Abstract
The synthetic routes to the natural products are designed with consideration of the structures of the reagents, functional group tolerance, total yields, and the environmental benignness of wastes. In natural product syntheses, the cross-couplings as carbon–carbon bond-forming reactions have been widely utilized for the construction of fragments as the key steps in the total syntheses.
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1 Introduction
Natural organic compounds with specific chemical structures and bioactivities have intimate relationships with pharmaceuticals, dyes, spices, etc., and are thus extremely important industrially. Frequently, only a small amount of a natural product can be harvested from its naturally occurring source; in these cases, organic synthesis is necessary if a large amount of the natural product is required. Furthermore, the synthetic route is often simply more cost-effective or practical. Some naturally occurring products with unique physical and chemical properties are preferable for the production of fine chemicals. In fact, the proportion of these products supplied from nature is only about 5 %. This extensive demand implies that partial or total synthesis is necessary and indispensable [1].
Although a variety of organic reactions (e.g., aldol reactions and Grignard reactions) have been conventionally used for carbon–carbon bond-formation in natural product syntheses, these reactions are not able to satisfy some demands due to a low selectivity and due to substrate limitations. However, the cross-coupling reactions are widely accepted as carbon–carbon bond-forming methodologies that can achieve high selectivity and functional group tolerance in the synthesis of natural products with complicated chemical structures [2].
Considering the establishment of convergent synthesis and the easy availability of starting materials in natural product syntheses, the cross-coupling methods introduced in this publication are very powerful strategic tools for carbon–carbon bond-formation. However, when the target molecules are synthesized with these cross-coupling reactions, appropriate selection of substrates and reagents is essential. This chapter will review recent examples of how the cross-coupling reactions have been used in practical natural product syntheses.
2 Kumada–Tamao–Corriu Coupling (sp3–sp2)
Because the highly reactive Grignard reagents can be employed in Kumada–Tamao–Corriu coupling, these reactions have been applied to natural product syntheses in recent years. Kumada–Tamao–Corriu coupling is advantageous due to the utility of commercially available Grignard reagents. For example, a precursor of (−)-hennoxazole A was synthesized selectively and quantitatively by methylation of the substrate bearing a protected hydroxy group with methylmagnesium bromide under palladium catalysis (Scheme 3.1) [3].
Total synthesis of (–)-hennoxazole A
Since Kumada–Tamao–Corriu coupling lacks functional group tolerance, its utilization in the final stages of synthesis of the natural products is rare. However, there is a natural abundance of magnesium with the eighth Clark’s number (1.93 wt %), and the preparation of Grignard reagents is relatively easy. Thus, Kumada–Tamao–Corriu coupling can play an important part in synthesis if the substrates are stable enough toward Grignard reagents. Hereafter, more examples of Kumada–Tamao–Corriu coupling as the key step in an overall synthesis will be introduced.
E/Z stereoisomerization is known to be one of the side reactions in the nickel-catalyzed Kumada–Tamao–Corriu coupling of alkenyl halides with Grignard reagents. However, this isomerization has been utilized for the selective synthesis of (−)-zampanolide by manipulating the steric effect of the substituent (Scheme 3.2) [4]. In this method, a selective synthesis of the trisubstituted dienyne as a target product was attained by the introduction of an alkynyl group stereoselectively through Sonogashira–Hagihara coupling and the subsequent isomerization of an olefinic moiety during the Ni-catalyzed Kumada–Tamao–Corriu coupling. Thus, this example shows the advantageous features of the Ni-catalyzed Kumada–Tamao–Corriu coupling—appropriate selection of the substituents and ligands enable control of the stereoselectivity of the products. In this reaction, the undesired side reaction does not take place at all, even under basic conditions, and the cross-coupling of aryl halides with achiral Grignard reagents can be achieved without isomerization.
