Convergent Synthesis of Taxol Skeleton via Decarbonylative Radical

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Convergent Synthesis of Taxol Skeleton via Decarbonylative Radical Coupling Reaction Hiroaki Matoba, Takahiro Watanabe, Masanori Nagatomo, and Masayuki Inoue* Graduate School of Pharmaceutical Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

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ABSTRACT: The highly oxygenated 6/8/6-membered ABC-ring 2 of taxol was assembled in a convergent fashion. A decarbonylative radical reaction between α-alkoxyacyl telluride 4 and cyanocyclohexenone 5 linked the A- and C-rings and stereoselectively installed the C2- and C3-tertiary carbon centers of 3. After the C8-quaternary stereocenter was constructed, the C9-methyl ketone and the C11-vinyl triflate of 30 participated in Pd(0)-promoted cyclization of the eight-membered B-ring, giving rise to the taxol skeleton 2.

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terpenoids.8 As part of our continued interest in exploring αalkoxy radicals, we decided to devise a new convergent strategy for assembling taxane diterpenoids. To do so, we selected 2 as the initial synthetic target. Taxol skeleton 2 was designed to have the four oxygen functional groups (C1, 2, 7, and 9) and the two quaternary carbons (C8 and 15) of 1 and possess the exo-olefin (C4) as a handle for D-ring construction. Herein, we report the development of a radical-based approach for constructing this advanced model compound of 1. A convergent strategy for 2 was planned based on decarbonylative radical coupling reactions of α-alkoxyacyl tellurides, which were previously reported by our group (Scheme 1).9 Thus, highly oxidized 6/8/6-tricyclic structure 2 was retrosynthetically dissected into the six-membered A-ring 4 and C-ring 5. The αalkoxyacyl telluride moiety of 4 would function as a precursor of the key α-alkoxy C2-radical, while the electron-deficient C3double bond of 5 would serve as an acceptor of the radical. We envisioned that the C2 and C3 positions of adduct 3 would be stereocontrolled by the intrinsic three-dimensional structures of the radical and its acceptor. The C15-geminal dimethyl group and the C20-methylene bridge were expected to block the undesired approaches of the reactants to achieve the desired C2,3-stereoselectivity upon coupling. After the C8-quaternary center and the C4-exo-olefin were built from 3, the eightmembered B-ring of 2 was to be cyclized at the C10,11-positions by the action of a palladium reagent.5i A-ring 4 and C-ring 5 were readily prepared from starting materials 6 and 13 in seven and five steps, respectively (Scheme 2). Commercially available diketone 6 with the C15-quaternary carbon was olefinated using the combination of NaH and

axol (1, Scheme 1) belongs to a taxane diterpenoid family1,2 and is clinically utilized as an anticancer agent.3 The 6/8/6-

Scheme 1. Structure of Taxol (1) and Synthetic Plan for Taxol Skeleton 2

membered carbon skeleton (ABC-ring) of 1 with a bridgehead olefin and two quaternary carbons are substituted by nine oxygen functional groups, two of which form an oxetane ring (D-ring). As the highly oxygenated and intricately fused tricarbocyclic structure of 1 poses formidable synthetic challenges, the efficient construction of 1 has been actively sought by synthetic chemists for several decades.4 These efforts have resulted in the development of numerous creative strategies for its assembly and have culminated in seven total syntheses and three formal syntheses of 1.5 Carbon radical reactions enable chemoselective formation of sterically hindered carbon−carbon (C−C) bonds in the presence of preexisting oxygen functionalities.6,7 We have recently demonstrated the high versatility of the α-alkoxy radical species for linking oxygenated substructures of architecturally complex © XXXX American Chemical Society

Received: October 16, 2018

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DOI: 10.1021/acs.orglett.8b03302 Org. Lett. XXXX, XXX, XXX−XXX

