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Diverse strategic approaches en route to Taxol total synthesis

Zexian Li ,  Jianfeng Zheng ,  Wei-Dong Z. Li

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Citation:  Zexian Li, Jianfeng Zheng, Wei-Dong Z. Li. Diverse strategic approaches en route to Taxol total synthesis[J]. Chinese Chemical Letters, 2022, 33(12): 4957-4968. doi: 10.1016/j.cclet.2022.04.029 shu

Diverse strategic approaches en route to Taxol total synthesis

English

  • 1. Introduction

    Taxol (1) is a complex polyoxygenated diterpenoid natural product which was originally isolated from the bark of Taxus brevifolia by Wall and co-workers [1]. Taxol is a well-known anticancer drug with a unique molecular mechanism for various human cancers [2-4], which has promoted significant interests from chemical and biological communities. The source of Taxol has always been a primary concern since its discovery due to the extremely low content in the natural plant [5]. Considerable efforts have been devoted to find alternative sources to natural harvesting of Taxol, including: (1) total synthesis, (2) semi-synthesis, (3) microbial systems, and (4) plant cell fermentation. Among them, the chemical semi-synthesis and plant cell fermentation of the Taxus species are documented as the clinical supply of Taxol.

    Accordingly, no natural product discovered in the last decades has stimulated as much public interests as Taxol. Structurally, Taxol has a highly strained 6−8−6 tricyclic carbocyclic core with two all-carbon quaternary stereocenters and a bridgehead double bond (Fig. 1). The potent bioactivity and intriguing chemical complexity of this oxygenated polycyclic diterpenoid has attracted considerable interests from the synthetic communities. Indeed, more than hundreds of reports presenting synthetic studies have been documented since the landmark total synthesis of Taxol achieved by Holton and Nicolaou groups in 1994, including ten total syntheses of Taxol (Fig. 2) [6-20]. It has been noted that the nature of substituents plays an important role in the construction of conformationally flexible central eight-membered ring. Various synthetic strategies including coupling reaction, ring-closing metathesis, oxy-Cope rearrangement, Diels−Alder reaction, radical cyclization, and ring expansion have been well developed to construct the eight-membered core ring. To maintain the coherence and focus of this review, the well-known success total syntheses of Taxol (Fig. 2) will not discuss further herein. Therefore, this mini-review mainly highlights on the diverse strategic approaches en route to Taxol's total synthesis, covering mainly the literature reports since 1995 [21-24].

    Figure 1

    Figure 1.  The structure of Taxol.
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    Figure 2

    Figure 2.  The ten-total synthesis of Taxol.
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    2. Biomimetic approaches to Taxol

    Early in 1966, Lythgoe and co-workers proposed a biosynthetic pathway, which suggested that the tricyclic carbon framework of the taxoids was envisioned to derive from geranylgeranyl pyrophosphate (GGPP) through intramolecular cyclization [25, 26]. Based on feeding studies by Croteau and co-workers, the proton at C11 of intermediate 3 shifted to C7 to generate carbocation intermediate 4, followed by transannular cyclization to afford the taxa-4(5), 11-(12)-diene 5 as the final product of the cyclase phase [27-29]. Notably, several research groups including Croteau, Coates, Floss, Pattenden and Williams have also proposed that biosynthetic pathway of Taxol can be conceptually divided into several discrete stages, namely: cyclization, stereospecific oxidation, acylation, benzoylation, and assembly of C13-side chain (Scheme 1) [30-35].

    Scheme 1

    Scheme 1.  Proposed biosynthetic pathway of Taxol.
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    In 1985, Pattenden and co-workers reported the total synthesis of verticillene (8), an assumed biosynthetic precursor of Taxol, by an intramolecular reductive carbonyl coupling as key step [34, 36]. Treatment of dialdehyde 6 with titanium trichloride and Zn−Cu couple, followed by 1, 4-reduction gave verticillene 8. However, various Lewis acid-catalyzed biomimetic transannular cyclization of 8 or its isomers failed to yield the desired tricyclic products 9 (Scheme 2a) [37]. In 2009, the same group developed a cascade radical cyclization strategy leading to the 6−8−6 tricyclic core of Taxol [38-40]. Treatment of the radical precursor 10 with Bu3SnH and AIBN in PhH at 80 ℃ afforded the desired tricycle 12 via presumably the intermediate 11 through the radical transannular cyclization. It is worthy to note that 12 contains oxidative substitutions at C1, C13 with desired stereochemistry and an unsaturated bond at C3−C4 (Scheme 2b).

    Scheme 2

    Scheme 2.  Pattenden's biomimetic approaches through Lewis acid-catalyzed and cascade radical cyclization (1985−2009).
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    In 1997, Takahashi and co-workers reported their biomimetic approach [41]. The aldol condensation of citral derivative 13 with γ-butyrolactone 14 generated compound 15 with three stereogenic centers at positions C1, C2 and C11 respectively, which corresponds to Taxol. A seven-step sequence of reduction of lactone, cyano-addition, and protection of hydroxyl groups afforded cyanohydrin ether 16. Then intramolecular alkylation of 16 efficiently formed the 12-membered ring intermediate 17 in 82% yield. A three-step sequence of reduction, epoxidation, and acetylation gave acetate 18 in 87% yield. However, all attempts of acid-catalyzed cyclization to the formation of B/C ring of Taxol failed, instead rearrangement product bicyclo[5.4.0]undecene 19 bearing the desired six membered C-ring was obtained (Scheme 3).