Total synthesis of (–)-zampanolide using (–)-dactylolide as a precursor with an inversion of the olefin geometry
Furthermore, in the next synthetic pathway, the catalyst was carefully selected. Ni(acac)2, which does not contain the phosphine ligands, was used for the enantioselective synthesis of (S)-macrostomine (Scheme 3.3) [5]. This result suggests that Kumada–Tamao–Corriu coupling has the drawbacks of poor selectivity and of substrate limitations. However, this reaction is an economical and preparative approach to natural product syntheses when substrates that are highly reactive toward Grignard reagents are not involved.
Total synthesis of (S)-macrostomine from (S)-nicotine
3 Sonogashira–Hagihara Coupling (sp–sp2)
Sonogashira–Hagihara coupling is often employed in the natural product syntheses owing to its ability to construct enyne frameworks through the formation of carbon(sp)–carbon(sp2) bonds. In general, in the natural product synthesis, the reactive substrates are first masked by a protecting group and economical bases such as triethylamine or diisopropylamine and copper iodide (CuI) are often used as essential reagents. Sonogashira–Hagihara coupling proceeds with high functional group tolerance under mild conditions, and often gives excellent results to afford molecules with complex structures. The total synthesis of paracentrone, shown in Scheme 3.4, is a representative example showing that Sonogashira–Hagihara coupling can be applied to a substrate bearing a reactive epoxide moiety which remains intact during the reaction [6].
A synthetic route to paracentrone
The air-stable PdCl2(PPh3)2 is often used for the palladium catalyst of Sonogashira–Hagihara coupling, instead of a Pd(0) complex, because PdCl2(PPh3)2 is reduced promptly during the reaction to form the Pd(0) species. Scheme 3.5 shows the demonstration of PdCl2(PPh3)2 as a Pd precursor in the total synthesis of (−)-disorazole C1 [7].
A synthetic route to (–)-disorazole C1
In the total synthesis of bongkrekic and isobongkrekic acids shown in Scheme 3.6, conjugate enynes were first synthesized by Sonogashira–Hagihara coupling. Then, chemoselective reduction of the alkyne moiety transformed the coupled product into the conjugate diene 1 and 2 [8]. In this reductive reaction, an excess amount of copper/silver activated with zinc was found to be the best synthetic method, since the chemoselectivity was fairly low when the syn reduction of the conjugate enyne by Lindlar’s catalyst was attempted [9, 10].
A synthetic route to iso- and bongkrekic acids
Sonogashira–Hagihara coupling of aryl halides/triflates with terminal arylethynes is one of the most useful synthetic methods to afford an array of diarylethynes which are important frameworks applicable to liquid crystals and pharmaceuticals. The total synthesis of (±)-tylophorine shown in Scheme 3.7 is a representative example using diarylethynes as a synthetic intermediate [11].
A synthetic route to (±)-tylophorine
Moreover, an intramolecular Sonogashira–Hagihara coupling enables the construction of large-membered rings; however, the yields of the cross-coupled products are generally very low, as shown in Scheme 3.8 [12]. Therefore, for the construction of large-membered rings, ring-closing metathesis by the Ru or Mo catalysts [13, 14] and macrolactonization [15] is often used rather than intramolecular Sonogashira–Hagihara couplings.
A synthetic route to penarolide sulfate A1
Additionally, the following are examples of total syntheses utilizing Sonogashira–Hagihara coupling reported after 2000: frondosin B [16], callipeltoside A [17], mucocin [18], borrelidin [19], tetrodotoxin [20], 34-hydroxyasimicin [21], oximidine II [22], (−)-siphonodiol, (−)-tetrahydrosiphonodiol [23], peroxyacarnoates A and D [24], leucascandrolide A [25], macbecin I [26], moracin O, moracin P [27] (+)-neopeltolide [28], furopyrans [29], leiodolide B [30], iso- and bongkrekic acids [31], cis- and trans- bupleurynol [32], and lukianol A [33].
