要約のみTohoku University有本博一課

Kawashima Yuki

Tohoku University博士（生命科学）博士学位論文 (Thesis(doctor))要約のみthesi

Kawashima, Yuki

Tohoku University Repository (TOUR) / 東北大学機関リポジトリ

Studies toward the Total Synthesis ofAmphidinolide N and Goniodomin A著者 Kawashima Yuki学位授与機関 Tohoku University学位授与番号 11301甲第18201号URL http://hdl.handle.net/10097/00122676  博士論文（要約）    Studies toward the Total Synthesis of Amphidinolide N and Goniodomin A  （アンフィジノリド Nおよびゴニオドミン Aの全合成研究）        平成 29年度   東北大学大学院生命科学研究科 分子生命科学専攻   川島	 悠岐    Amphidinolide N (1, Figure 1), which was isolated from the cultured Amphidinium sp. (Y-5 strain) by the Kobayashi group in 1994, is the most potent cytotoxic member of the amphidinolide family discovered so far, and its IC50 values against murine lymphoma L1210 and human epidermoid carcinoma KB cells are 0.05 and 0.06 ng/mL, respectively.1) The gross structure of amphidinolide N, including its partial stereochemical assignment, was proposed on the basis of 2D NMR spectroscopic studies. The structure has recently been revised, and the relative configuration has been reported.2) Amphidinolide N consists of a 26-membered macrolide skeleton containing a six-membered hemiacetal, 2,5-trans-disubstituted tetrahydrofuran, allylic epoxide, and 13 stereogenic centers. Although several synthetic studies of amphidinolide N have been reported to date,3) complete stereostructure of 1 has not been elucidated yet. We previously reported the synthesis of the tetrahydrofuran 2.4) However, it was unable to establish the synthetic route to the C8–C29 segment of 1. Here the author reports his efforts toward a stereocontrolled synthesis of the C8–C29 model compound 3, which involves the construction of the challenging six-membered acetal unit of amphidinolide N (Scheme 1). The key features of the synthesis are a Tebbe methylenation/ring-closing metathesis sequence5) to construct a dihydropyran ring 4 and a late-stage introduction of the oxygen functionalities at C15 and C16 with m-CPBA.6)    OOPMBHH16OHO12MeMeHOOMeBnMe293OOPMBHHOHMe OBnMeMe4OOPMBHHOH5DCC, DMAPCH2Cl2, 95%Me OOPMBHHMeOOOBnMeMe7MeMeOOHOBnMeMe1. Tebbe reagnt    THF, 0 ºC, 81%1. m-CPBA, NaHCO3     CH2Cl2/ MeOH    (2:1), 0 ºC2. DMP, NaHCO3     CH2Cl2, 51% (2 steps)3. L-selectride, -78 ºC    85%, dr >20:162. G-II, toluene     45 ºC, 82%Scheme 1. Synthesis of the C8–C29 model compound 3OOPMBHHMe2O128HOHOMeMeOOHOOHMeOOH OHHHMe29OFigure 1. amphidinolide N (1)Goniodomin A (8, Figure 2) is a marine polyether macrolide, which was isolated as a potent antifungal substance from the dinoflagellate Alexeandrium hiranoi by Murakami and coworkers.7) We previously assigned the complete stereostructure of 8 on the basis of 2D NMR analysis, degradation experiments of the authentic sample, and synthesis of model compounds.8) Aiming