    Scheme 3

    Scheme 3.  Takahashi's biomimetic approach through Lewis acid-catalyzed cyclization (1997).
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    In 1998, Nishizawa and co-workers reported synthetic efforts toward biomimetic construction of the taxane skeleton via transannular cyclization [42, 43]. The aldol reaction of acetal aldehyde 21 with vinyl iodide 22 gave alcohol 23 in 90% yield. A three-step sequence of protection of hydroxyl group, cleavage of acetal and TBS groups, and Swern oxidation provided ketoaldehyde 24. TiCl4−Zn promoted McMurry coupling yielded diols 25 and 26 with bicyclo[9.3.1]pentadecatriene skeleton in 60% yield. However, all attempts to achieve the biomimetic transannular cyclization leading to the B/C ring system of Taxol failed and an unexpected rearrangement product 28 was obtained (Scheme 4). Although the biomimetic synthesis of Taxol has not yet achieved to date, the studies along this direction have enriched our understanding of the unique role of Taxol synthases in the plant biosynthesis assembly. Future research would be much needed to simulate the delicate conformational control of the GGPP precursor for a smooth tandem cationic C−C bond-forming and transannular cyclization to the core ring system with proper stereochemical control.

    Scheme 4

    Scheme 4.  Nishizawa's biomimetic approach through McMurry coupling and Lewis acid catalyzed cyclization (1998).
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    3. Linear strategies toward A/B/C ring core

    Among the strategies applied to the construction of the A/B/C ring core of Taxol, linear strategy is widely developed to the synthesis of challenging taxane framework, including Diels−Alder strategy, A to A/B/C strategy, and C to A/B/C strategy.

    3.1 Diels−Alder strategy

    In 2002, Malacria and co-workers described the combination of cobalt(I)-mediated [2 + 2 + 2] cyclotrimerization and intramolecular Diels−Alder reaction to construct the 6−8−6 tricyclic core of Taxol [44]. Exposure of polyunsaturated precursor 29 to CpCo(CO)2 afforded alcohol 30 with all carbon D ring in 50% yield. Next, oxidation of the secondary alcohol with IBX, followed by BF3·Et2O mediated intramolecular Diels−Alder reaction afforded the desired pentacyclic framework 31 as only one diastereomer (Scheme 5).

    Scheme 5

    Scheme 5.  Malacria's approach to the tricyclic ring system through cobalt(I)-mediated [2 + 2 + 2] cyclotrimerization and intramolecular Diels−Alder reaction (2002).
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    In 2003, Fallis and co-workers also applied intramolecular Diels−Alder reaction coupled with the ring-closing metathesis to the synthesis of 6−8−6 tricyclic core of Taxol [45, 46]. The sequential combination of Grignard reagent 32 with alcohol 33 generated the magnesium chelate 34 in situ, followed by condensation with aldehyde 35 to afford the diol 36 in 64% yield. A six-step sequence of selective protection the secondary alcohol, oxidation the primary alcohol, Grignard addition, and oxidation of the resulting secondary alcohol was preformed, thus converting 36 to the Diels–Alder precursor 37. With the key intermediate 37 in hand, the desired Diels−Alder cycloaddition was smoothly performed, thus affording the adduct 39 as a single diastereomer via chelation control model 38. Lastly, the bicycle 39 annulated to give 6−8−6 tricyclic ring-system 40 by ring-closing metathesis (Scheme 6).

    Scheme 6

    Scheme 6.  Fallis's approach to the tricyclic ring system through Diels−Alder reaction and ring-closing metathesis (2003).
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    In 2018, Li and co-workers documented a highly concise and elegant enantioselective synthesis of the 6−8−6 tricyclic core of taxezopidine A and B [47]. The aldehyde 42 was prepared from 41 based on Shea's work [48, 49], which includes glycolate Ireland−Claisen rearrangement, reduction, and Swern oxidation. Next, treatment of 42 with bromofuran and subsequent transformations of functional groups gave 43. Then the type II intramolecular Diels−Alder furan reaction of 43 was carried out, thus giving 6−8−6 tricyclic core of Taxol 44 as a single diastereomer in 55% yield. It is worthy note that the acetoxy group at the allylic position of 43 is crucial for high diastereoselectivity (Scheme 7).

