Formal Total Synthesis of ( Taxol

1． Introduction

Taxol (Figure 1) was �rst isolated from the bark of the Paci�c yew tree (Taxus brevifolia) by Wani et al. 1,2 and it is widely used as the best anticancer drug in the 21th century. 3 In addition to its potent bioactivity, taxol features a highly dis-torted 6─ 8─ 6 tricyclic bridged scaffold bearing nine stereogenic centers, including an all─ carbon quaternary stereogenic center, a variety of functional groups (such as oxetane, trans ─ 1,2─ diol, acyloin, and a bridgehead double bond), and an amino alcohol side─ chain linked by an ester.

The potent bioactivity and intriguing complex structures have made taxol an attractive synthetic target. Indeed, more than 200 papers that describe synthetic studies 4,5 and nine total syntheses of taxol (including formal total syntheses) have been published thus far. 6─ 14 However, medium rings (8─ 11 membered rings) are dif�cult to form owing to steric strain, transannular interactions, and entropy; therefore, taxol is still considered to be a dif�cult synthetic target. Herein, we describe our formal total synthesis of (-)─ taxol via a convergent approach.

2． Construction of the Eight─ Membered Ring by an Intramolecular B ─ Alkyl Suzuki─ Miyaura Coupling Reaction 15

A convergent total synthesis allows the parallel preparation of building blocks, which reduces time and also provides the advantage of independent transformations of functional groups that are otherwise incompatible with each other. More-over, a convergent synthesis is useful for preparing derivatives with diverse structures. Thus, convergent syntheses of taxol, i.e., the preparation and coupling of the A─ and C─ ring frag-ments, followed by the formation of the eight─ membered B─

ring and further transformations, have been studied by many research groups, and six convergent total syntheses of taxol, 7,8,11 including formal syntheses, 12─ 14 have been reported. However, the formation of the eight─ membered ring has been a synthetic problem, as described above, and indeed, the convergent total syntheses of taxol suffered from dif�culties in the formation of the eight─ membered B─ ring (Scheme 1).

Thus, the yield for the pinacol coupling of Nicolaou et al. was only 23─ 25%, 7 while the Heck reaction of Danishefsky et

Figure 1.　Structure of (-)─ taxol.

Scheme 1.　 Formation of the eight─ membered ring of taxol in the convergent synthesis.

Formal Total Synthesis of (-)─ Taxol

Masayuki Utsugi, Mitsuhiro Iwamoto, Sho Hirai, Hatsuo Kawada, and Masahisa Nakada ＊

＊Graduate School of Advanced Science and Engineering, Waseda University 3─ 4─ 1 Ohkubo, Shinjuku─ ku, Tokyo 169─ 8555, Japan

(Received July 27, 2017; E─ mail: [email protected])

Abstract: Formal total synthesis of (-)─ taxol is described herein. This convergent synthesis was accomplished by utilizing two chiral fragments, both of which were prepared via asymmetric catalysis. A palladium─ cata-lyzed reaction was found to afford the eight─ membered ring effectively, i.e., a B─ alkyl Suzuki─ Miyaura cou-pling reaction and an intramolecular alkenylation of a methyl ketone successfully constructed the B─ ring of taxol in excellent yield. During the preparation of a substrate for the palladium─ catalyzed reaction, a unique rearrangement of the epoxy benzyl ether, via a 1,5─ hydride shift that generates the C3 stereogenic center and subsequently forms the C1─ C2 benzylidene moiety, was observed. Strenuous efforts were required for transfor-mations after the construction of the taxane scaffold to achieve the formal total synthesis of taxol because very few approaches are available for the synthesis of the target compound.

（ 16 ） J. Synth. Org. Chem., Jpn.1102

al. required a stoichiometric amount of the palladium reagent to afford the product in 46% yield. 8 Kuwajima’s group suc-ceeded in the cyclization of a relatively simple substrate by reacting silyl dienol ether with acetal, but the yield was 59% (2 steps). 11 and Takahashi et al. used microwaves for the alkyla-tion 12 of cyanohydrin ethoxy ethyl ether, but the yield was 49%. Recently, Chida’s group reported the formation of the eight─ membered ring using SmI 2 which afforded the product in 66% yield, but their synthesis required some additional steps to introduce the double bond into the bridgehead position because the SmI 2─ mediated reaction was accompanied by double bond migration. 14

Overall, the reported eight─ membered ring formations illustrated in Scheme 1 could be successfully used to form the B─ ring of taxol; however, the scheme also indicates the dif�cul-ties associated with this step. Development of ef�cient methods for forming eight─ membered rings would be valuable for natu-ral product synthesis because a number of terpenoids includ-ing eight─ membered rings have been reported. Furthermore, the developed methods could be applied for constructing other medium─ size rings. Hence, we decided to start an investigation into ef�cient methods for constructing eight─ membered rings that could be applied for the total synthesis of taxol.

We focused on constructing eight─ membered rings by pal-ladium─ catalyzed reactions because of the high ef�ciency and mild conditions of these reactions. Indeed, a number of natu-ral product syntheses have proved the utility of palladium─ catalyzed reactions. 16 The B ─ alkyl Suzuki─ Miyaura coupling reaction was reported in 1986 17 and an intramolecular version followed. 18 The reaction’s ef�ciency has been proved, and it has also been uti-lized for natural product synthesis. However, to the best of our knowledge, the B ─ alkyl Suzuki─ Miyaura coupling reaction has only been utilized for fabricat-ing ten─ membered rings. We expected that the palla-dium─ mediated reaction would be effective for form-ing eight─ membered rings because it proceeds via reductive elimination of the nine─ membered pallada-cycle intermediate, which is presumed to be more unstable than the corresponding eight─ membered carbocyclic product. Thus, we investigated the for-mation of eight─ membered rings by the B ─ alkyl Suzuki─ Miyaura coupling reaction.