4 Negishi Coupling
4.1 sp2–sp2 Negishi Coupling
Negishi coupling has also been widely used as a highly selective, efficient cross-coupling reaction in the natural product syntheses. The total synthesis of brevisamide as a natural product can be accomplished using the sp2–sp2 Negishi coupling (Scheme 3.9) [34]. Negishi coupling is often used in combination with hydrozirconation of alkynes by a Schwartz reagent, because hydrozirconation of alkynes generates an alkenylzirconium complex in a highly regioselective manner; the iodination and treatment with zinc salts of that complex yield the corresponding alkenyl iodides and alkenylzinc reagents, respectively, in one pot.
A synthetic route to brevisamide
The sp2–sp2 Negishi coupling has been recently reported as applicable to other total syntheses: cis and trans bupleurynol [32] (−)-motuporin [35], xerulin [36], pitiamide A [37], FR901464 [38, 39], eunicenone A [40], bisabolene [41], xerulinic acid [42], callystatin A [43, 44], anguinomycin C [45], anguinomycin C and D [46], and 6,7-dehydrostipiamide [47].
4.2 sp3–sp2 Negishi Coupling
Herein, the natural product syntheses by Negishi cross-coupling of alkenyl or aryl halides (pseudo-halides) (sp2) with alkylzinc reagents (sp3) are described. In general, alkyl halides are converted into alkylzinc compounds by halogen–zinc exchange, as shown in Eq.3.1. In addition, a transformation with tert-BuLi of alkylzinc halides into dialkylzinc compounds is widely used, because the tert-butyl functionality can be used as a dummy group for Negishi coupling, leading to the selective formation of the desired cross-coupled products by carbon(sp2)–carbon(sp3) bond formation (See Chap. 8 for the details of carbon(sp2)–carbon(sp3) bond formation).
As shown in Scheme 3.10, reactivity between the dialkylzinc compound and alkylzinc chloride was compared to the total synthesis of (+)-pumiliotoxin B [48]. Starting from substrate 4 in Path A, alkylzinc chloride was prepared by halogen–lithium exchange with tert-BuLi and the subsequent transmetalation using zinc chloride. On the other hand, in Path B the dialkylzinc reagent was synthesized from iodine–zinc exchange between substrate 4 and zinc chloride, followed by addition of tert-BuLi. As a result, Path B of Negishi coupling with the dialkylzinc reagent was found to give the desired product in better yield (50 vs 28 %).
Synthetic strategies of (+)-pumiliotoxin B
In recent years, the sp3–sp2 Negishi cross-coupling has been a frequently used synthetic method for multi-substituted aliphatic olefins and the substituted aryl or heteroaryl compounds. Furthermore, the utility of the sp3–sp2 Negishi cross-coupling has been recently observed in other total syntheses: borrelidin [19] (−)-callystatin A [43], anguinomycin C [45], anguinomycin C, D [46], (+)-discodermolide [49], dysiherbaine [50], bisabolene [41, 51], (–)-4a,5-dihydrostreptazolin [52], a core structure of mycolactones [53], coenzyme Q10, (E,Z,E)-geranylgeranoil [54], trans-epothilone A [55], oleandolide [56], sphingofungin F [57], ionomycin [58], (–)-longithorone A [59], (−)-delactonmycin [60], capensifuranone [61], (+)-murisolin [62], a side chain of scyphostatin [63], (+)-scyphostatin [64], (−)-stemoamide [65], dysiherbaine [66], maleic anhydride, maleimide [67], OF4949-III, K-13 [68], harveynone, tricholomenyn A [69], and in the synthesis of important intermediates of ionomycin and borrelidin [70].
4.3 sp–sp2 Negishi Coupling
In Negishi coupling, the coupling partners (alkenyl or aryl halides/triflates and alkynylzinc reagents) are employed to form carbon(sp)–carbon(sp2) bonds. In the total synthesis of (–)-salicylihalamide shown in Scheme 3.11, Negishi coupling with the combination of the aforementioned substrates afforded the intermediate 5 in 90 % yield while retaining the Z-configuration [71].