    Scheme 7

    Scheme 7.  Li's approach to the tricyclic ring system through type II intramolecular Diels−Alder furan reaction (2018).
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    In 2020, Fletcher and co-workers described the concise procedure to prepare the Taxol core by type II intramolecular Diels−Alder reaction and Cu(I)-catalyzed asymmetric conjugate addition [50]. The addition reaction of cyclohexanone 45 and alkyl zirconocene (generated from bromodiene 46 and Cp2ZrHCl) with copper-phosphoramidite complexes as catalyst followed by Vilsmeier−Haack reaction generated β-chloroaldehyde 47 in 69% yield with 92% ee. A three-step sequence of Grignard addition, Suzuki−Miyaura reaction, and oxidation of the resulting secondary alcohol afforded the intermediate 48. Finally, treatment of 48 with TiCl4 in CH2Cl2, the Diels−Alder reaction proceeded smoothly to give tricyclic ring core 49 in 35% yield with 1:1 dr and 92% ee (Scheme 8).

    Scheme 8

    Scheme 8.  Fletcher's approach to the tricyclic ring system through type II intramolecular Diels−Alder reaction and Cu(I)-catalyzed asymmetric conjugate addition (2020).
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    3.2 A to A/B/C strategy

    The A/B ring system of Taxol contains bicyclo[5.3.1]undecane, which has attracted considerable attention since Taxol's discovery. Significant efforts have been made regarding to synthesis of A/B ring, such as ring-expansion of cyclopropane [51-53], oxy-Cope rearrangement [54-57], ring-closing metathesis [58-60], transition metal-catalyzed carbocyclization [61, 62] and so on (Scheme 9).

    Scheme 9

    Scheme 9.  Selected strategies to the A/B ring system.
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    During the past decades, Paquette and co-workers made remarkable efforts to pursue Taxol by using an anionic oxy-Cope rearrangement as the key strategic reaction [63-65]. Treatment of 61 with KHMDS and 18-crown-6 via the crucial anionic oxy-Cope rearrangement smoothly generated nine-membered ring, followed by methylation in situ, thus affording 62 in 81% overall yield. A four-step sequence of dihydroxylation, protection, desilylation, and Swern oxidation afforded keto aldehyde 63. Intramolecular aldol reaction of 63 generated the C-ring stereoselectively, then transannular hydride shift of the resulting alcohol with KOt-Bu gave 64. A seven-step sequence was carried out to generate 65. Finally, 65 underwent α-ketol rearrangement with Al(Ot-Bu)3 to provide highly functionalized taxane system 66 (Scheme 10).

    Scheme 10

    Scheme 10.  Paquette's approach to the tricyclic ring system through anionic oxy-Cope rearrangement (1989−2003).
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    In 1995, Martin and co-workers achieved the 6−8−6 tricyclic ring of taxane via an anionic oxy-Cope rearrangement protocol [66]. The crucial anionic oxy-Cope rearrangement reaction of alcohol 67, followed by alkylation in situ, furnished the bicyclo[5.3.1]undecenone 68 in 76% yield with 2:1 ratio of diastereoselectivity. Finally, exposure of excess MeLi by a vinyllithium reagent generated tricyclic compound 69 in 58% yield (Scheme 11).

    Scheme 11

    Scheme 11.  Martin's approach to the tricyclic ring system through anionic oxy-Cope rearrangement (1995).
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    In 1995, Kanematsu and co-workers applied tandem intramolecular [2 + 2] cycloaddition and Cope rearrangement strategy to the enantioselective synthesis of 6−8−6 tricyclic core of Taxol [67]. Treatment of enyne 70 with t-BuOK in t-BuOH, generated intermediate 71 in situ via a [2 + 2] cycloaddition, followed by Cope rearrangement affording product 72 bearing 6−8−6 tricyclic skeleton of taxane (Scheme 12).

    Scheme 12

    Scheme 12.  Kanematsu's approach to the tricyclic ring system through tandem intramolecular [2 + 2] cycloaddition and Cope rearrangement reaction (1995).
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    In 1997, Little and co-workers reported the synthesis of 6−8−6 tricyclic ring of the taxane via intramolecular diyl trapping and oxidation of cleavage of olefin strategy [68]. The intramolecular diyl trapping reaction of bicyclic diazene 73 formed compound 74 in 80% yield. A five-step sequence of the addition of phenylselenyl trifluoroacetate, Swern oxidation, elimation, alkylation, and ketalization was carried out, thus affording 75. Oxidation of cleavage of olefin by using sodium periodate and ruthenium dioxide, followed by removing the silyl ether gave 76 with eight-membered ring in 76% yield over two steps. Then mesylation and iodization of 76 afforded 77. Lastly, treatment of 77 with excess of LDA afford 6−8−6 tricyclic scaffold 78 with highly functionalized eight membered ring in 63% yield (Scheme 13).

    Scheme 13

    Scheme 13.  Little's approach to the tricyclic ring system through intramolecular diyl trapping and oxidation of cleavage (1997).
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    In 1998, Nagaoka and co-workers described the synthesis of 6−8−6 tricyclic core of Taxol via oxy-Cope rearrangement and intermolecular Diels−Alder cycloaddition [69]. Treatment of 79 with (TMS)2NLi in a mixture of o-xylene and HMPA (10:1) at 150 ℃ gave bicyclo[5.3.1]undecane 80 in 76% yield through oxy-Cope rearrangement. Then a seven-step sequence of stereoselective reduction, methyl etherification, epoxidation, ring-opening, oxidation, and olefination was carried out to give diene 81. Lastly, intermolecular Diels−Alder reaction of diene 81 with trans-1, 2-bis(phenylsulfony)ethylene 82 was carried out in o-xylene at 100 ℃ to afford the tricyclic product 83 in 70% yield (Scheme 14).