We �rst examined the hydroboration and subse-quent B ─ alkyl Suzuki─ Miyaura coupling reaction in a one─ pot manner by using 1 (Table 1). 9─ BBN was used because it could accelerate the transmetalation owing to its electron─ rich properties. The B ─ alkyl Suzuki─ Miyaura coupling reaction of 1 under the Johnson’s conditions ((PdCl 2(dppf), AsPh 3, CsCO 3)),

19 which have been reported to be effective for the B ─ alkyl Suzuki─ Miyaura coupling reaction, required a long reaction time to afford the product in 32% yield (entry 1). The use of Tl 2CO 3

20 as the base (entry 2) and MeCN/H 2O (10:1) as the solvent (entry 3) slightly improved the yield to 37% and 41%, respectively. Hence, with MeCN/H 2O (10:1) �xed as the solvent, further optimization was conducted. The reaction in the absence of AsPh 3 had a decreased yield (18%, entry 4), and the use of Pd(PPh 3) 4 instead of PdCl 2(dppf) further reduced the yield to 8%

(entry 5). However, the reaction with Pd(PPh 3) 4 and NaOH afforded the product in 33% yield (entry 6), while the use of CsF 21 improved the yield to 51% (entry 7), which indicated that the use of AsPh 3 and/or Tl 2CO 3 was unnecessary to obtain the product in a reasonable yield.

Next, we examined the B ─ alkyl Suzuki─ Miyaura coupling reaction of a known taxol model compound 3 (Table 2). The hydroboration of 3 with 9─ BBN and subsequent palladium─ catalyzed reaction under Johnson’s conditions in a one─ pot manner afforded the cyclized product 5 (9%), which lacked the carbonate group (entry 1). The coupling reaction with Pd(PPh 3) 4 and CsCO 3 in MeCN/H 2O (10:1) increased the yield to 31% (entry 2), but use of Tl 2CO 3 (entry 3) or NaOH (entries 4 and 5) did not increase the yield. To suppress the hydrolysis of the carbonate group, CsF was used as the base and, gratifyingly, compound 4 was obtained in 62% yield (entry 6). The reaction with CsF at 80 ℃ gave a decreased yield (entry 7).

Because the carbonate group was removed under basic conditions in the B ─ alkyl Suzuki─ Miyaura coupling reaction, we further examined the reactions of 6 and 7 bearing the pro-tecting groups resistant to basic conditions (Table 3). The reaction of 6 afforded 8 in 70% yield when NaOH was used as the base (entry 1), and the yield decreased to 58% when CsF was used (entry 2). Surprisingly, the reaction under Johnson’s conditions gave a decreased yield (50%, entry 3). The use of NaOH was also effective in the reaction of 7 bearing separate

Table 1.　Intramolecular B ─ alkyl Suzuki─ Miyaura coupling reaction of 1.


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protecting groups, and product 9 was obtained in 82% yield (entry 4). The yield again decreased (59%) when CsF was used (entry 5). The higher yield of the reaction of 7 relative to that of the reaction with 6 bearing the cyclic protecting group indi-cated that the selection of the C1 and C2 protecting groups is important to attain high yield, the cyclic protecting group probably increased strain in the transition states, which led to the lower yield.

As described above, we have established a method for con-structing the eight─ membered ring of taxol via a B ─ alkyl Suzuki─ Miyaura coupling reaction. It was also found that the selectin of the C1 and C2 protecting groups is important to attain high yield. 22

3． Preparation of the A─ Ring Fragment

3.1　 Preparation of the A─ Ring Fragment via a Silicon─ Tethered Reaction 23

Having established a construction method of eight─ mem-bered rings, we addressed the convergent total synthesis of (-)─ taxol. We envisioned that the synthesis of taxol could be accomplished via allylic oxidation of 10 at the C10 position, followed by the formation of acyloin on the B─ ring and intro-duction of the side─ chain (Scheme 2). Thus, compound 11 was selected as a key synthetic intermediate, which could be obtained via the B ─ alkyl Suzuki─ Miyaura coupling reaction of 12. We proposed that compound 12 could be obtained by assembling two fragments, the A─ and C─ ring fragments, fol-lowed by the construction of the C3 stereogenic center. The A─ and C─ ring fragments should be chiral, but no commercially available compounds that were suitable for the starting materi-als were found. Hence, we decided to prepare both fragments with asymmetric catalysis.

At the preliminary stage of our total synthesis, we prepared the A─ ring fragment from chiral compound 17 bearing a ger-minal dimethyl group, which had been prepared by utilizing baker’s yeast, as described by Mori and co─ workers (Scheme 3). 24

In the synthesis of the A─ ring fragment, construction of the chiral tertiary alcohol was a problem. We utilized a silicon─ tethered intramolecular alkylation of a ketone, a reaction developed by us, to generate the chiral tertiary alcohol. 25 Thus, compound 17 was converted into 18, and subsequent treat-ment with tert ─ BuLi caused a rapid halogen─ lithium exchange reaction owing to stabilization of the generated anion by sili-

con. The crude product was subjected to Tamao oxidation, 26 followed by acetonide formation and Dess─ Martin oxidation, to afford 19. Mono─ methylation of 19 was troublesome because the reaction with LDA and MeI was not reproducible and the reaction with NaH and MeI afforded an inseparable mixture of the mono─ and di─ methylated products. However, Stork’s protocol 27 solved this problem. Thus, the reaction of the TMS enol ether of 19 with MeLi and subsequent reaction with MeI suppressed the formation of the di─ methylated prod-uct, cleanly affording the mono─ methylated product 20. The

Table 3.　 Intramolecular B ─ alkyl Suzuki─ Miyaura coupling reactions of 6 and 7.

Scheme 2.　Retrosynthetic analysis of (-)─ taxol.