at the determination of complete stereostructure of goniodomin A, we have been engaged in the total synthesis of 8.9) Although we have achieved the synthesis of a seco-acid, our previous efforts on its macrolactonization were fruitless.10)  Here the author reports his studies toward the total synthesis of goniodomin A based on newly devised convergent strategy, which featured a palladium-catalyzed coupling11) of vinylstannane 9 with thioester 10, and an intramolecular Nozaki–Hiyama–Kishi (NHK) reaction12) for the construction of the macrocyclic skeleton 11 (Scheme 2).    The author established scalable synthetic routes to vinylstannane 9 and carboxylic acid 12. The synthesis of vinylstannane 9 involved a Wittig reaction and a reductive cycloetherification for the construction of the dihydropyran ring.13) The synthesis of carboxylic acid 12 utilized a titanium-enolate mediated aldol reaction14) for stereocontrolled installation of the acyclic moiety with a correct configuration of the C7 stereogenic center (Scheme 3).    OOMeOMeOTBSOOTBDPSOAcOMeOOOMeMePMBOOOMeOMeOOOOHOMeOHOHOOHspiroacetalization intramolecularNozaki–Hiyama–Kishi reactionesterificationLiebeskind coupling8 11OOTBSSnMe3TESOPMBOMeMeTolSOTESOTBDPSOOOHAcOMeDEIPSOODEIPSOO91210Scheme 2. Synthesis plan of goniodomin ADEIPSOOOMeOMeOOOOHOMeOHOHOOHFigure 2. goniodomin A (8) The author next focused his attention on the formation of the macrocyclic skeleton of goniodomin A. Palladium-catalyzed cross-coupling11) of vinylstannane 9 with thioester 10 gave advanced intermediate 30, which was further elaborated to aldehyde 36 in 16 steps. Intramolecular NHK reaction12) of 36 successfully afforded the corresponding cyclization product, which was oxidized to give enone 11. Desilylation and subsequent acid treatment led to the corresponding spiroacetal as a mixture of diastereomers. The two diastereomers were separated by column chromatography on silica gel after silylation to afford natural (11S)-spiroacetal 37. Formation of a hemiacetal, followed by removal of the acetyl group provided alcohol 39 as an inseparable mixture of isomers. Unfortunately, the 1H NMR spectrum of 39 was different from that of the authentic derivative.8) The author OOBnHOPMBOHOOBnHO 2. TrCl, 98%3. NaH, PMBCl4. TsOH•H2O, 93% (2 steps)1. (–)-DET, Ti(Oi-Pr)4,CHP    4 Å MS, 84%, dr >20:1OOBnTBDPSOOPMBOTES1. TEMPO, KBr, NaOCl2. NaHMDS83%  (2 steps)Z/E >20:1TBDPSOP+Ph3I-OTES3. TMSOTf    Et3SiH    THF, 89%    (2 steps)    dr >20:1O OOBnTBDPSO1. DDQ, 86%2. TPAP, NMO 1. Li naphtalenide, 84%O OTBDPSO2. DMSO, (COCl)2, Et3N3. Ohira-Bestmann    K2CO3, MeOH    87% (2 steps)O OOH1. TBAF, 96%2. SO3•py, Et3N    DMSO3. allyl SiMe3    MgBr2•OEt2    78% (2 steps)    dr >20:1O OOTBSSnMe3O OOTBSMeO1. HgSO4    aq H2SO42. TBSCl    93% (2 steps)2. (Me3Sn)2, Pd(PPh3)4    LiCl, 76% (2 steps)1. KHMDS, PhNTf2HOOBn1. G-II    methyl acrylate    68%, E/Z = 17:12. DIBALH, 89%13 14 15161718 1920 21 9OOHCOPMBPMBOOOOHHPhOHH6 steps OTBDPSOMeN OOBn63%LiBH4O7OPMBPMBOHOTBDPSOOXX =N OOBnMeOOPMBPMBOMeHOTBDPSO1. 