    Scheme 14

    Scheme 14.  Nagaoka's approach to the tricyclic ring system through oxy-Cope rearrangement and intermolecular Diels−Alder cycloaddition (1998).
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    In 1998, Stork and co-workers applied cyanohydrin cyclization and aldol reaction to the synthesis of the 6−8−6 tricyclic core of Taxol [70, 71]. The compound 85 containing A ring was prepared from stannylactone 84. Then the cyanohydrin cyclization of 85 was easily conducted with NaHMDS as base, thus resulting in the desired closure of the cyclooctane ring B to afford 86 in 72% yield. Next, a five-step sequence of desilylation, hydrolysis of cyanohydrin, Johnson−Claisen elongation, reduction, and oxidation was carried out to give dicarbonyl compound 87. Finally, 87 underwent a smoothly intramolecular facile aldol reaction with K2CO3 in MeOH and 18-crown-6 to provide the desired 6−8−6 tricyclic core 88 (Scheme 15).

    Scheme 15

    Scheme 15.  Stork's approach to the tricyclic ring system through cyanohydrin cyclization and aldol reaction (1998).
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    In 1999, Kajiwara and co-workers described the synthesis of the 6−8−6 tricyclic core of Taxol by lactam-sulfoxide ring contraction and intramolecular pinacol coupling [72-76]. Ring contraction of lactam-sulfoxide 89 was achieved with LDA, followed by reductive removal of the spacer moiety with Na−Hg to afford A/B ring system 90. Treatment of 90 with aldehyde 91, followed by MOM protection afforded ether 92 in 89% yield. Removal of the TBS group of 92 with TBAF and Dess−Martin oxidation of the resulting primary alcohol gave aldehyde 93 in 91% yield. Lastly, upon treatment of aldehyde with SmI2 in THF, the pinacol-type reaction proceeded smoothly to yield 6−8−6 tricyclic ring system 94 in 43% yield (Scheme 16).

    Scheme 16

    Scheme 16.  Kajiwara's approach to the tricyclic ring system through lactam-sulfoxide ring contraction and pinacol coupling (1999).
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    In 2011, Suffert and co-workers completed the synthesis of 6−8−6 tricyclic core of Taxol through a palladium catalyzed domino reaction [77]. Reaction of alkenylbromide 95 with a catalytic amount of Pd(PPh3)4 produced the desired tetracyclic ring 100, in which a tandem cyclization process including 4-exo-dig, 6-exo-trig cyclizations and a disrotatory 6π electrocyclization were performed. Subsequent oxidation of the secondary alcohol with Dess–Martin periodinane generated enone 101. Finally, regioselective oxidation cleavage of 101 delivered taxane skeleton 102 (Scheme 17).

    Scheme 17

    Scheme 17.  Suffert's approach to the tricyclic ring system through palladium catalyzed domino reaction (2011).
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    3.3 C to A/B/C strategy

    In 1995, Magnus and co-workers provided the synthesis of 6−8−6 tricyclic core of Taxol via [5 + 2]-pyrylium ylide-alkene cyclization and ring expansion [78, 79]. Treatment of pyrylium-ylide precursor 103 with DBU generated pyrylium-ylide intermate 104 in situ, followed by stereoselective [5 + 2] cycloaddition to give bicyclo[5.4.0]undecenone 105 in 77% yield with 10:1 dr. Then a three-step sequence of bromination, cyanation, and asymmetric cyclopropanation was performed, giving cyclopropane 106 in 91% yield over three steps. Subsequent, taxane 107 with B/C ring of Taxol was obtained in 95% yield with 2:1 dr through the cleavage of the internal cyclopropane bond. A six-step sequence of addition and reduction was carried out to give methyl ester 108. Lastly, intramolecular nucleophilic addition and desulfonylation were carried out to obtain the desired tricyclic product 109 in 95% yield (Scheme 18).

    Scheme 18

    Scheme 18.  Magnus's approach to the tricyclic ring system through [5 + 2]-pyrylium ylide-alkene cyclization and ring expansion (1995).
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    In 1998, d'Angelo and co-workers described the synthesis of 6−8−6 tricyclic core of Taxol via a Mukaiyama-type condensation [80, 81]. Regioselective annulation diketone 110 with piperidine and acetic acid provided cyclohexanone 111 in 83% yield. Then a three-step sequence of oxidation, Wittig olefination, methylation, and silylation was carried out, thus affording silyl enol 112. Then intramolecular Mukaiyama-type condensation of 112 was performed with TiCl4 as catalyst, affording the expected tricyclic product 113 in 61% yield with 2:1 dr (Scheme 19).