Scheme 3.　Preparation of the A─ ring fragment 14─ I.


following conversion needed modi�cation of Barton’s proto-col 28 to increase the yield, the use of cyclopentyl methyl ether as the solvent accelerated the reaction rate to afford 21─ I in 71% yield (four steps). The protective group of the C1 hydroxy group had to be removed under neutral conditions because acidic conditions have been reported to induce rearrangement of the taxane scaffold. Hence, the acetonide group of 21─ I was changed to a benzylidene group, and subsequent treatment with DIBAL─ H afforded 22─ I, bearing a benzyl ether group, which was converted into the corresponding aldehyde 14─ I by Dess─ Martin oxidation. It should be noted that the benzyli-dene group was removed under the conditions required for the formation of the TMS enol ether; hence, conversion of aceto-nide to the benzylidene was necessary at a later stage in the preparation of 14─ I.

As described above, the A─ ring fragment 14─ I was pre-pared from chiral hydroxy ketone 17 in 48% overall yield (14 steps) via a silicon─ tethered intramolecular addition reaction.3.2　 Preparation of the A─ Ring Fragment via an

Enantioselective Organocatalytic Reaction 29

Although the A─ ring fragment had been prepared, we explored an alternative short approach to the A─ ring fragment. The enantioselective formation of α ─ hydroxy aldehyde 24─ I from 23─ I (Scheme 4) via organocatalysis attracted our atten-tion. Proline─ or its derivative─ catalyzed α ─ aminoxylation of an aldehyde with nitrosobenzene to afford a chiral α ─ hydroxy-aldehyde has been reported. 30─ 32 However, to the best of our knowledge, the organocatalytic asymmetric α ─ oxygenation of α ─ branched aldehyde is rare, 33,34 and the enantiomeric excess (ee) values of the products did not exceed 45%. List et al. 35 reported the organocatalytic asymmetric α ─ benzoyloxylation of α ─ branched aldehydes and enals, but this protocol cannot be applied for the preparation of 24─ I from 23─ I, because 24─ I decomposes via fragmentation under the basic reaction condi-tions required for removing benzoate.

Thus, preparation of the A─ ring fragment via an organo-catalytic reaction was challenging. However, we expected that the tertiary hydroxy group could be introduced enantioselec-tively by the organocatalytic reaction because the tertiary hydroxy group is adjacent to the germinal dimethyl group. That is, (E)─ enamine 25─ I would be preferentially formed from 23─ I with (R)─ proline (Scheme 5) owing to the steric strain between the organocatalyst and the quaternary carbon atom; therefore, high enantioselectivity was expected.

Aldehyde 23─ I was prepared in 67% yield by the reaction of known compound 26─ I with methoxymethylidene triphe-nylphosphorane and susequent one─ pot acid hydrolysis (Scheme 6). The reaction of 23─ I with nitrosobenzene (3.0 equiv) in the presence of 10 mol % of (R)─ proline in DMSO at room temperature for 48 h afforded a mixture of 27─ I and 24─ I (entry 1, Table 4). An extended reaction time did not improve the yield. The mixture of products was treated with NaBH 4 in a one─ pot manner to give 28─ I in 11% yield (2 steps). The ee of the product was 52%, as determined by HPLC analysis of the corresponding acetonide 21─ I. The use of 30 mol % of (R)─ proline improved the yield and ee to 45% and 86%, respectively (entry 2), but the yield was not further improved by an extended reaction time. The use of 100 mol % of (R)─ proline did not increase the yield and ee (entry 3), and the addition of another 30 mol % of (R)─ proline after 24 h reduced the yield (entry 4). Reaction at 50 ℃ improved the yield slightly, but reduced the ee (entry 5). Use of the additive (1─ (2─ (dimethyl-amino)ethyl)─ 3─ phenylurea), 35 which was reported to increase the rate of proline─ catalyzed α ─ aminoxylations, was also inef-fective (entry 6). The reaction was also tested in a variety of solvents; however, no improvement was observed (entries 7─ 16).

Scheme 4.　Synthetic approach to 24─ I via organocatalysis.

Scheme 5.　Presumed structure of (E)─ enamine 25─ I.

Scheme 6.　Preparation of 23─ I.

Table 4.　 (R)─ Proline─ catalyzed α ─ aminoxylation of 23─ I with nitrosobenzene.

Vol.75 No.11 2017 （ 19 ） 1105

The asymmetric α ─ aminoxylation of 23─ I was further examined with other organocatalysts (Table 5). The reactions with 29 36a and 30 36b afforded the desired products, but the yield and ee were low (entries 1 and 2). The reaction with 31, 36a,37 the acidity of which in a polar solvent is comparable to that of carboxylic acid, and subsequent reduction afforded 28─ I in 53% yield with 85% ee (entry 3). Although the ee was almost the same as that in entry 2 of Table 4, the yield was improved from 45%. The reaction catalyzed by 32 38 afforded the product ent─ 21─ I with 94% ee, but the yield was only 28%. Interest-ingly, the reactions in the presence of 30 mol % of 33, 39a 34, 39b 35, 39c and 36 36a gave no products (Figure 2).

Considering both the yield and ee of 28─ I, the conditions in entry 3 of Table 5 could be utilized for the preparation of the A─ ring fragment because compound 28─ I would be con-verted to 14─ I, which is crystalline and its ee can be improved by recrystallization. 23

Moreover, compound 26─ I (Scheme 6) was prepared from commercially available compounds in �ve steps; 40 therefore, the number of synthetic steps required for the preparation of the A─ ring fragment 14─ I was reduced to ten steps. However, the yield of the organocatalyzed α ─ aminoxylation of 23─ I with nitrosobenzene is unsatisfactory. Hence, we explored another possibile short preparation of the A─ ring fragment

14─ I.3.3　 Enantioselective Preparation of the A─ Ring Fragment via

the Sharpless Asymmetric Dihydroxylation (SAD) 29

Considering the structures of 24─ I and 28─ I, we envisioned an alternative approach to the A─ ring fragment via Sharpless asymmetric dihydroxylation (SAD). Thus, 24─ I and 28─ I were expected to be prepared via SAD of the corresponding alkenes. SAD of 37─ I was examined �rst because it was easily prepared from 26─ I by a Wittig reaction (Ph 3P=CH 2, THF, re�ux, 83%).