A synthetic route to salicylihalamide A and B
As shown above, the sp–sp2 Negishi coupling is highly effective for the construction of the conjugate enyne frameworks. Although conjugate enynes can be synthesized by Sonogashira–Hagihara coupling, the functional group tolerance is dramatically improved with Negishi coupling because the addition of bases is not required. Other natural product syntheses by the sp–sp2 Negishi coupling are known for the total syntheses of cis- and trans-bupleurynol [32], xerulin [36], 6,7-dehydrostipiamide [47], and harveynone, tricholomenyn A [69].
4.4 Carbometalation and Negishi Coupling Sequences
One of the applied Negishi cross-coupling reactions is the synthesis of a carotenoid having a conjugate polyene structure, e.g., β-carotene (Fig. 3.1). Since these compounds possess multi-substituted polyene motifs, a synthetic strategy that selectively introduces the substituents in appropriate positions is necessary.
Representative examples of carotenoids
Because these conjugated polyene-type natural products are organic compounds with valuable antioxidant property, efficient and selective innovation for synthetic methods is still actively sought. It is likely that a combination of regioselective carbometalation of alkynes and sequential Negishi coupling could be used for the synthesis of such natural products.
In the syntheses of β-carotene and vitamin A, the Zr-catalyzed regio- and stereoselective methylalumination across the terminal alkyne in precursor 6 is the first step [72], as shown in Scheme 3.12. The formed alkenylaluminum compound 7 is transmetalated to zinc to afford the corresponding alkenylzinc compound 8, which reacts consecutively with a half molar amount of 1-bromo-2-iodoethene leading to the successful total synthesis of β-carotene. This method is very advantageous from the viewpoint of the facile formation of the organozinc reagents without the addition of the bases. Using the regioselective alkylmetalation of the alkynes and sequential Negishi coupling, the total syntheses of coenzyme Q10, (E,Z,E)-geranylgeranoil [54], and piericidin A1 [73] have also been accomplished.
A synthetic route to β-carotene
In addition, when the terminal olefins are treated with chiral reagents, regio- and stereoselective carbometalation can be achieved. The synthesis of a side chain in scyphostatin, shown in Scheme 3.13, is an applied example [63]. Moreover, the total synthesis of 6,7-dehydrostipiamide has been attained by regio- and stereoselective methylalumination and the subsequent Negishi coupling [47]. The applied synthetic methods for ionomycin, for the intermediate of borrelidin, and for the total synthesis of doliculide have also been achieved [74].
A synthetic route to the scyphostatin side chain
4.5 Utility of Negishi Coupling toward Carbonyl Compound Synthesis
In Negishi coupling, acyl halides can be utilized as electrophiles to synthesize the corresponding ketones. This type of Negishi coupling has been used for the total synthesis of amphidinolide derivatives (Fig. 3.2), as shown in Scheme 3.14 [75].
Structures of amphidinolide derivatives
Synthetic route for amphidinolide T1, T3–T5
As mentioned above, because Negishi coupling possesses a large number of advantages (including a wide scope of substrate options, high regio- and stereoselectivities, and preparative reactions under mild conditions), it can be a very powerful tool in the natural product syntheses through its combination with the alkylmetalation of the terminal alkynes and alkenes.
5 Migita–Kosugi–Stille Coupling
Although some cross-couplings might not be useful for highly reactive substrates bearing functional groups such as epoxides which are sensitive to both acids and bases, the mild and neutral Migita–Kosugi–Stille coupling has often been used in the key steps of the natural product syntheses. This section introduces representative examples of how Migita–Kosugi–Stille coupling can be used in natural product synthesis.
5.1 Synthetic Methods of Organotin Compounds
When Migita–Kosugi–Stille is employed as a coupling reaction, synthesis of organotin compounds is required. Since the preparation of organotin compounds can be achieved by various synthetic methods, the reaction conditions and the reagents used in the natural product synthesis offer many choices for stannation. First, some recently reported stannation reactions used in the natural product synthesis will be introduced.
