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Synlett 2009(8): 1303-1306  
DOI: 10.1055/s-0029-1216723
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Asymmetric Total Synthesis of (+)-Brefeldin A: Intramolecular Epoxide-Opening/RCM Strategy

Myung-Yeol Kim, Hyemi Kim, Jinsung Tae*
Department of Chemistry and Center for Bioactive Molecular Hybrids (CBMH), Yonsei University, Seoul 120-749, Korea
Fax: +82(2)3647050; e-Mail: jstae@yonsei.ac.kr;
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Publikationsverlauf

Received 6 February 2009
Publikationsdatum:
17. April 2009 (online)

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Abstract

A highly efficient asymmetric total synthesis of (+)-brefeldin A was accomplished by using intramolecular epoxide opening of an epoxy allylsilane and RCM reaction for the constructions of the cyclopentane and macrocyclic lactone rings of (+)-brefeldin A, respectively.

Key words

(+)-brefeldin A - cyclizations - epoxides - metathesis - ­total synthesis

    References and Notes

  • 1 Singleton VL. Bohonos N. Ullstrup AJ. Nature (London)  1958,  181:  1072 
    CrossrefGoogle Scholar
  • 2 Weber HP. Hauser D. Sigg HP. Helv. Chim. Acta  1971,  54:  2763 
    CrossrefGoogle Scholar
  • For the representative recent syntheses of BFA and related references, see the following references:
  • 3a Wu Y. Gao J. Org. Lett.  2008,  10:  1533 
    Google Scholar
  • 3b Lin W. Zercher CK. J. Org. Chem.  2007,  72:  4390 
    Google Scholar
  • 3c Seo S.-Y. Jung J.-K. Paek S.-M. Lee Y.-S. Kim S.-H. Suh Y.-G. Tetrahedron Lett.  2006,  47:  6527 
    Google Scholar
  • 3d Wu Y.-K. Shen X. Yang Y.-Q. Hu Q. Huang J.-H. J. Org. Chem.  2004,  69:  3857 
    Google Scholar
  • 3e Wu Y.-K. Shen X. Yang Y.-Q. Hu Q. Huang J.-H. Tetrahedron Lett.  2004,  45:  199 
    Google Scholar
  • 3f Kim D. Lee J. Shim PJ. Lim JI. Jo H. Kim S. J. Org. Chem.  2002,  67:  764 
    Google Scholar
  • 3g Kim D. Lee J. Shim PJ. Lim JI. Doi T. Kim S. J. Org. Chem.  2002,  67:  772 
    Google Scholar
  • 3h Suh YG. Jung J.-K. Seo S.-Y. Min K.-H. Shin D.-Y. Lee Y.-S. Kim S.-H. Park H.-J. J. Org. Chem.  2002,  67:  4127 
    Google Scholar
  • 3i Trost BM. Crawley ML. J. Am. Chem. Soc.  2002,  124:  9328 
    Google Scholar
  • 3j Wang Y. Romo D. Org. Lett.  2002,  4:  3231 
    Google Scholar
  • See also the following pioneering works on brefeldin A synthesis:
  • 3k Corey EJ. Wollenberg RH. Tetrahedron Lett.  1976,  4705 
    Google Scholar
  • 3l Bartlett PA. Green FR. J. Am. Chem. Soc.  1978,  100:  4858 
    Google Scholar
  • 3m Baudouy R. Crabbé P. Greene AE. Le Drian C. Orr AF. Tetrahedron Lett.  1977,  2973 
    Google Scholar
  • 3n Kitahara T. Mori K. Matsui M. Tetrahedron Lett.  1979,  3021 
    Google Scholar
  • For recent reviews on olefin metathesis, see:
  • 4a Diver ST. Giessert AJ. Chem. Rev.  2004,  104:  1317 
    Google Scholar
  • 4b Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4490 
    Google Scholar
  • 5 Gradillas A. Perez-Castells J. Angew. Chem. Int. Ed.  2006,  45:  6086 
    Google Scholar
  • 6a Kim Y.-J. Tae J. Synlett  2006,  61 
    Google Scholar
  • 6b Lee J. Jung Y.-H. Tae J. Bull. Korean Chem. Soc.  2007,  28:  513 
    Google Scholar
  • 6c Jung Y.-H. Lee J. Tae J. Chem. Asian J.  2007,  2:  656 
    Google Scholar
  • 7 For an asymmetric desymmetrization method, see: Li Z. Zhanh W. Yamamoto H. Angew. Chem. Int. Ed.  2008,  47:  7520 
    Google Scholar
  • 8a Tokunaga M. Larrow JF. Kakiuchi F. Jacobsen EN. Science  1997,  277:  936 
    Google Scholar
  • 8b Brandes BD. Jacobsen EN. Tetrahedron: Asymmetry  1997,  8:  3927 
    Google Scholar
  • 9 Connon SJ. Blechert S. Angew. Chem. Int. Ed.  2003,  42:  1900 
    Google Scholar
  • 10a Thibaudeau S. Gouverneur V. Org. Lett.  2003,  5:  4891 
    Google Scholar
  • 10b Engelhardt FC. Schmitt MJ. Taylor RE. Org. Lett.  2001,  3:  2209 
    Google Scholar
  • 10c Taylor RE. Engelhardt CE. Schmitt MJ. Yuan H. J. Am. Chem. Soc.  2001,  123:  2964 
    Google Scholar
  • 11a Molander GA. Andrews SW. J. Org. Chem.  1989,  54:  3114 
    Google Scholar
  • 11b Procter G. Russell AT. Murphy PJ. Tan TS. Mather AN. Tetrahedron  1988,  44:  3953 
    Google Scholar
  • For the synthesis of BFA by intramolecular cyclization reactions using allylsilanes, see:
  • 12a Epoxide opening: Hatakeyama S. Sugawara K. Kawamura M. Takano S. Synlett  1990,  691 
    Google Scholar
  • 12b