SAD of 37─ I with a catalytic amount of (DHQ) 2PHAL and K 2OsO 2·2H 2O afforded 28─ I in 83% yield (Scheme 7), but the ee was low (45% ee). Use of DHQ─ PHN as the ligand improved the ee; however, the obtained 76% ee was still unsat-isfactory.

Therefore, we decided to examine the SAD of the silyl enol ether of 23─ I, which was expected to give good results, because the highly enantioselective SAD of a similar compound has been reported by Kuwajima and co─ workers. 41 In addition, we examined the SAD of the silyl enol ether of 23─ Br which was prepared by the Diels─ Alder reaction of commercially avail-able 38 and acryloyl chloride to afford 39 42 and subsequent reactions via compound 40 (Scheme 7).

TIPS enol ethers 41─ I and 41─ Br were prepared from 23─ I and 23─ Br as single (E)─ isomers, respectively. SAD of 41─ I using a catalytic amount of (DHQ) 2PHAL (Figure 3) and K 2OsO 2·2H 2O under the conditions given in Table 6 afforded 24─ I in 86% yield and with 24% ee (entry 1, Table 6). The use of an increased amount of (DHQ) 2PHAL (10.0 mol %) did not improve the ee (entry 2), and reaction at 0 ℃ reduced the yield (entry 3).

As the use of (DHQ) 2PHAL resulted in a low ee, the reac-tions was surveyed with other ligands. SAD of 41─ I using (DHQ) 2PHAL afforded 24─ I in 71% yield with 85% ee (entry 4), and with DHQ─ PHN the yield and ee were slightly improved (entry 5). The reaction with a lightly increased amount of DHQ─ PHN (15.0 mol %) and K 2OsO 2·2H 2O (5.0 mol %) gave 24─ I with 91% ee, but the yield was only 64% (entry 6).

The SAD of 41─ Br was also examined with DHQ─ PHN

Table 5.　 α ─ Aminoxylation of 23─ I with nitrosobenzene with other catalysts.

Figure 2.　Structures of 33─ 36.

Scheme 7.　The SAD of 37─ I.

Scheme 8.　Preparation of 23─ Br.


(15.0 mol %) and K 2OsO 2·2H 2O (5.0 mol %). The reaction was complete after 20 h and afforded 24─ Br in 78% yield with 88% ee (entry 7). Finally, the reaction with DHQ─ PHN (10.0 mol %) and K 2OsO 2·2H 2O (5.0 mol %) afforded 24─ Br in 92% yield and with 91% ee (entry 8), this result was reproduc-ible in a gram─ scale reaction.

Direct conversion of 24─ Br to 14─ Br failed, owing to the decomposition via allene formation. Hence, compound 24─ Br was subjected to benzylidene formation to afford compound 42 (Scheme 9), followed by regioselective cleavage of the ben-zylidene acetal by DIBAL─ H and subsequent Dess─ Martin oxidation to give 14─ Br, which was crystalline; the enantio-merically pure compound was obtained through recrystalliza-

tion.Compound 14─ Br was prepared from 38 in seven steps.

Hence, the preparation of 14─ Br via SAD was shortest prepa-ration of our A─ ring fragment.

4． Enantioselective Preparation of the C─ Ring Fragment Utilizing a Chiral Building Block 15

We planned to carry out the coupling of the A─ and C─ ring fragments between the C2 and C3 positions of taxol, so that the coupling has to include stereoselective formation of the C2 and C3 stereogenic centers. Hence, the stereoselective coupling reaction was surveyed with model compounds. How-ever, the aldol reaction of 43 and reactions of 43 with allylic metal compounds, which are potent coupling reactions (Scheme 10), did not proceed, probably owing to the steric hindrance.

Hence, we decided to select 16 as the C─ ring fragment, which was to be used for the addition reaction with compound 14 to afford 44 (Scheme 11), and the C3 stereogenic center would be formed after the coupling. We have previously reported the preparation of 46 by the enantio─ and diastere-oselective reduction of 45 using Baker’s yeast (Scheme 12). 43 Compound 46 possesses two stereogenic centers which have the same con�gurations as those of the C─ ring fragment 16. Accordingly, transformation of 46 into 16 was examined.

The transformation of 46 to 16 is shown in Scheme 13. The benzyl group of 46 was removed by hydrogenolysis, followed by benzylidene formation to afford 47. Barton’s protocol 28 was employed for the transformation of 47 into the iodide 48.

Scheme 10.　 Attempted aldol reaction and Nozaki─ Hiyama type reaction.

Scheme 11.　Structure of 16 and coupling reaction with 14.

Scheme 12.　 Preparation of β ─ hydroxyketone 46 by Baker’s yeast reduction of 45. 43

Figure 3.　Structures of (DHQ) 2·PHAL, Q·PHN, and DHQ·PHN.

Table 6.　Sharpless asymmetric dihydroxylation (SAD) of 41.

Scheme 9.　Transformation of 24─ Br to 14─ Br.

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Thus, 47 was �rst converted to the corresponding hydrazone, followed by the treatment with iodine and DBU to afford iodoalkene 48. The reductive cleavage of the benzylidene with DIBAL─ H and subsequent Dess─ Martin oxidation afforded the aldehyde. A subsequent Wittig reaction to obtain 16 was low─ yielding, but Takai’s protocol successfully afforded 16 in high yield.