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diastereomeric mixture. Compound 11 was subjected to an aqueous LiOH solution to simultaneously attain ester hydrolysis and C12-epimerization, yielding carboxylic acid 12 as a single isomer. The thus-obtained 12 was converted into α-alkoxyacyl telluride 4 via a one-pot procedure: formation of the activated ester with i-BuOCOCl and N-methylmorpholine (NMM) and subsequent replacement of the i-BuOCO2 group with a TePh group using NaBH4 and (PhTe)2.9 Synthesis of C-ring 5 started with an α-bromination reaction of enantioenriched enone 13 (90% ee) (Scheme 2).13 A reagent system of TMSCl and LiN(TMS)2 realized site-selective deprotonation at C6 over C4 and formation of the TMS enol ether, which was in situ treated with N-bromosuccinimide (NBS) in THF to furnish C6-bromide 14. Removal of the TBS group using aqueous HF and subsequent ether ring formation from primary alcohol 15 with n-Bu4NI and Ag2O gave rise to bicycle 16. Then the α-position of α,β-enone 16 was iodinated by employing I2 and N,N-dimethyl-4-aminopyridine (DMAP) to afford 17. The C8-iodide of 17 was exchanged with the C8cyanide of 5 using CuCN,14 and the obtained product was recrystallized to afford cyanocyclohexenone 5 in 98% ee. Next, a radical coupling reaction between A-ring 4 and C-ring 5 was realized under mild conditions (Scheme 3). Treatment of 4 and 5 (1.5 equiv) with Et3B (3.5 equiv) and O2 (1 equiv) in benzene (0.1 M) at room temperature resulted in the formation of adduct 3. The enolizable C7-carbonyl group of C7,11diketone 3 was regioselectively converted into the TBS-enol ether with TBSCl and Et3N, generating 18 in 48% yield in two steps. Remarkably, the intermolecular radical addition reaction connected the sterically cumbersome C2−C3 bond in a stereoselective fashion. Notably, the LUMO level of radical acceptor 5 had to be lowered by the two electron-withdrawing groups (CO and CN) to ensure successful coupling. Namely, the same reaction conditions did not couple 4 and 16 (the des-C19-cyanide version of 5), despite the sterically lesshindered character of the olefin (Scheme S1).15 A proposed mechanism of the key radical reaction is illustrated in Scheme 4.9 An ethyl radical generated from Et3B and O216

Scheme 2. Synthesis of A- and C-Rings

(EtO)2P(O)CH2CO2Et to generate α,β-unsaturated ester 7. (DHQ)2PHAL-assisted asymmetric dihydroxylation of 7 was performed in the presence of phenyl boronic acid, leading to optically pure boronic ester 8 (>99% ee) after recrystallization.10 Treatment of 8 with aqueous KHF2 solution in turn cleaved the phenyl boronic ester to provide C1,2-vicinal diol 9.11 After diol 9 was protected as the methylene acetal using (MeO)2CH2 and P2O5,12 the C12-position of ketone 10 was methylated by the action of MeI and LiN(TMS)2, producing 11 as a 1.2:1 C12Scheme 3. Construction of the Taxane Skeleton

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DOI: 10.1021/acs.orglett.8b03302 Org. Lett. XXXX, XXX, XXX−XXX

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unfavorable contacts between the two atoms within the sum of the van der Waals radii, whereas TS-2S3R has one such disfavored interaction (indicated by the blue dotted line). By reflecting the three-dimensional structures of the two components, the three transition states TS-2R3R/2S3S/2R3S possess close interatom relationships at C16−H, C17−H, and/or C20− H, which would explain their higher energies in comparison with that of TS-2S3R. Therefore, these calculations corroborated that both the C16,17-methyl and C20-methylene groups functioned as the stereocontrolling elements in establishing the C2,3stereochemistry. Having realized the C2,3-stereoselective coupling reaction, the remaining tasks were the formation of the C8-quaternary carbon, the C4-methylene group, and the eight-membered B-ring (Scheme 3). First, Comins’ reagent D20 and KN(TMS)2 were applied to the C11-ketone of 18 to construct the C11-vinyltriflate of 19 as the handle for the last Pd(0)-promoted cyclization. nBu4NF converted TBS-enol ether 19 to C7-ketone 20. Treatment of 20 with SmI2 in turn chemoselectively induced reductive opening of the bridged ether ring,21 leading to primary alcohol 21 without reducing the potentially reactive C8cyanide.22 By taking advantage of the pKa difference between the C8−H and C20-OH, 21 was chemoselectively transformed into propargyl enol ether 22 using tosylate E and K2CO3. Then the primary hydroxy group of 22 was benzoylated to provide 23. When propargyl vinyl ether 23 was heated to 170 °C under microwave irradiation, [3,3]-sigmatropic rearrangement proceeded from the opposite face of the large C3-substituent to stereoselectively introduce the C8-quaternary carbon of allene 24.23,24 The last seven-step sequence completed the synthesis of the targeted 2 from 24. NaBH4 reduction of 24 in MeOH produced β-oriented C7-alcohol 25, which was treated with TESOTf and 2,6-lutidine to generate TES-ether 26. After chemoselective removal of the benzoyl group of 26 by allylmagnesium bromide,25 mesylation and subsequent substitution with benzeneselenolate converted alcohol 27 to selenide 29. The C9-ketone and C4-exo-olefin of 30 were then simultaneously built from 29. O3-oxidation of 29 at −78 °C chemoselectively cleaved the allene moiety in the presence of the C11-vinyl triflate, affording selenoxide. Olefin formation efficiently occurred by warming the reaction mixture with Et3N as a base and 1-hexene as a trapping agent of phenylselanol,26 leading to 30. Finally, the C11-vinyl triflate and the C9-methyl ketone of 30 were utilized for the C10−C11 bond formation. Upon subjecting 30 with Pd(PPh3)4 and PhOK at 100 °C in toluene,5i,27 the eightmembered B-ring was cyclized via enolization of methyl ketone 30, delivering the taxane skeleton 2. In summary, we developed a new radical-based strategy to construct the 6/8/6-membered carbon skeleton 2 of taxol (1) in 22 steps from diketone 6. Intermolecular radical addition of Aring 4 to C-ring 5 connected the C2- and C3-tertiary carbon centers in a completely stereoselective fashion, demonstrating the versatility of the present strategy for assembling the highly oxygenated carbon skeletons. DFT calculations confirmed that the C2,3-stereoselectivity is controlled by the three-dimensional shapes of both reactants. Then the [3,3]-sigmatropic rearrangement of the propargyl vinyl ether 23 installed the requisite C8quaternary carbon, and O3-oxidation of 29 resulted in the formation of the C9-methyl ketone and the C4-exo-olefin. The C11-vinyl triflate and the C9-methyl ketone of 30 participated in the Pd(0)-promoted cyclization of the eight-membered B-ring to produce the targeted 2, which possesses multiple reacting