    Scheme 19

    Scheme 19.  d'Angelo's approach to the tricyclic ring system through Mukaiyama condensation (1998).
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    In 2000, Shair and co-workers disclosed an elegant synthesis of 6−8−6 tricyclic core of Taxol by a tandem alkylation, oxy-Cope rearrangement, and transannular Dieckmann cyclization procedure [82]. The triple-domino cyclization was initiated by treating of 114 with the vinyl Grignard reagent, affording the C-aromatic taxane framework 117 directly in 63% yield. The elegant transformation underwent a tandem anion-accelerated oxy-Cope rearrangement (115) followed by spontaneous transannular Dieckmann cyclization (116) (Scheme 20).

    Scheme 20

    Scheme 20.  Shair's approach to the tricyclic ring system through a tandem alkylation, oxy-Cope rearrangement, and transannular Dieckmann cyclization (2000).
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    In 2005, Arseniyadis and co-workers applied Grob fragmentation and SmI2-mediated intramolecular aldol reaction to the synthesis of 6−8−6 tricyclic core of Taxol [83-85]. Methylsulfonylation of acetonide 118 set the stage for the crucial B-ring formation through a Grob-type fragmentation, thus affording bicyclo[6.4.0]-system 119 in 82% yield over two steps, which corresponded to the taxoid B/C subunit. An eleven-step sequence including epoxide-opening, methylation, reduction, and oxidation was carried out, thus affording seco-taxane 120. Finally, SmI2-mediated intramolecular aldol reaction of 120 resulted in the desired product 121 in 74% yield (Scheme 21).

    Scheme 21

    Scheme 21.  Arseniyadis's approach to the tricyclic ring system through Grob fragmentation and SmI2-mediated intramolecular aldol reaction (2005).
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    In 2007, Granja and co-workers documented a cascade dienyne ring-closing metathesis approach to the construction of 6−8−6 tricyclic core of Taxol [86-89]. The RCM precursor 124 was obtained from aldehyde 122 and ketone 123 through a three-step sequence of addition, carbonyl allylation and protection. Lastly, in the presence of Grubbs II catalyst, the tandem ring-closing reaction of readily available enyne 124 was performed, thus affording tricycle 125 in 62% yield bearing with C2, C8-hydroxy groups and the methyl of C18 in a single-step (Scheme 22).

    Scheme 22

    Scheme 22.  Granja's approach to the tricyclic ring system through cascade dienyne ring-closing metathesis (2007).
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    In 2014, Tanino and co-workers applied [6 + 2] cycloaddition reaction to the synthesis of the 6−8−6 tricyclic core of Taxol [90]. Initially, the coupling reaction of dicobalt acetylene complex 126 with enol ether 127 was induced with EtAlCl2 as Lewis acid, affording B/C ring intermediate 128. Then a five-step sequence of transformations was carried out, affording nitrile 129 as a mixture of diastereomers. Finally, treatment of nitrile 129 with LiNEt2 afforded the tricyclic skeleton 130 in 84% yield with 10:1 dr via epoxy nitrile cyclization (Scheme 23).

    Scheme 23

    Scheme 23.  Tanino's approach to the tricyclic ring system through [6 + 2] cycloaddition reaction (2014).
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    In 2016, Prunet and co-workers applied a ring-closing dienyne metathesis reaction to the synthesis of 6−8−6 tricyclic core of Taxol [91-98]. The Shapiro coupling reaction of aldehyde 131 with trisylhydrazone 132, hydrolysis of the trimethylsilyl ether and protection of the diols gave the carbonate 133. Then a five-step sequence of hydrolyzation, reduction, and elimination using the Grieco protocol was carried out to furnish the metathesis precursor 134. With enyne 134 as cyclic precursor, the desired tricycle product 135 with A/B/C ring was obtained in 47% yield through tandem metathesis reaction (Scheme 24).

    Scheme 24

    Scheme 24.  Prunet's approach to the tricyclic ring system through ring-closing dienyne metathesis (2016).
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    4. Convergent strategies toward A/B/C ring core

    The construction of taxane framework via convergent strategies has also attracted great attention from synthetic communities with different strategies, including pericyclic reaction, transition metal-catalyzed cyclization and miscellaneous cyclization.

    4.1 Pericyclic reaction

    In 1995, Rigby and co-workers reported Cr(0)-promoted [6 + 4] cycloaddition for the synthesis of 6−8−6 tricyclic core of Taxol [99]. The tricyclic product 138 was prepared from Cr(0)-promoted [6 + 4] cycloaddition of 136 with diene 137. Then a four-step sequence of transformations of protecting group, epoxidation, and enolate oxidation was carried out, thus giving epoxide 139. Finally, α-ketol rearrangement of 139 with Al(Oi-Pr)3 gave the required tricyclic product 140 in 65% yield (Scheme 25).