5． Coupling of the A─ and C─ Ring Fragments and Construction of the C3 Stereogenic Center via a 1,5─ Hydride Shift and Benzylidene Formation Cascade

After preparation of the C─ ring fragment, the coupling of the A─ and C─ ring fragments was executed (Scheme 14). Treat-ment of the C─ ring fragment 16 with n ─ butyllithium to gene-rate the corresponding alkenyllithium and subsequent reaction with the A─ ring fragment 14─ I afforded 49 as a single isomer. The con�guration of 49 was determined as shown in Scheme 13 by X─ ray crystallographic analysis; the results indicated that the reaction took place at the Si ─ face of the aldehyde which can be well explained by the chelation model.

Although the construction of the C3 stereogenic center was a problem, we carried out the intramolecular B ─ alkyl Suzuki─ Miyaura coupling reaction of 50, which was prepared by benzylation of 49, to evaluate its ef�ciency. The reaction of 50 was performed under the optimized conditions in Table 3 to afford the product 51 in 87% yield, which con�rmed the effec-tiveness of the palladium─ catalyzed ring─ closing reaction.

Although 51 was successfully formed, the stereoselective construction of the C3 stereogenic center was dif�cult to achieve after B─ ring formation because the delivery of a hydrogen atom was required from the inside of the cage─ like taxane scaffold. Indeed, only one example can be found, in the

Kuwajima group’s total synthesis, which succeeded in the stere-oselective protonation of the enol at the C3 position by the C13 hydroxyl group. 11

Hence, we decided to construct the C3 stereogenic center prior to forming the B─ ring. Because the iodoalkene in the A─ ring moiety of 49 is sensitive to the reaction conditions involv-ing radical, transition metal, and hydrides, suitable methods for constructing the C3 stereogenic center were limited. We envisioned that regioselective reduction of the C3─ C4 epoxide at the C3 position could generate the desired C3 stereogenic center. The regioselectivity of the reduction of the epoxide depends on the reaction conditions; i.e., the hydride reduction could occur at the more substituted side of the epoxide with inversion of the con�guration under selected conditions. How-ever, the C3─ C4 epoxide must have a suitable con�guration to generate the C3 stereogenic center by reduction with inversion.

The desired C3─ C4 epoxide was expected to be formed by an epoxidation directed by the C2 hydroxy group. Indeed, the epoxidation of 49 with VO(acac) 2 and TBHP 44 afforded epox-ide 52 as the single isomer (Scheme 15). The yield was improved to 94% by the use of less acidic VO(OEt) 3.

45 The stereoselectiv-ity is well explained by allylic hydroxy group─ directed epoxida-tion, as depicted in Scheme 15. Thus, the favored transition state would lead to the formation of 52, and the other transi-tion state would be unfavorable owing to severe steric strain.

Thus, prepared epoxide 52 was subjected to reaction condi-tions that induce the reduction of epoxides on the more substi-tuted side, such as Red─ Al, ZnBH 4, or LiAlH 4/AlCl 3, but none of the desired product 53 (Scheme 16) was formed. After sev-eral attempts, the reaction of epoxide 52 with NaBH 3CN 46 in the presence of BF 3·OEt 2 afforded a product which was differ-ent from 53. Detailed NMR studies revealed that the product included a benzylidene group; hence, the product was proposed to be compound 54.

Scheme 13.　Transformation of 46 to 16.

Scheme 14.　 Assembly of the A─ and C─ ring fragments and the Suzuki─ Miyaura coupling reaction of 50.

Scheme 15.　Highly diastereoselective epoxidation of 49.

Scheme 16.　The product of the attempted reduction of epoxide 52.


The mechanism of this reaction can be explained as shown in Scheme 17. First, BF 3·OEt 2 coordinated to epoxide 52, which activated the epoxide to induce a 1,5─ hydride shift from the proximal benzylic hydrogen atom of the C1 benzyl ether to the C3 position; i.e., a hydride derived from the C1 benzyl ether attacked the epoxide at the backside of the C3 position. Finally, the benzylidene was formed by the generated benzylic cation with the C2 hydroxy group. The ring─ contracted 55 was also formed in this reaction, which suggests that the coordina-tion of BF 3·OEt 2 to the epoxide generated the carbocation in part, which underwent rearrangement to generate 55. It should be noted that both 54 and 55 were formed as the only isomers, indicating that the rearrangement proceeded in a highly stereo-selective manner.

The oxidation state of 54 was the same as that of 52, which indicated that the reaction proceeded without the action of the reducing agent, NaBH 3CN. Hence, we optimized the reaction conditions of the rearrangement in the absence of NaBH 3CN. First, we examined the solvent and carried out the reaction of 52 at a concentration of 0.016 M to suppress the intermolecu-lar side─ reaction. The reaction in CH 2Cl 2 resulted in decompo-sition of the substrate (Table 7, entry 1). The reactions in Et 2O (entry 2) or cyclopentyl methyl ether (CPME) (entry 3) were low─ yielding, but the reaction in THF afforded 54 and 55 in 61% and 39%, respectively (entry 4). More polar solvents were also screened, but the substrate decomposed in DME (entry 5) or MeCN (entry 6), and 55 was the major product when DMF was used (entry 7). The solvent studies indicated that polar solvents accelerate the formation of the carbocation which undergoes the ring─ contraction and less polar solvents result in the decomposition of the substrate or products, probably because the solvents are less basic and less able to reduce the acidity of BF 3·OEt 2.

Because THF was the most suitable solvent, the use of additives, concentration of the substrate, and use of other acid catalysts were surveyed. Molecular sieves (4 Å, MS 4A) was used to remove trace amounts of water (entry 8), but the yield was decreased. A change in the concentration of the substrate between 0.016 M and 0.033 M did not change the yield (entry 9), and concentrations above 0.033 M (entries 10─ 12) resulted in decreased yields of 54. The amount of BF 3·OEt 2 was also examined, and the use of 8 equivalents was optimal (entries 13─ 15). Use of a lower amount of BF 3·OEt 2 resulted in incomplete conversion, and use of a greater amount caused decomposition of the substrate and products.