2-NO2PhSeCN    PBu3OOPMBPMBOHOTBDPSO OHMe2. aq H2O2, pyridine    76% (2 steps)1. TBAF, 88%2. DEIPSOTf    2,6-lutidine    quant3. DDQ, 77%OHOMeDEIPSODEIPSOOH1. TEMPO, PhI(OAc)2, 87%OHOMeDEIPSODEIPSO OOMe2. NaClO2, NaH2PO4    2-methyl-2-butene3. TMSCHN2, 84% (2 steps)1. Ac2O    DMAP    79%2. LiOH    77%OAcOMeDEIPSODEIPSO OOHTiCl4, i-Pr2NEt, NMP71%, dr >20:122 23242526 2728 29 12Scheme 3. Synthesis of vinylstannane 9 and carboxylic acid 12inferred that the originally proposed relative configuration of goniodomin A might be incorrectly assigned.     O OOTBSSnMe3TESOPMBOMeMeTolSOTESOTBDPSO+Pd2(dba)3, P(OEt)3 CuDPPOTESOOOTESPMBOMeMeOTBSTBDPSOOTHF/hexane (1:2)40 ºC, 87%OHOOPMBOMeMeOTBSTBDPSOOOMeMeIOOOHAcODEIPSOMeDEIPSOOOMeOMeOTBSOOPMBOTBDPSODEIPSOAcOMeOOMeMeIDCC, PPTS, pyridine(CH2Cl)2, rt, 69%OTESOOPMBOMeMeOTBSTBDPSOOOMeMeOMe2. DMP3. MeMgBr4. DMP    84%   (3 steps)1. KHMDS, PhNTf22. (Me3Sn)2, LiCl    Pd(PPh3)4    71% (2 steps)3. I24. PPTS    92% (2 steps)12DEIPSOOOMeOMeOOOOAcOMeOOPMBOTBDPSOMeMe1. Et3N•3HF    Et3N/MeCN    75%2. ClCH2CO2H3. TBDPSCl     imidazole    15% (2 sptes)1. AcOH/H2O    THF, 89%2. DMP, 70%OHOOOHPMBOMeMeOTBSTBDPSOOH1. NaBH4, EtOH    CeCl3•7H2O    85%, dr >20:12. PPTS, 95%OTESOOPMBOMeMeOTBSTBDPSOOOMeMe1. Me2C(OMe)2    PPTS2. PPTS, 93%    (2 steps)3. TESOTf     2,6-lutidine     96%OOMeOMeOTBSOOPMBOTBDPSODEIPSOAcOMeOOMeMeIOHCOOMeOMeOTBSOOTBDPSODEIPSOAcOMeOOMeMePMBOO2. DMP, 94%9103031 32 33343536 11 371. 9-BBN-H;    aq NaHCO3    aq H2O2    91%1. NiCl2, CrCl2    DMSO, rt    69%, dr 1:1Scheme 3. Synthesis of spiroacetal 39OOMeOMeOOOOAcOMeOOOTBDPSOMeMeOOMeOMeOOOOHOMeOOMeMe1. DDQ, 69%2. DMP, 68%1. Et3N•3HF    Et3N/MeCN    88%2. K2CO3, MeOH    36%OOH38 391) M. Ishibashi, N. Yamaguchi, T. Sasaki, J. Kobayashi, J. Chem. Soc., Chem. Commun. 1994, 1455. 2) Y. Takahashi, T. Kubota, M. Imachi, M. R. Wälchli, J. Kobayashi, J. Antibiot. 2013, 66, 277. 3) (a) K. C. Nicoalou, W. E. Brenzovich, P. G. Bulger, T. M. Francis, Org. Biomol. Chem. 2006, 4, 2119. (b) K. C. Nicolaou, P. G. Bulger, W. E. Brenzovich, Org. Biomol. Chem. 2006, 4, 2158. (c) B. M. Trost, J. Rey, Org. Lett. 2012, 14, 5632. (d) K. Ochiai, S. Kuppusamy, Y. Yasui, T. Okano, Y. Matsumoto, N. R. Gupta, Y. Takahashi, T. Kubota, J. Kobayashi, Y. Hayashi, Chem. Eur. J. 2016, 22, 3282. 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Studies toward the Total Synthesis of Amphidinolide N and Goniodomin A

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アンフィジノリドNおよびゴニオドミンAの全合成研究

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