One well-known method for the preparation of organotin is via organolithium reagents; organotin reagents can be prepared by halogen–lithium exchange of alkenyl halides with n-BuLi, followed by treatment of the intermediate organolithium reagents with tin halides, as shown in Scheme 3.15. These organotin reagents can be conveniently synthesized due to the commercial availability of tin chlorides and organolithium compounds, but this synthetic method cannot be used for the substrates that have base-sensitive functional groups.
Preparation of organostannanes from organolithium reagents
On the other hand, tin-containing functional groups can be introduced into unsaturated organic molecules in a highly regioselective fashion through hydrostannation and carbostannation reactions catalyzed by the transition metal complexes. A synthetic example of a precursor of nicandrenones by the Rh-catalyzed regioselective hydrostannation and the subsequent Migita–Kosugi–Stille coupling is shown in Scheme 3.16 [76].
A synthetic route to nicandrenones
5.2 sp2–sp2 Migita–Kosugi–Stille Coupling
Migita–Kosugi–Stille coupling is often used at the key stage when the convergently synthesized fragments are bonded in natural product syntheses. Most of the reactions involve sp2–sp2 coupling to give the conjugate dienes and polyenes. The total syntheses of rutamycin B and oligomycin C are shown in Scheme 3.17 [77].
A synthetic route to rutamycin B and oligomycin C
In Migita–Kosugi–Stille coupling, LiCl and CuI are added to promote transmetalation (see, Chap. 2). In regard to the effect of these additives, it is assumed that the added copper salt can trap the excess phosphine ligands retarding transmetalation. The more nucleophilic organocopper species, generated via transmetalation from tin to copper, accelerate the transmetalation [78]. The total synthesis of deoxyvariolin B can be achieved by applying these reaction conditions (Scheme 3.18) [79, 80].
A synthetic route to deoxyvariolin B
In some cases AsPh3, which has a moderate electron-donating ability, gives better results for the construction of sp2–sp2 carbon–carbon bonds in Migita–Kosugi–Stille coupling. For instance, such a ligand is used in the total synthesis of marinomycin A (Scheme 3.19) [81, 82].
A synthetic route to a monomer of marinomycin A
As mentioned above, the mild Migita–Kosugi–Stille coupling enables application to the substrates that are unstable under acidic and basic condition. Hence, this reaction is useful for the total synthesis of amphidinolide H, which bears an epoxide functionality (Scheme 3.20) [83]. A stoichiometric amount of copper(I)-thiophene-2-carboxylate (CuTC) can enhance Migita–Kosugi–Stille coupling as an activator [84].
A synthetic route to amphidinolide H
Migita–Kosugi–Stille coupling, using a stoichiometric amount of CuTC, can be used in the total synthesis of phoslactomycin A, while avoiding the side reaction of allylphosphate with the Pd catalyst (Scheme 3.21) [85]. Other stoichiometric reactions mediated by a copper compound have been reported for the total synthesis of dictyostatin [86], formamicin [87], and amphidinolide A [88].
A synthetic route to phoslactomycin A
The total synthesis of gambierol, shown in Scheme 3.22, is another example of a synthetic strategy utilizing Migita–Kosugi–Stille coupling [89–92]. An important aspect of this synthesis is that a silyl protecting group was removed before the cross-coupling. This underscores the fact that Migita–Kosugi–Stille coupling will not take place if the reaction site of the cross-coupling is sterically hindered by the presence of a bulky TBS group. Deprotection of the silyl group counteracts the steric congestion to smoothly accelerate the cross-coupling.