To improve the yield, we also examined the rearrangement of 56 bearing a p ─ methylbenzyl ether at the C1 position, which was intended to increase the stability of the benzylic cation (Scheme 18). The corresponding p ─ methoxybenzyl ether was very dif�cult to prepare because of its acid─ sensitive nature. The reaction of 56 was performed under the optimized reac-tion conditions given in Table 7, but the yield of 57 was 49%. The primary reason for the low yield is the acid sensitivity of the substrate and products. Indeed, deprotected products were isolated. Accordingly, the most suitable C1 protecting group was found to be benzyl ether.

6． Construction of the Taxane Scaffold by the B ─ Alkyl Suzuki─ Miyaura Coupling Reaction

Having successfully constructed the C3 stereogenic center by the rearrangement involving the 1,5─ hydrogen shift, we next examined the formation of the B─ ring moiety by the B ─ alkyl Suzuki─ Miyaura coupling reaction. To avoid side─ reactions in the coupling reaction, we used 58, the TES ether of 54, as the substrate.

Compound 58 was subjected to the reaction conditions that had been optimized in the B ─ alkyl Suzuki─ Miyaura cou-pling reaction of the model substrate, but the hydroboration of 58 was sluggish and accompanied by decomposition of the

Scheme 17.　 Proposed mechanism of the reaction of 52 with BF 3·OEt 2.

Scheme 18.　 The 1,5─ hydride shift and benzylidene formation cascade from 56.

Table 7.　 The 1,5─ hydride shift and benzylidene formation cascade from 52.

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substrate. The subsequent B ─ alkyl Suzuki─ Miyaura coupling reaction afforded the product in 35% yield, with 4% of the inseparable de─ iodonated compound 60 (Table 8, entry 1), which could be formed via β ─ elimination of the nine─ mem-bered palladacycle intermediate or protonation of the gene-rated palladium complex.

To accelerate the hydroboration, CPME, which is less polar and has a higher boiling point than THF, was used as the sol-vent and the reaction was carried out at re�ux temperature (entry 2). As a result, the reaction was complete after 12 h and afforded the product in 62% yield, but the side─ product 60 was formed in 7% yield.

The B ─ alkyl Suzuki─ Miyaura coupling reaction was car-ried out without changing the solvent to afford 59 in 51% yield and the yield of 60 was reduced to 2% (entry 3).

We speculated that a higher boiling point of the solvent could reduce the formation of 60, because the use of CPME decreased the yield of 60 relative to that with MeCN. In addi-tion, MeCN has been successfully used for the B ─ alkyl Suzuki─ Miyaura coupling reaction that forms eight─ membered rings in our studies. Hence, we examined the reaction with EtCN and n ─ BuCN, which have higher boiling points than MeCN. As the result, the yield was improved in both cases, with the formation of 60 suppressed. It should be noted that formation of 60 was minimized by the use of EtCN (entry 4) or n ─ BuCN (entry 5), but the same effect on reducing the formation of 60 was observed when the reaction was performed in n ─ BuCN at 80 ℃ (entry 6), which has the same boiling pont as that of MeCN, this indicates that the solvent effect would be the major factor for reducing the formation of 60.

The product 59 was treated with TBAF to afford com-pound 61, which was formed into a single crystal suitable for X─ ray crystallographic analysis. The complete structure of 61 was con�rmed as shown in Figure 4.

As described above, we have successfully constructed the taxane scaffold in 71% yield by the B ─ alkyl Suzuki─ Miyaura coupling reaction. The coupling reaction was easily carried out, even in a large scale, and reproducibly afforded the prod-uct on a multigram scale.

Unfortunately, the introduction of the oxygen atoms on the B─ ring of 59 was found to be dif�cult, despite of our exten-

sive efforts; hence, the oxygen atoms should be introduced on the B─ ring prior to the formation of the B─ ring. 47

We also examined the intramolecular B ─ alkyl Suzuki─ Miyaura coupling reaction of 62, but the major product was less─ strained 63, which was presumed to be formed via head─ tail coupling (Scheme 19). 48

Thus, we reached a dead─ lock in the approach to taxol via the B ─ alkyl Suzuki─ Miyaura coupling reaction; however, we were convinced that the palladium─ catalyzed cyclization would be a powerful method for constructing the eight─ membered ring and continued to research an effective formation of the taxane scaffold by the palladium─ catalyzed reaction.

7． Construction of the Eight─ Membered Ring by Palladium─ Catalyzed Alkenylation of a Methyl Ketone 49

As the iodoalkene of the A─ ring underwent oxidative addi-tion of palladium, we believed that the palladium─ catalyzed coupling reaction would be a potent method for forming the taxane scaffold. Hence, our attention was next focused on the formation of the eight─ membered ring by the palladium─ cata-

lyzed alkenylation of a methyl ketone.Historically, alkenylation and arylation 50 of

enolates has been dif�cult to achieve. However, in 1997, the groups of Miura, Buchwald, and Hartwig independently reported the palladium─ catalyzed intermolecular arylation of ketones, 51 which was followed by the development of the alkenylation of ketones, its intramolecular vari-ant, 52 and its application to natural product syn-thesis. 53 However, the yield of the palladium─ cata-lyzed alkenylation of ketones was not very high, and no report on palladium─ catalyzed eight─ membered ring formation by intramolecular alke-nylation could be found.

Hence, we �rst examined the intramolecular alkenylation of methyl ketone 64 (Scheme 20) to evaluate its feasibility for forming the eight─ mem-bered ring. With the Solé group’s reaction condi-tions, the reaction was carried out by using 30 mol % of Pd(PPh 3) 4 and 3.0 equivalent of t ─

Scheme 19.　 Attempted intramolecular Suzuki─ Miyaura coupling reaction of 62.


