coupling of organostannanes with organic halides/triflates usually in the presence of palladium catalyst to connect carbon–carbon bonds in a variety of compounds. It finds enormous use in the preparation of precursors of drugs, for instance valsartan and imatinib C and in the formulation of electronic materials such as transistors and photovoltaic cells [132, 133].

Synthesis of lactones

Glabramycin B 277 was isolated through an antisense screening method from fermentation broth of Neosartorya glabra by Singh and co-workers in 2009 (Fig. 38). It exhibited antibacterial activity [134].

Fig. 38

Structure of glabramycin B 277

Yamamoto et al. [135] reported an enantioselective synthesis of glabramycin B 277 through Stille coupling as one of the main step and corrected its relative configuration (Scheme 45). Compound 278 was used as starting material to produce tricyclic core 279 over several steps and was converted to vinyl triflate 280 on hydrogenation using H₂, Rh/Al₂O₃ in ethyl acetoacetate followed by the addition of KHMDS and Tf₂O in DME. Later, vinyl triflate 280 and trienylstannane 281 were coupled in the presence of Pd-PEPPSI-IPr 282, CsF in THF at 60 °C and cleavage of MOM group with TMSBr produced compound 283 in good yield (75% over 3 steps). The final skeleton of glabramycin B 277 was obtained by oxidation (with DMP) and deprotection (with tris(dimethylamino)sulfonium difluorotrimethylsilicate (TAS-F)).

Scheme 45

Synthesis of glabramycin B 277

Heliolactone 284, a non-sesquiterpene lactone stimulates the germination of root parasitic weeds which causes harmful effects on many crops (Fig. 39). It has been investigated that production of heliolactone increased in the presence of water while lowered in the presence of phosphorous and nitrogen supplements [136].

Fig. 39

Structure of heliolactone 284

Woo and McErlean [137] reported enantioselective total synthesis of heliolactone 284 by using Stille coupling and confirmed the stereochemical nature (Scheme 46). α-Ionone 285 and chiral iodide 287 gave enantiomers 286 and 288, respectively, which were coupled in the presence of Pd₂dba₃, AsPh₃, CuI in NMP to obtain target product 284 in 49% yield.

Scheme 46

Synthesis of heliolactone 284

Synthesis of terpenoids

Plant of East Asia of genus Isodon is used as traditional medicine for the treatment of different infections including respiratory, cancer and inflammation problems in China. Mainly, its aerial parts such as stems and leaves are used for this purpose and some species of Isodon bears swollen rhizomes which also exhibit medicinal value. Hispidanin A-D are asymmetric dimeric diterpenoids which have been obtained from rizhomes of Isodon (Fig. 40) [138].

Fig. 40

Structure of hispidanin A 289

Deng et al. [139] reported the asymmetric total synthesis of hispidanin A 289 via Stille coupling approach (Scheme 47). Compound 290 produced 291 over 3 steps, masking of phenol of tricyclic compound 291 (using MOMCl) and coupling with substrate 292 in the presence of palladium catalyst PdCl₂(PhCN)₂, CuI, Ph₃As in NMP at 120 °C furnished compound 293 in 75% yield (2 steps). The compound 293 upon deprotection (with Amberlyst-15) followed by base promoted lactonization (with K₂CO₃) gave dienophile 294. Diels–Alder cycloaddition was conducted between fragment 294 and diene 295 (obtained from an epoxide) in toluene followed by addition of NaBH₄ and MgClO₄, acetic anhydride to produce diterpenoid 289 in 75% yield.

Scheme 47

Synthesis of hispidanin A 289

Synthesis of macrolides

The resorcyclic macrolides account for important family of natural products containing β-resorcylate motif and macrocyclic lactone core. trans-Resorcylide 296 with a distinctive structure acts as plant growth inhibitor and is an influential template from synthetic point of view (Fig. 41) [140, 141].

Fig. 41

Structure of trans-resorcylide 296

Luo et al. [142] prepared trans-resorcylide 296 via Stille carbonylation protocol (Scheme 48). In this regard, bromide 297 reacted with magnesium metal, CuI and epoxide 298 for regioselective ring opening to form alcohol which was transformed to cis-vinylstannane 299 (66%). It involved the treatment with cesium carbonate, subsequent formation of terminal alkyne (using n-BuLi, n-Bu₃SnCl) and stereoselective reduction of alkyne bond (using Cp₂ZrHCl). Compound 301 was shaped from starting material 300 over 4 steps. Fragments 299 and 301 gave Stille carbonylative precursor 302 in 52% yield with TEA in DCM. In the following step, 302 was reacted in the presence of 10 mol% Pd(PPh₃)₄, 20 mol% P(2-furyl)₃ and CO in dioxane to furnished macrocyclic product 303 in 36% yield. The addition of BCl₃ produced the required structure of trans-resorcyclide 296 in an excellent yield (97%).

Scheme 48

Synthesis of trans-resorcylide 296

Miscellaneous

Mycophenolic acid 304 isolated from Penicillium fungus is associated with a variety of biological properties including antifungal, antibacterial, antiviral, anticancer and acts as immunosuppressive agent, etc. The presence of arene bearing six substituents make it an interesting molecule in synthetic chemistry (Fig. 42). Halle et al. [143] reported a short synthesis of mycophenolc acid 304 (quantitative yield) via Stille coupling of compound 306 (prepared from ethyl allenoate 305) with stannane 308 (obtained from acetate 307) in the presence of Pd(PPh₃)₄, PPh₃ in DMF at 100 °C followed by hydrolysis using LiOH/H₂O mixture (Scheme 49).

Fig. 42

Structure of mycophenolic acid 304

Scheme 49

Synthesis of mycophenolic acid 304

Schisandrene 310 (Suzuki and Stille coupling) [144], hemigeran C 311 and hemigeran D 312 (Negishi and Heck coupling) [145], patellazole B 313, raputimonoindole A 314 (Suzuki and Heck coupling) [146, 147] and diptoindonesin G 315 (Suzuki and Sonogashira coupling) [148] are examples of natural products incorporating more than one type of cross-coupling reactions to connect their synthons (Fig. 43).

Fig. 43

Structures of natural products (310–315) illustrating the role of more than one type of cross-coupling in the synthesis

Conclusion

In summary, cross-coupling reactions have made immense progress in shaping structurally diverse natural products. We have explored the synthesis of natural products via Suzuki, Negishi, Heck, Sonogashira and Stille cross-coupling reactions to recognize the benefits of these strategies in synthetic as well as pharmaceutical sectors. The interesting features of these reactions have played role in the production of diastereoselective, stereoselective, regioselective and enantioselective fragments of naturally occurring molecules with moderate to good yields. Mostly palladium-based catalysts including Pd(PPh₃)₄, Pd(OAc)₂, PdCl₂(PPh₂)₂, PdCl₂(dppf) and Pd₂(dba)₃ with various combination of ligands, bases and solvents have been used in this respect. Furthermore, the important biological activities of natural compounds such as anticancer, antiviral, antituberculosis, hCE2 inhibitor, ATPase inhibitor, etc. add supremacy to the entire constructed framework. However, this review would serve as a parameter to attract the attention of chemists towards the applications of cross-coupling reactions to make more adorable advancements with no shortcomings.