    β-Lactone opening: ref 3j

    Google Scholar
  • 13a Jastrzebska I. Scaglione JB. DeKoster GT. Rath NP. Covey DF. J. Org. Chem.  2007,  72:  4837 
    Google Scholar
  • 13b Fürstner A. Thiel OR. Ackermann L. Org. Lett.  2001,  3:  449 
    Google Scholar
  • 13c Takahata H. Yotsui Y. Momose T. Tetrahedron  1998,  54:  13505 
    Google Scholar
  • 14a Rao KS. Mukkanti K. Reddy DS. Pla M. Iqbal J. Tetrahedron Lett.  2005,  46:  2287 
    Google Scholar
  • 14b Meta CT. Koide K. Org. Lett.  2004,  6:  1785 
    Google Scholar
  • 14c Zhu G. Lu X. Tetrahedron: Asymmetry  1995,  6:  1657 
    Google Scholar
  • 15 Rao KS. Mukkanti K. Reddy DS. Pal M. Iqbal J. Tetrahedron Lett.  2005,  46:  2287 
    CrossrefGoogle Scholar
  • 16 Meta CT. Koide K. Org. Lett.  2004,  6:  1785 
    CrossrefGoogle Scholar
17

We were not able to isolate the minor Z-isomers. Only
E-isomers were isolated after column chromatography.