Figure 4.　X─ ray crystallographic structure of 61.


BuOK in THF to afford 65 in 58% yield. A certain amount of de─ iodinated compound of 64 was formed, too. However, the reaction in toluene increased the yield to 82%. When CsCO 3 was used as base, the yield was 91%.

In the palladium─ catalyzed reaction of enolate with alke-nylhalide, it has been proposed that oxidative addition of Pd(0) to alkenylhalide takes place, which is followed by ligand exchange with the enolate and, �nally, reductive elimination to afford the α ─ alkenylated ketone. In this reaction, PhOK has been reported to stabilize the intermediate L nPdOPh and also accelerate the enolization of the ketone. 54 Hence, the reaction with PhOK was performed, and as a result, the yield was improved to 96%.

Reactions with a variety of ligands did not improve the yield, and no reaction was observed when Pd/C was used as the catalyst. These results indicate that the use of the ligand is necessary in this reaction.

The high yield of the alkenylation would be explained by the facts that the two reaction points were proximal, which is attributed to the Thorpe─ Ingold effect, and that only one eno-late is formed from the methyl ketone. In addition, the stability of the palladium complex or palladium enolate of ketones is also important for the high yield, because those of ketones are generally unstable intermediates, except those of methyl ketones.

As described above, we have found an ef�cient method for constructing eight─ membered rings by palladium─ catalyzed alkenylation. To the best of our knowledge, this is the �rst example of construction of eight─ membered rings by the pal-ladium─ catalyzed alkenylation of a methyl ketone.

8． Formal Total Synthesis of (-)─ Taxol via Palladium─ Catalyzed Alkenylation of a Methyl Ketone 13

We applied the palladium─ catalyzed alkenylation of a methyl ketone to the total synthesis of taxol. Two fragments, the A─ ring fragment 14─ I and the C─ ring fragment 66, were assembled to afford 67─ I as a single isomer via a halogen lith-ium exchange reaction (Scheme 21). Subsequent epoxidation by using TBHP and VO(OEt) 3 exclusively afforded 68─ I. Treat-ment of 68─ I with BF 3·OEt 2 induced the stereoselective 1,5─ hydride shift and benzylidene formation cascade.

This cascade reaction was found in the synthesis of com-pound 53, but the same reaction proceeded without a problem although the substrate and products included an acid─ sensitive ethoxyethyl group. Because the ethoxyethyl group was partly removed under the acidic conditions, the products were treated with hydrochloric acid to obtain 69─ I (61%, 2 steps). Com-pound 69─ I was converted to methyl ketone 70─ I by selective oxidation of the primary hydroxyl group, TES ether formation of the secondary hydroxyl group, reaction of the aldehyde with MeMgI, and Dess─ Martin oxidation of the resultant alcohol.

Methyl ketone 70─ I was subjected to the palladium─ cata-lyzed alkenylation to afford product 71 in 97% yield (Scheme 22). We also con�rmed that compound 70─ Br, which was prepared from 14─ Br (Scheme 21), could be used as an alternative substrate for the palladium catalyzed alkenylation, and the cyclized product 71 was formed in 89% yield.

In comparison with the yields of other methods for con-structing the B─ ring of taxol, 97% yield is exceptionally high yield. Considering that nearly twenty steps are required to achieve the total synthesis of taxol after the construction of the taxane scaffold, an ef�cient ring─ closing method would be a relief in supplying a requisite amount of the key synthetic intermediate.

Moreover, although the taxane scaffold was successfully constructed, the synthetic approach to taxol thereafter was limited owing to the speci�c taxane ring system, i.e., one can easily be caught in a trap leading to the deadlocks that are hid-den everywhere in the approach toward taxol.

Thus, construction of the eight─ membered ring is just one of the problems in the total synthesis of taxol, although it may be the largest problem, and the other problems that remain to be solved still make the total synthesis of taxol dif�cult.

For example, the C10 hydroxy group can only be intro-duced to limited compounds owing to the speci�c structure of taxol, and moreover, the C10 con�guration must be epimerized when the C10 hydroxy group is introduced by oxidation of the enolate of the C9 ketone. Kuwajima et al. successfully obtained compound 78 by the epimerization of compound 77

Scheme 20.　 Formation of the eight─ membered ring by the palladium─ catalyzed alkenylation of methyl ketone 64.

Scheme 21.　 Preparation of the methyl ketone for the palladium─ catalyzed alkenylation.

Vol.75 No.11 2017 （ 25 ） 1111

(Scheme 23). However, the structurally related compound 79 prepared by us did not undergo epimerization under the same reaction conditions, and 80 was not formed. The reaction, which was carried out in the presence of D 2O, did not result in any incorporation of deuterium to 79, which indicates that the enolate of 79 was not generated. Thus, the structural differ-ences between 77 and 79 are seemingly small, but the com-pound’s properties are very different.

For another example, the C4 hydroxy group resists acetyla-tion in many synthetic intermediates and derivatives of taxol, and the acetylation is only possible in the reaction of limited compounds. Indeed, after extensive studies, we found that acetylation and epimerization were possible when compound 74, which was prepared from compound 71 by the removal of

the TES group, Dess─ Martin oxidation, and Takai methylena-tion to afford 72 and then conversion via intermediate 73 based on the reported reaction conditions, 7 was used to introduce the C10 hydroxy group.

