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. 2015 Nov 1;6(11):6407-6412.
doi: 10.1039/c5sc00814j. Epub 2015 Aug 6.

A highly convergent synthesis of the C1-C31 polyol domain of amphidinol 3 featuring a TST-RCM reaction: confirmation of the revised relative stereochemistry

Aleksandr Grisin  1 , P Andrew Evans  1
Affiliations

A highly convergent synthesis of the C1-C31 polyol domain of amphidinol 3 featuring a TST-RCM reaction: confirmation of the revised relative stereochemistry

Aleksandr Grisin et al. Chem Sci. .

Abstract

The concise enantioselective synthesis of the revised C1-C31 fragment of the polyketide amphidinol 3 was accomplished in 16 steps and 12.8% overall yield. Salient features of the strategy include chemoselective Weinreb amide coupling and concomitant CBS reduction for the preparation of the C1-C15 tris-syn-1,5-diol motif and a temporary silicon-tethered ring-closing metathesis (TST-RCM) reaction in combination with a diastereoselective hydroboration for the construction of the C16-C31 polypropionate fragment. The union of the fragments was accomplished by a regioselective ring-opening of the terminal epoxide with a phenyl sulfone stabilized carbanion, which upon reduction and deprotection permits a comparison of the relative configuration with the natural product.

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Figures

Fig. 1
Fig. 1. Structure of the polyene–polyhydroxy secondary metabolite, amphidinol 3 (1).
Scheme 1
Scheme 1. Retrosynthetic analysis of the C1–C31 polyol fragment of amphidinol 3. TIPS = triisopropylsilyl, TBS = tert-butyldimethylsilyl, TES = triethylsilyl, Bn = benzyl, PMB = p-methoxybenzyl.
Scheme 2
Scheme 2. Preparation of the C1–C9 iodide 5 and the C10–C15 epoxide 6. Conditions: (a) Acrolein, HG-II, CH2Cl2, 40 °C, then TESOTf, Et3N, CH2Cl2, –78 °C, 93%, E/Z ≥ 19 : 1; (b) AllenylSnBu3, (lIpc)2BH, Et2O, –40 °C to –20 °C, then 10, Et2O, –78 °C, 89%, ds ≥ 19 : 1; (c) TBSOTf, Et3N, CH2Cl2, 0 °C, 95%; (d) I2, Et2O, 0 °C, 99%; (e) CDI, then BnNH(OMe), CH2Cl2, 0 °C to RT, 92%; (f) Acetone, Oxone®, NaHCO3, EtOAc/H2O (1 : 1), RT, 98%; (g) (S,S)-Co-OAc, H2O, THF, RT, 60% (based on 50% conv.), ≥99% ee; HG-II = Hoveyda–Grubbs’ second-generation catalyst, Tf = trifluoromethanesulfonyl, Ipc = isopinocampheyl, CDI = 1,1′-carbonyldiimidazole, Oxone® = potassium peroxymonosulfate, THF = tetrahydrofuran.
Scheme 3
Scheme 3. Preparation of the C1–C15 fragment 3. Conditions: (a) iPrMgCl·LiCl, 15-crown-5, THF, –10 °C, 64%; (b) (S)-Me-CBS, BH3·DMS, THF, –40 °C, 99%, ds ≥ 19 : 1; (c) MTBSTFA, DMAP, MeCN, RT, 99%; (R)-Me-CBS = (R)-methyl oxazaborolidine, DMS = dimethyl sulfide, MTBSTFA = N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide, DMAP = 4-(dimethylamino)pyridine.
Scheme 4
Scheme 4. Preparation of the C16–C23 fragment 7 and the C24–C30 fragment 8. Conditions: (a) Br2, PPh3, imid, 2-methyl-2-butene, CH2Cl2, 0 °C; (b) AD-mix-α, tBuOH/H2O (1 : 1), 0 °C, 75% (over 2 steps), 92% ee; (c) TBSCl, imid, CH2Cl2, 0 °C to RT, 80%; (d) Isopropenylmagnesium bromide, Li2[CuCl4], Et2O, –78 °C to RT, 99%; (e) Boc-ON, LiHMDS, THF, 0 °C, 95%; (f) IBr, PhMe, –85 °C, ds = 15 : 1; (g) K2CO3, MeOH, RT, 81% (over 2 steps); (h) TBSCl, TMEDA, DMF, 0 °C to RT, 97%; (i) Me3SOTf, nBuLi, THF, –10 °C to 0 °C, 92%; imid = imidazole, AD = asymmetric dihydroxylation, Boc-ON = 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile, HMDS = hexamethyldisilazane, PhMe = toluene, TMEDA = tetramethylethylenediamine, DMF = dimethylformamide.
Scheme 5
Scheme 5. Construction of the C16–C30 fragment 4 using the TST-RCM/hydroboration reaction. Conditions: (a) 7, iPr2SiCl2, imid, CH2Cl2, 0 °C to RT, then 8, imid, CH2Cl2, 0 °C to RT, 84%; (b) 2 × 15 mol% G-II, CH2Cl2, 40 °C, 97%, Z/E ≥ 19 : 1; (c) BH3·THF, THF, RT, then H2O2, NaOH, 0 °C to RT; (d) TBSOTf, Et3N, CH2Cl2, –40 °C, 72% (over 2 steps), ds ≥ 19 : 1; (e) DDQ, CH2Cl2/pH 7 buffer (20 : 1), 0 °C, 87%; (f) PhSSPh, PBu3, MeCN, RT, then TPAP, NMO, 40 °C, CH2Cl2, 76%; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, imid = imidazole, TPAP = tetra-n-propylammonium perruthenate, NMO = 4-methylmorpholine N-oxide.
Fig. 2
Fig. 2. Model for the stereocontrol in the hydroboration and the NMR analysis of the stereochemical outcome.
Scheme 6
Scheme 6. Completion of the C1–C31 fragment of amphidinol 3. Conditions: (a) 4, nBuLi, THF, –78 °C, then 3, BF3·Et2O; (b) TBSOTf, Et3N, CH2Cl2, 0 °C, 90% (over 2 steps); (c) LiDBB, THF, –78 °C, 64%; (d) TPAP, NMO, molecular sieves (4 Å), CH2Cl2, 0 °C; (e) Me(CO)C(N2)P(O) (OMe)2, K2CO3, THF/MeOH (1 : 1), 0 °C to RT, 89% (over 2 steps); LiDBB = lithium di-tert-butylbiphenylide.
Fig. 3
Fig. 3. Comparison of 1H and 13C NMR data of synthetic and natural polyol fragment of AM3.
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References