    Scheme 25

    Scheme 25.  Rigby's approach to the tricyclic ring system through Cr(0)-promoted [6 + 4] cycloaddition (1995).
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    In 1995, Winkler and co-workers reported the synthesis of the 6−8−6 tricyclic core of Taxol by tandem Diels−Alder strategy [100]. The condensation of iodide 141 with butadiene sulfone 142, followed by extrusion of SO2, resulted in the formation of tetraene compound 143. The ZnCl2 catalytic intermolecular Diels−Alder reaction of 143 with 144 give cyclohexene 145 bearing C-ring core in 63% yield. Lastly, the desired tricyclic enone 146 was obtained as a single diastereomer via BF3·Et2O mediated intramolecular Diels−Alder reaction (Scheme 26). Later then, Winkler and co-workers disclosed the synthesis of tricyclic ring system through the intramolecular Diels−Alder reaction starting from A-ring synthon [101, 102].

    Scheme 26

    Scheme 26.  Winkler's approach to the tricyclic ring system through tandem Diels−Alder reaction (1995).
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    In 1998, Sonawane and co-workers applied novel sequential transacetalation oxonium ene reaction to the synthesis of 6−8−6 tricyclic core of Taxol [103]. The B-seco-taxane 149 was prepared from the coupling reaction of 147 with aryllithium 148 in 75% yield with 3.4:1 dr. In the presence of SnCl4, the intramolecular nucleophilic substituted reaction and ene reaction were carried out to the assemble of the C-aromatic taxane skeleton 152 in 74% yield (Scheme 27).

    Scheme 27

    Scheme 27.  Sonawane's approach to the tricyclic ring system through sequential transacetalation oxonium ene reaction (1998).
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    4.2 Transition metal-catalyzed cyclization

    In 2004, Nakada and co-workers described the synthesis of 6−8−6 tricyclic core of Taxol by using Nozaki–Hiyama reaction [104]. Trisyl hydrazone 153 was converted to the corresponding alkenyllithium with n-butyllithium, followed by reaction of aldehyde 154 to produce 155 in 91% yield with 6:1 dr. Then, an eight-step sequence of oxidation, reduction, Witting reaction, and hydrolysis was carried out, producing the allylic phosphate 156. Pleasingly, the cyclization reaction could be achieved under the condition of excessive CrCl2 and LiI in THF, which gave the secure 6−8−6 tricyclic target 157 in only 15% yield (Scheme 28).

    Scheme 28

    Scheme 28.  Nakada's approach to the tricyclic ring system through Nozaki–Hiyama reaction (2004).
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    In 2015, the same group described the formal synthesis of Taxol via a palladium-catalyzed alkenylation of methyl ketone to furnish the eight-membered ring [105, 106]. Firstly, treatment of the A-ring precursor 158 with alkenyllithium 159 in THF at −78 ℃ afforded 160 as a single isomer in 95% yield. Then the key precursor 161 was obtained through a six-step sequence of transformations. Palladium-catalyzed alkenylation of methyl ketone 161 was smoothly taken place, thus producing the tricyclic compound 162 with the oxygen atom at C9 in 97% yield. Finally, 162 transformed to Nicolaou's intermediate 163 via a fourteen-step sequence to complete the challenging work (Scheme 29).

    Scheme 29

    Scheme 29.  Nakada's approach to the tricyclic ring system through Pd-catalyzed alkenylation (2015).
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    In 2018, Inoue and co-workers applied decarbonylative radical coupling and Pd-catalyzed intramolecular alkenylation to assemble the eight-member ring [107]. Treatment of 164 and 165 with Et3B and O2 in benzene at room temperature, followed by regioselectively protecting with TBSCl, afforded 166 in 48% yield over two steps. Then C10−C11 seco-taxane 167, bearing the C8-quaternary carbon was achieved via the linear twelve-step sequence of transformations from 166. Finally, subjecting with Pd(PPh3)4 and PhOK at 100 ℃ in toluene, the eight-member ring was cyclized to deliver the tricyclic product 168 in 49% yield (Scheme 30).

    Scheme 30

    Scheme 30.  Inoue's approach to the tricyclic ring system through decarbonylative radical coupling and Pd-catalyzed alkenylation (2018).
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    4.3 Miscellaneous cyclization

    In 1997, Nagaoka and co-workers described the synthesis of 6−8−6 tricyclic core of Taxol via Friedel−Crafts type cyclization [108]. Initially, the coupling of ring A precursor 169 with aryllithium reagent 170 gave alcohol 171 as a mixture. Then the major isomer of 171 was transformed into nitro compound 172 through an eight-step sequence. Treatment of precursor 172 with excess p-chlorophenyl isocyanate afforded tricyclic product 173 in 94% yield (Scheme 31).

    Scheme 31

    Scheme 31.  Nagaoka's approach to the tricyclic ring system through Friedel−Crafts type cyclization (1997).
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    In 1999, Arseniyadis and co-workers applied intramolecular aldol reaction to assemble of taxoid A/B/C ring system [109-111]. The addition of organostannane 174 to A-ring building block 175 generated 176. Then desilylation and oxidation afforded B-seco-taxoids 177. Finally, the A/B/C tricycle 178 was accomplished by intramolecular aldol reaction in 31% yield, in which only the C3-α substituted precursor could be cyclized smoothly (Scheme 32).