A synthetic route to gambierol
The following are known examples of the utility of the sp2–sp2 Migita–Kosugi–Stille coupling reactions for the natural product syntheses: paracentrone [6], iso- and bongkrekic acids [8], leiodolide B [30], (−)-callystatin A [43], sanglifehrin A [93–95], a biaryl moiety of TMC-95 [96], (−)-reveromycin B [97], manzamine A [98], quadrigemine C, psycholeine [99], pentacyclic skeletons [100], SNF4435 C, SNF4435 D [101], (−)-crispatene [102], (–)-SNF4435 C, (+)-SNF4435 D [103], 28-19F-amphotericin B methyl ester [104], FR252921, pseudotrienic acid B [105, 106], (−)-spirangien A and its methyl ester [107], amphidinolide H1 [108], (+)-crocacin C [109], amphidinolides B1, B4, G1, H1 [110], (±)-havellockate [111], (±)-goniomitine [112], amphidinolide A [113], CD-D’ rings in angelmicin B (hibarimicin B) [114], and brevenal [115, 116].
5.3 Other Migita–Kosugi–Stille Couplings
In addition to the sp2–sp2 coupling, sp2–sp3 Migita–Kosugi–Stille coupling is also utilized for natural product syntheses. The total syntheses of piericidin A1 and B1 [117] and (±)-neodolabellane-type diterpenoids [118] are shown in Schemes 3.23 and 3.24, respectively.
A synthetic route to piericidin A1 and B1
A synthetic route to (±)-neodolabellane-type diterpenoids
Because stable π-benzyl- and π -allylpalladium complexes are generated, these sp2–sp3 Migita–Kosugi–Stille couplings can be utilized with a low risk of β-hydrogen elimination. The sp3 organotin reagents have rarely been utilized in Migita–Kosugi–Stille coupling because they cause β-hydrogen elimination (See also Chap. 8).
In addition, using the sp3–sp2 Migita–Kosugi–Stille coupling, the total syntheses of amphidinolide A [113], azaspiracid-1 [119, 120], tardioxopiperazine A, isoechinulin A, and variecolorin C [121] have been reported.
6 Suzuki–Miyaura Coupling
Suzuki–Miyaura coupling is extremely advantageous because the organoboron compounds have low toxicity and have stability toward water and air; this cross-coupling has been used extensively in natural product syntheses. However, Suzuki–Miyaura coupling requires the use of bases, thus functional groups that are unstable under basic conditions are incompatible. Herein, the applications of Suzuki–Miyaura coupling to natural product syntheses are described.
6.1 sp2–sp2 Suzuki–Miyaura Coupling
Construction of biaryl and conjugate diene motifs using the sp2–sp2 Suzuki–Miyaura coupling is particularly important in the natural product syntheses. Some examples include: 5,6-DiHETE methyl esters [122], (−)-chlorothricolide [123], and rutamycin B [124]. Although Negishi and Migita–Kosugi–Stille couplings can be used for sp2–sp2 carbon–carbon bond-formation, Suzuki–Miyaura coupling is more widely utilized owing to its versatility of ligands and its various types of boron-containing reagents. The total synthesis of lamellarin D shown in Scheme 3.25 is one such example employing pinacolborane as the boron moiety [125].
A synthetic route to lamellarin D
Pd(PPh3)4 is generally the most frequently used Pd(0) complex in Suzuki–Miyaura coupling, but PdCl2(dppf) also shows high catalytic activity in the synthesis of (+)-complanadine A (Scheme 3.26) [126].
A synthetic route to (+)-complanadine A
In general, as the substrate becomes larger, the achievement of cross-coupling becomes more difficult due to poor access to the reaction sites. However, Kishi reported in 1989 that the reactivity of a congested substrate was drastically improved by the use of thallium hydroxide as the base in the total synthesis of palytoxin [127]. More recently, TlOEt and Tl2CO3 have been utilized as a precursor of thallium hydroxide because thallium hydroxide is difficult to handle due to its instability to light and air [128]. The example of the synthesis of apoptolidinone via Suzuki–Miyaura coupling with TlOEt as the base is shown in Scheme 3.27 [129].