In the hydrogenolysis of benzyl or benzylidene groups of intermediates or derivatives of taxol that bear the oxetane group, it has been reported that the liberated C2 hydroxy group attacks the proximal oxetane to form a tetrahydrofuran ring. We surmised that this side─ reaction would be caused by impu-rities included in the palladium catalyst. As most palladium catalysts for hydrogenation are prepared from PdCl 2, acidic impurities including Pd(II) could activate the oxetane during the hydrogenolysis. Hence, we surveyed the hydrogenolysis in the presence of base, and use of alumina as additive was found to be effective for suppressing the side─ reaction. After exten-sive studies, this problem was solved by conducting the hydro-genolysis using Pd(OH) 2/C in the presence of alumina in CPME at -5 ℃ and the desired product from 75 without forming the tetrahydrofuran ring.

Finally, formation of the cyclic carbonate at the C1 and C2 diol and the C7 TES ether afforded the Nicolaou group’s syn-thetic intermediate 76, therby accomplishing the formal total synthesis of (-)─ taxol.

We also found that compound 75 could be converted into another synthetic intermediate of Nicolaou group, 81, in 3 steps (Scheme 24). Thus, Ru─ catalyzed oxidation, which was reported to be used for allylic oxidation, 55 was found to convert the C1─ C2 benzylidene moiety of 75 into the C2 benzoate.

The ruthenium─ catalyzed reaction afforded only the C2 benzoate because the C1 benzoate was probably dif�cult to form owing to steric strain. Allylic oxidation at the C13 posi-tion was not observed in the ruthenium─ catalyzed reaction. There was no reaction of 75 with KBrO 3/Na 2S 2O 3,

56a,b and the reaction with Ph 3CBF 4

56c caused ring opening of the oxetane. Subsequent removal of the benzyl group and formation of a TES ether afforded compound 81.

9． Conclusion

In conclusion, the problem in forming the eight─ membered ring in the total synthesis of taxol was solved by using the pal-ladium─ catalyzed intramolecular alkenylation of a methyl ketone. This palladium─ catalyzed reaction afforded the cyclized product in an excellent yield (97%), allowing an ef�-cient formal total synthesis of (-)─ taxol by a convergent approach. To the best of our knowledge, this is the �rst exam-ple of a palladium─ catalyzed intramolecular alkenylation that is used for the formation of an eight─ membered carbocyclic ring in natural product synthesis. During the preparation of a substrate for the palladium─ catalyzed reaction, a rearrange-ment of an epoxy benzyl ether including a 1,5─ hydride shift, generating the C3 stereogenic center and subsequently forming

Scheme 23.　 Difference of epimerization between Kuwajima’s 77 and our 79.

Scheme 24.　 Transformation of 75 to Nicolaou’s advenced synthetic intermediate 81.

Scheme 22.　 The palladium─ catalyzed alkenylation and formal total synthesis of (-)─ taxol.


the C1─ C2 benzylidene, was discovered and contributed to the concise synthesis of (-)─ taxol. The number of linear steps via 81 from a commercially available compound to taxol was 37 when 14─ Br was used, although some steps require optimiza-tion to improve the overall yield. 57 The number of linear steps, 37, is one of the shortest syntheses of (-)─ taxol; however, the overall yield (0.22%) needs improvement. In our synthesis, the number of linear steps from a commercially available com-pound to (-)─ taxol via compound 76 was 42 with 0.75% over-all yield when 14─ I was used and 38 with 0.31% overall yield when 14─ Br was used.

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PROFILE

Masayuki Utsugi received his B.S. (2003), M.S. (2005), and Ph.D. (2008) degrees from Waseda University under the supervision of Prof. Masahisa Nakada. During his Ph.D. course, he was appointed Assistant Professor (2006─ 2008) and worked with Prof. Masahisa Nakada. In 2008, he joined Mitsubishi Tanabe Pharma Co., Ltd. where he is cur-rently a researcher. He won the Japanese So-ciety of Process Chemistry Award for Excel-lence (2012). His current research interests are in the areas of medicinal chemistry and process chemistry.

Mitsuhiro Iwamoto received his B.S. (2000), M.S. (2002), and Ph.D. (2005) degrees from Waseda University under the supervision of Prof. Masahisa Nakada. During his Ph.D. course, he was appointed Assistant Professor (2004─ 2005) and worked with Prof. Masahisa Nakada. In 2005, he joined Sankyo Co., Ltd. and in 2007, joined Daiichi Sankyo Co., Ltd. where he is currently a researcher. His current research interests are in the areas of medici-nal chemistry.

Sho Hirai received his B.S. (2008), M.S. (2010), and Ph.D. (2013) degrees from Wase-da University under the supervision of Prof. Masahisa Nakada. During his Ph.D. course, he was appointed Assistant Professor (2012─ 2013) and worked with Prof. Masahisa Nakada. In 2013, he joined Nippon Shinyaku Co., Ltd. where he is currently a researcher. His current research interests are in the areas of medicinal chemistry.

Hatsuo Kawada received his B.S. (2003) and M.S. (2005) degrees from Waseda University under the supervision of Prof. Masahisa Nakada. In 2005, he joined Chugai Pharma Co., Ltd. where he is currently a researcher. He received his Ph.D. (2017) from Tohoku University. His current research interests are in the areas of medicinal chemistry and pro-cess chemistry.

Masahisa Nakada received his B.S. (1982), M.S. (1984), and Ph.D. degrees (under the supervision of Prof. Masaji Ohno) from The University of Tokyo, and was appointed As-sistant Professor during his Ph.D. course in 1987. He joined Prof. Shibasaki’s group in 1991 and spent one year and four months from the beginning of FY1992 as a postdoc-toral fellow with Prof. K. C. Nicolaou at The Scripps Research Institute. In 1995, he was promoted to Associate Professor of Depart-ment of Chemistry at Waseda University, and has been Professor since FY2000. In 1997, he received the Pharmaceutical Society of Japan Award for Young Scientists. His re-search interests include total synthesis of bioactive natural products, asymmetric catal-ysis, new synthetic reactions, and chemical biology.


Documents

Formal Total Synthesis of ( Taxol