    Scheme 32

    Scheme 32.  Arseniyadis's approach to the tricyclic ring system through intra-molecular Aldol reaction (1999).
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    In 2006, Takahashi and co-workers documented their efforts toward the formal synthesis of Taxol by using microwave-assisted alkylation reaction as a novel step [112, 113]. The Shapiro coupling reaction of A ring hydrazone 179 with aldehyde 180 provided the desired product 181 in 54% yield with 2α/2β = 12:1. Then they achieved the ideal intermediate 182 via an eight-step sequence of transformations from 181. Upon treatment of 182 with LiN(TMS)2 in refluxing dioxane under microwave irradiation triggered the intramolecular alkylation reaction, thus affording cyclization product 183 in 49% yield. Further transformations were carried out to complete the synthesis of Danishefsky's intermediate 184 (Scheme 33).

    Scheme 33

    Scheme 33.  Takahashi's approach to the tricyclic ring system through microwave-assisted alkylation (2006).
    DownLoad: Full-Size Img PowerPoint

    In 2007, Chavan and co-workers employed the strategy of Pummerer reaction and oxidative cleavage to the synthesis of 6−8−6 tricyclic core of Taxol [114]. The bicyclic system 186 was generated from β-oxo sulfoxide 185 through Pummerer reaction, followed by coupling with bromo-2-(bromomethyl)cyclohex-1-ene 187 to obtain 188 in 70% yield. The addition of s-BuLi to 188 delightfully afforded the tetracyclic compound 189 in 60% yield. Upon treatment of 189 with Pb(OAc)4 broke C2−C10 bond, thus affording the A/B/C ring system 190 in 75% yield. Lastly, 190 was isomerized to 191 with catalytic amount of rhodium trichloride (Scheme 34).

    Scheme 34

    Scheme 34.  Chavan's approach to the tricyclic ring system through sulfur-assisted synthetic protocol (2007).
    DownLoad: Full-Size Img PowerPoint

    In 2019, Inoue and co-workers applied decarbonylative radical coupling protocol and pinacol coupling reaction to build tricyclic core [115]. Vinyl iodide 192 bearing A ring framework was transformed into telluride 193 via a five-step sequence. Then coupling of 193 with C ring fragment 194 was carried out under the previous decarbonylative radical condition [107], followed by oxidation of the resulting borane enolate by DDQ, thus affording the adduct 195. Then 195 was converted to the key precursor ketoaldehyde 196 via a three-step sequence of methylation, reduction, elimination, reduction of the nitrile, and deprotection. Treatment of 196 with TiCl4, Zn, and pyridine in THF at 50 ℃, followed by acetylation furnished the tricyclic compound 197 in 45% yield over two steps. Finally, 1-hydroxytaxinine 198 was synthesized via an eight-step sequence of transformations (Scheme 35).

    Scheme 35

    Scheme 35.  Inoue's approach to the tricyclic ring system through decarbonylative radical coupling and pinacol coupling reaction (2019).
    DownLoad: Full-Size Img PowerPoint

    5. Summary and outlook

    Taxol has attracted considerable attention from the synthetic communities due to its intriguing structure and important anticancer bioactivity. Since the pioneering total synthesis of Holton and Nicolaou groups, ten total syntheses of Taxol have been achieved up to the present. Nevertheless, development of efficient synthetic methods to construct the eight-membered B-ring remains a challenging task for organic synthesis in general. This mini-review has summarized the synthetic approaches toward eight-membered B-ring formation. Tremendous efforts made by a number of research groups worldwide have resulted in a range of diverse creative and elegant strategic approaches and methodologies. For example, oxy-Cope rearrangement, Diels–Alder reaction, Pd-catalyzed domino reaction, [5 + 2]-pyrylium ylide-alkene cyclization, cascade radical cyclization, ring-closing metathesis, oxidative cleavage, and diverse coupling reactions (Pd-catalyzed intramolecular alkenylation, decarbonylative radical coupling, acid/base/SmI2-mediated aldol condensation, intramolecular Michael addition of sulfonyl carbanion, Nozaki–Hiyama reaction, and so on) have been successfully employed to construct these eight-membered B-rings (Fig. 3). These novel approaches could provide inspiration to synthetic communities. The further possible approach may be the combination of synthetic convergency and biomimetic conciseness, which could address the overall efficiency of total synthesis. Taxol will still stand for an ideal target molecule in total synthesis for many years to come. We believe that novel synthetic strategies and tactics would be well developed further and could be successfully applied to the total synthesis of Taxol in future.

    Figure 3

    Figure 3.  Highlights of diverse approaches en route to the taxane core ring.
    DownLoad: Full-Size Img PowerPoint

    Declaration of competing interest

    The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

    Acknowledgments

    We acknowledge financial support from the National Natural Science Foundation of China (Nos. 21901215, 21672030), and the Fundamental Research Funds for the Central Universities (No. 2682021CG020).


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  • Figure 1  The structure of Taxol.