A synthetic route to apoptolidinone
Buchwald reported that the bulky phosphine ligands with a biaryl backbone such as SPhos have a high activity in Suzuki–Miyaura coupling [130]. In the total synthesis of eupomatilones, as little as 0.005 mol % of the Pd catalyst can afford the cross-coupled products in 93 % yield (Scheme 3.28) [131, 132].
A synthetic route to eupomatilones
Furthermore, Suzuki–Miyaura coupling is practical because it offers a superior selection of bases and ligands. As the result of recent research utilizing the benefits of organoboronic acids, many progressive synthetic routes have been established. Herein, some examples of modified organoboron compounds used in natural product syntheses are introduced. As shown in Scheme 3.29, the total synthesis of oximidine II [22] is an example of the application of organotrifluoroborates [133] to the natural product synthesis. The construction of an unsaturated 12-membered ring with a large strain was achieved.
A synthesis route to oximidine II
In addition, Suzuki–Miyaura couplings using N-methyliminodiacetic acid (MIDA) have been invented [134]. (–)-Peridinin has been synthesized by repeated reactions with MIDA-containing organoborates (Scheme 3.30) [135].
A synthesis route to (–)-peridinin
Thus, the sp2–sp2 Suzuki–Miyaura coupling has achieved selective and efficient carbon–carbon bond-formation in natural product syntheses through the use of a wide variety of substrates. The following examples of natural product syntheses using sp2–sp2 Suzuki–Miyaura coupling have been recently reported: iso- and bongkrekic acids [8, 31], furopyrans [29], lukianol A [33], maleic anhydride, maleimide [67], (+)-crocacin C [109], CD-D′ rings in angelmicin B (hibarimicin B) [114], (+)-fostriecin [136], dragmacidin D [137], (−)-FR182877 [138, 139], nakadomarin A [140], styelsamine C [141], (±)-spiroxin C [142], diazonamide A [143], quinine, quinidine [144], lamellarin G trimethyl ether [145], (+)-dragmacidin F [146], eupomatilone diastereomers [147], biphenomycin B [148], (−)-spirofungin A, (+)-spirofungin B [149], pulvinic acids [150], N-shifted and ring-expanded buflavine [151, 152], (±)-hasubanonine [153], altenuene, isoaltenuene [154], C-15 vindoline analogs [155], (−)-erythramine and 3-epi-(+)-erythramine [156], biaryl hybrids of allocolchicine and steganacin [157], ratanhine [158], palmerolide A [159], eupomatilones [160], butylcycloheptylprodigiosin [161], isotetronic acids [162], 1/2 of amphotericin B macrolide [163], GEX1A [164], (±)-cyclocolorenone, (±)-α-gurjunene [165], withasomnines [166], the vacidin A (E,E,E,Z,Z,E,E)-heptaene framework [167], fortuneanoside E [168], (–)-exiguolide [169], dunnianol [170], and hirtellanine A [171].
6.2 sp3–sp2 Suzuki–Miyaura Coupling
Suzuki–Miyaura coupling has also been used to construct sp3–sp2 carbon–carbon bonds (See also Chap. 8). One such example is the methylation using trimethylboroxine, which is a dehydrated trimer of methylboronic acid, toward aryl or alkenyl halides [172]. The total synthesis of (−)-FR182877 using the sp3–sp2 Suzuki–Miyaura coupling is shown in Scheme 3.31 [138].
A synthetic route to (–)-FR182877
In most cases, the sp3–sp2 Suzuki–Miyaura coupling employs a typical hydroboration of the terminal olefin by 9-BBN and the subsequent B-alkyl Suzuki–Miyaura coupling. Since hydroboration using a bulky 9-BBN takes place in a highly regioselective fashion [173], B-alkyl Suzuki–Miyaura coupling has been widely utilized for the connection of fragments in the natural product syntheses, e.g., the total synthesis of brevenal (Scheme 3.32) [115, 116, 174].