    1. For isolation, structural characterization and bioactivity evaluation of the amphidinol family, see:

    2. Satake M., Murata M., Yasumoto T., Fujita T., Naoki H. J. Am. Chem. Soc. 1991;113:9859.
    3. Paul G. K., Matsumori N., Murata M., Tachibana K. Tetrahedron Lett. 1995;36:6279.
    4. Paul G. K., Matsumori N., Konoki K., Sasaki M., Murata M. and Tachibana K., in Harmful and Toxic Algal Blooms, Proceedings of the Seventh International Conference on Toxic Phytoplankton, ed. T. Yasumoto, Y. Oshima and Y. Fukuyo, UNESCO, Sendai, Japan, 1996, p. 503.
    5. Paul G. K., Matsumori N., Konoki K., Murata M., Tachibana K. J. Mar. Biotechnol. 1997;5:124.
    6. Echigoya R., Rhodes L., Oshima Y., Satake M. Harmful Algae. 2005;4:383.
    7. Morsy N., Matsuoka S., Houdai T., Matsumori N., Adachi S., Murata M., Iwashita T., Fujita T. Tetrahedron. 2005;61:8606.
    8. Morsy N., Houdai T., Matsuoka S., Matsumori N., Adachi S., Oishi T., Murata M., Iwashita T., Fujita T. Bioorg. Med. Chem. 2006;14:6548. - PubMed
    9. Meng Y., Van Wagoner R. M., Misner I., Tomas C., Wright J. L. C. J. Nat. Prod. 2010;73:409. - PubMed
    10. Nuzzo G., Cutignano A., Sardo A., Fontana A., J. Nat. Prod., 2014, 77 , 1524 , and pertinent references therein . - PubMed
    1. For a recent report that proposes a barrel-stave pore model, see: Espiritu R. A., Matsumori N., Tsuda M., Murata M., Biochemistry, 2014, 53 , 3287 , and pertinent references cited therein . - PubMed
    1. De Kruijff B., Demel R. A. Biochim. Biophys. Acta. 1974;339:57. - PubMed
    2. Andreoli T. E. Ann. N. Y. Acad. Sci. 1974;235:448. - PubMed
    1. For the original structural elucidation of amphidinol 3 (1), see: Murata M., Matsuoka S., Matsumori N., Paul G. K., Tachibana K., J. Am. Chem. Soc., 1999, 121 , 870 .

    1. For structural revision of amphidinol 3 (1), see:

    2. Oishi T., Kanemoto M., Swasono R., Matsumori N., Murata M. Org. Lett. 2008;10:5203. - PubMed
    3. Swasono R. T., Kanemoto M., Matsumori N., Oishi T., Murata M. Heterocycles. 2011;82:1359.
    4. Manabe Y., Ebine M., Matsumori N., Murata M., Oishi T. J. Nat. Prod. 2012;75:2003. - PubMed
    5. Ebine M., Kanemoto M., Manabe Y., Konno Y., Sakai K., Matsumori N., Murata M., Oishi T. Org. Lett. 2013;15:2846. - PubMed

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