    下载: 全尺寸图片 幻灯片

    Figure 2  The ten-total synthesis of Taxol.

    下载: 全尺寸图片 幻灯片

    Scheme 1  Proposed biosynthetic pathway of Taxol.

    下载: 全尺寸图片 幻灯片

    Scheme 2  Pattenden's biomimetic approaches through Lewis acid-catalyzed and cascade radical cyclization (1985−2009).

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    Scheme 3  Takahashi's biomimetic approach through Lewis acid-catalyzed cyclization (1997).

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    Scheme 4  Nishizawa's biomimetic approach through McMurry coupling and Lewis acid catalyzed cyclization (1998).

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    Scheme 5  Malacria's approach to the tricyclic ring system through cobalt(I)-mediated [2 + 2 + 2] cyclotrimerization and intramolecular Diels−Alder reaction (2002).

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    Scheme 6  Fallis's approach to the tricyclic ring system through Diels−Alder reaction and ring-closing metathesis (2003).

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    Scheme 7  Li's approach to the tricyclic ring system through type II intramolecular Diels−Alder furan reaction (2018).

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    Scheme 8  Fletcher's approach to the tricyclic ring system through type II intramolecular Diels−Alder reaction and Cu(I)-catalyzed asymmetric conjugate addition (2020).

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    Scheme 9  Selected strategies to the A/B ring system.

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    Scheme 10  Paquette's approach to the tricyclic ring system through anionic oxy-Cope rearrangement (1989−2003).

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    Scheme 11  Martin's approach to the tricyclic ring system through anionic oxy-Cope rearrangement (1995).

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    Scheme 12  Kanematsu's approach to the tricyclic ring system through tandem intramolecular [2 + 2] cycloaddition and Cope rearrangement reaction (1995).

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    Scheme 13  Little's approach to the tricyclic ring system through intramolecular diyl trapping and oxidation of cleavage (1997).

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    Scheme 14  Nagaoka's approach to the tricyclic ring system through oxy-Cope rearrangement and intermolecular Diels−Alder cycloaddition (1998).

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    Scheme 15  Stork's approach to the tricyclic ring system through cyanohydrin cyclization and aldol reaction (1998).

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    Scheme 16  Kajiwara's approach to the tricyclic ring system through lactam-sulfoxide ring contraction and pinacol coupling (1999).

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    Scheme 17  Suffert's approach to the tricyclic ring system through palladium catalyzed domino reaction (2011).

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    Scheme 18  Magnus's approach to the tricyclic ring system through [5 + 2]-pyrylium ylide-alkene cyclization and ring expansion (1995).

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    Scheme 19  d'Angelo's approach to the tricyclic ring system through Mukaiyama condensation (1998).

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    Scheme 20  Shair's approach to the tricyclic ring system through a tandem alkylation, oxy-Cope rearrangement, and transannular Dieckmann cyclization (2000).

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    Scheme 21  Arseniyadis's approach to the tricyclic ring system through Grob fragmentation and SmI2-mediated intramolecular aldol reaction (2005).

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    Scheme 22  Granja's approach to the tricyclic ring system through cascade dienyne ring-closing metathesis (2007).

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    Scheme 23  Tanino's approach to the tricyclic ring system through [6 + 2] cycloaddition reaction (2014).

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    Scheme 24  Prunet's approach to the tricyclic ring system through ring-closing dienyne metathesis (2016).

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    Scheme 25  Rigby's approach to the tricyclic ring system through Cr(0)-promoted [6 + 4] cycloaddition (1995).

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    Scheme 26  Winkler's approach to the tricyclic ring system through tandem Diels−Alder reaction (1995).

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    Scheme 27  Sonawane's approach to the tricyclic ring system through sequential transacetalation oxonium ene reaction (1998).

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    Scheme 28  Nakada's approach to the tricyclic ring system through Nozaki–Hiyama reaction (2004).

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    Scheme 29  Nakada's approach to the tricyclic ring system through Pd-catalyzed alkenylation (2015).

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    Scheme 30  Inoue's approach to the tricyclic ring system through decarbonylative radical coupling and Pd-catalyzed alkenylation (2018).

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    Scheme 31  Nagaoka's approach to the tricyclic ring system through Friedel−Crafts type cyclization (1997).

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    Scheme 32  Arseniyadis's approach to the tricyclic ring system through intra-molecular Aldol reaction (1999).

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    Scheme 33  Takahashi's approach to the tricyclic ring system through microwave-assisted alkylation (2006).

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    Scheme 34  Chavan's approach to the tricyclic ring system through sulfur-assisted synthetic protocol (2007).

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    Scheme 35  Inoue's approach to the tricyclic ring system through decarbonylative radical coupling and pinacol coupling reaction (2019).

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    Figure 3  Highlights of diverse approaches en route to the taxane core ring.

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  • 发布日期:  2022-12-15
  • 收稿日期:  2022-02-15
  • 接受日期:  2022-04-12
  • 修回日期:  2022-04-11
  • 网络出版日期:  2022-04-15
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