A synthetic route to brevenal
In addition, the B-alkyl Suzuki–Miyaura coupling can be applied to the intramolecular cyclization in the total synthesis of phomactin D; compared with other sp3–sp2 cross-coupling reactions, the organoboron compounds have low toxicity and are highly stable (Scheme 3.33) [175].
A synthetic route to phomactin D
Other synthetic examples using the sp3–sp2 Suzuki–Miyaura coupling include the total synthesis of: anguinomycin C [45], anguinomycin C and D [46], trans-epothilone A [55], oleandolide [56], salicylihalamide [71], CP-225,917, CP-263,114 [176], epothilone A [55, 177], 12,13-desoxyepothilone F [178], FGH ring fragments of gambierol [179], sphingofungin E [180], GHIJKLM ring fragments in ciguatoxin (CTX1B) [181], ABCD ring fragments of ciguatoxin (CTX3C) and ciguatoxin (51-hydroxyCTX3C) [182], (−)-ebelactone A [183], gymnocin-A [184–187], (+)-phomactin [188], the C6–C21 segment of amphidinolide E [189], (±)-geigerin [190], (+)-oocydin A [191], 4-hydroxydictyolactone [192], jatrophane diterpenes [193], (+)-brefeldin C, (+)-nor-Me brefeldin A, (+)-4-epi-nor-Me brefeldin A [194], ABC ring fragments of brevesin [195], and (−)-brevisin [196].
7 Hiyama Coupling (sp2–sp2)
Finally, recent examples utilizing the sp2–sp2 Hiyama coupling in the natural product syntheses will be briefly introduced. As shown in Scheme 3.34, silanol (the substrate bearing a hydroxyl group on silicon) is activated by TBAF to react with an alkenyl iodide in the total synthesis of isodomoic acid G [197].
A synthetic route to isodomoic acid G
Another alkenylsilane substituted with a benzyldimethylsilyl group was successfully subjected to Hiyama coupling for the synthesis of a precursor of herboxidiene/GEX 1A (Scheme 3.35) [198]. It should be noted that in this synthetic example, during the Hiyama coupling, the alcohol was protected by a silyl protecting group.
A synthetic route to herboxidiene/GEX 1A
In the total synthesis of papulacandin D, after a hydrosilane was converted into a silanol using the Ru catalyst, Hiyama cross-coupling of silanol was applied (Scheme 3.36) [199].
A synthetic route to papulacandin D
In addition, a conjugate diene bearing two different silicon functional groups was subjected to the successive Hiyama coupling, achieving the total synthesis of RK-397, as shown in Scheme 3.37 [200].
A synthetic route to RK-397
Moreover, the total synthesis of a highly strained 9-membered compound, (+)-brasilenyne, has been achieved through intramolecular Hiyama coupling (Scheme 3.38) [201, 202].
A synthetic route to (+)-brasilenyne
Thus, Hiyama coupling has a large number of advantages from the viewpoints of high stability, low toxicity, and natural abundance of the organosilicon compounds. Thus, Hiyama coupling can be a powerful tool in the natural product syntheses. However, Hiyama coupling has not been advanced much, because the silyl functionalities require the introduction of hydroxyl or fluoride substituents to be activated, which limits the selection of substrates.
8 Summary
The cross-coupling reactions have facilitated the synthesis of complex organic compounds with high selectivity and reactivity in the natural product syntheses. In addition, recent advancement of technologies for cross-couplings includes: the expansion of organometallic reagents, increased reactivity and safety by the improvement of catalysts, and the reduction of chemical wastes. This remarkable progress has made the cross-coupling reactions increasingly easy to utilize. Complicated natural product syntheses that have not yet been achieved will likely be artificially synthesized by using the cross-coupling reactions in the future. More technological development is expected toward clarification and application of the biologically active compounds.
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Okuda, Y., Nishihara, Y. (2013). Natural Product Synthesis. In: Nishihara, Y. (eds) Applied Cross-Coupling Reactions. Lecture Notes in Chemistry, vol 80. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32368-3_3
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