Scheme 4. Proposed Mechanism of the Decarbonylative Radical Coupling Reaction

induces homolysis of the weak C−Te bond of 4 to form α-alkoxy acyl radical A. Rapid decarbonylation from A affords α-alkoxy radical B and loses the C2-stereochemical information.17 While one side of the C2-radical of B is sterically shielded by the proximal C16,17-methyl groups, the C20-methylene bridge of 5 defines the convex/concave faces. Accordingly, both nucleophilic radical B and electrophilic olefin 5 approach from their less hindered faces, thereby simultaneously introducing the requisite C2- and C3-stereogenic centers of C-2S3R. Finally, radical C2S3R is captured by Et3B to expel an ethyl radical and form the corresponding boron enolate, which is hydrolyzed by H2O to yield 3. To further rationalize the C2,3-stereoselectivity, we performed DFT calculations using the Gaussian 09 and Reaction Plus Pro programs (UM06-2X/6-31+G(d),18 298 K, 1 atm Scheme 5 and Scheme 5. Rationale for the C2,3-Stereoselectivitya,b

Values in parentheses are relative free energies: ΔG (kcal/mol), 298 K, 1 atm. bPink dotted lines indicate forming C−C bonds, and blue dotted lines indicate interatomic distances within the sum of the van der Waals radii [H−H (2.40 Å), H−O (2.72 Å), H−C (2.90 Å), and C−O (3.22 Å)]. a

Table S3).19 Thus, the energy levels of radical B and olefin 5, the four possible transition states TS-2S3R/2R3R/2S3S/2R3S, and the corresponding four diastereomeric intermediates C-2S3R/ 2R3R/2S3S/2R3S were evaluated. The energy of TS-2S3R (ΔG = +11.7 kcal/mol) that leads to the desired isomer C-2S3R is smaller than that of the other three transition states TS-2R3R (ΔG = +15.3 kcal/mol), TS-2S3S (ΔG = +13.7 kcal/mol), and TS-2R3S (ΔG = +21.5 kcal/mol). Inspection of the transition state structures revealed that TS-2R3R/2S3S/2R3S have several C

DOI: 10.1021/acs.orglett.8b03302 Org. Lett. XXXX, XXX, XXX−XXX

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functional groups for further derivatization into various taxane diterpenoids.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03302. Experimental procedures and characterization data (1H and 13C NMR, HRMS, FTIR) for all new compounds; full Gaussian reference; Cartesian coordinates (PDF) Accession Codes

CCDC 1870990 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Masanori Nagatomo: 0000-0001-9204-194X Masayuki Inoue: 0000-0003-3274-551X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was financially supported by Grants-in-Aid for Scientific Research (S) (17H06110) for Scientific Research on Innovative Areas (17H06452) to M.I. and Grants-in-Aid for Scientific Research (C) (16K08156) for Scientific Research on Innovative Areas (18H04384) to M.N. from JSPS.

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REFERENCES

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DOI: 10.1021/acs.orglett.8b03302 Org. Lett. XXXX, XXX, XXX−XXX