18

Lewis Acid Mediated Intramolecular Epoxide Opening: To a solution of 5 (365 mg, 1.14 mmol) in toluene (230 mL) was added BF3˙OEt2 (0.21 mL, 2.3 mmol) at -78 ˚C for 2 h using a syringe pump. The reaction mixture was treated with sat. aq NaHCO3 (20 mL) at -78 ˚C and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 20 mL) and the combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and the residue was purified by silica gel chromatography (hexane-EtOAc, 6:1) to give 8 and the cis isomer (trans/cis = 88: 12, 203 mg, 72%) as a colorless oil. The ratios were determined by HPLC.
8: R f 0.29 (hexane-EtOAc, 3:1); [α]²4 D -51 (c 0.125, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 6.76-6.86 (m, 4 H), 5.78-5.89 (m, 1 H), 4.94-5.09 (m, 2 H), 4.65-4.72 (m, 1 H), 3.76 (s, 3 H), 3.68-3.75 (m, 1 H), 3.55-3.63 (m, 1 H), 2.26-2.42 (m, 2 H), 2.12-2.22 (m, 1 H), 2.03-2.12 (m, 1 H), 1.69-1.79 (m, 2 H), 1.36 (t, J = 5.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 154.06, 152.42, 142.55, 116.70, 114.81, 65.19, 55.88, 46.18, 40.30, 36.33. IR (film, neat): 3447, 3066, 2923, 2353, 1735, 1631, 1584, 1497, 1463, 1436, 1355, 1221, 1177, 1104, 1035, 992, 905, 823, 737 cm-¹. HRMS: m/z [M]+ calcd for C15H20O3: 248.1412; found: 248.1417.
cis-Isomer of 8: R f 0.29 (hexane-EtOAc, 3:1). ¹H NMR (400 MHz, CDCl3): δ = 6.76-6.86 (m, 4 H), 5.85-5.97 (m, 1 H), 5.04-5.16 (m, 2 H), 4.74-4.81 (m, 1 H), 3.77 (s, 3H), 3.65 (dd, J = 11.2, 7.0 Hz, 1 H), 3.55 (dd, J = 11.2, 6.0 Hz, 1 H), 3.03 (q, J = 4.2 Hz, 1 H), 2.47-2.58 (m, 1 H), 2.00-2.13 (m, 2 H), 1.88-1.97 (m, 1 H), 1.78-1.88 (m, 1 H). 1.40 (t, J = 5.5 Hz, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 139.13, 116.77, 115.62, 114.82, 78.52, 64.06, 55.08, 43.73, 43.70, 38.39, 35.39.
Macrolactone Synthesis by Ring-Closing Metathesis: A solution of 2 and 4-epi-2 (32 mg, 0.060 mmol) and 7 (10 mol%) in CH2Cl2 (60 mL) was refluxed at 55 ˚C for 8 h under N2. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (hexane-EtOAc, 30:1) to give the macrocyclic lactones (25 mg, 81%) as a colorless oil. These lactones (22.6 mg, 0.045 mmol) in THF (0.5 mL) were treated with 1 M TBAF in THF (2.19 mL, 2.19 mmol) at r.t. for 3 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (hexane-EtOAc, 5:1) to give 14 (7 mg) and 4-epi-14 (7 mg) in 78% yield.
14: mp 178-179 ˚C; R f 0.26 (hexane-EtOAc, 2:1); [α]²0 D +42.6 (c 0.9, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 7.38 (dd, J = 15.7, 3.2 Hz, 1 H), 6.81 (m, 4 H), 5.91 (dd, J = 15.6, 1.8 Hz, 1 H), 5.70 (ddt, J = 16.4, 11.4, 5.8 Hz, 1 H), 5.29 (dd, J = 15.2, 9.2 Hz, 1 H), 4.81-4.91 (m, 1 H), 4.63-4.71 (m, 1 H), 4.10-4.18 (m, 1 H), 3.76 (s, 3 H), 2.25-2.48 (m, 3 H), 2.00 (q, J = 9.3 Hz, 2 H), 1.80-1.91 (m, 2 H), 1.70-1.80 (m, 3 H), 1.63-1.70 (m, 1 H), 1.47-1.55 (m, 1 H), 1.26 (d, J = 6.2 Hz, 3 H), 0.90-1.00 (m, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 166.31, 154.02, 151.69, 136.72, 130.67, 117.76, 116.94, 114.81, 78.49, 76.39, 71.89, 55.90, 52.60, 44.50, 40.31, 39.00, 34.33, 31.93, 26.85, 21.01. IR (film, neat): 3496, 2925, 2851, 1709, 1681, 1506, 1443, 1377, 1268, 1227, 1032, 969, 824 cm-¹. HRMS: m/z [M]+ calcd for C23H30O5: 386.2093; found: 386.2090.
4-epi-14: mp 105-106 ˚C; R f 0.31 (hexane-EtOAc, 2:1); [α]²0 D +40.3 (c 0.65, CHCl3). ¹H NMR (400 MHz, CDCl3): δ = 7.10 (dd, J = 15.6, 8.4 Hz, 1 H), 6.81 (s, 4 H), 5.78 (d,
J = 16.0 Hz, 1 H), 5.66 (ddt, J = 14.9, 10.2, 4.6 Hz, 1 H), 5.28 (dd, J = 14.9, 9.6 Hz, 1 H), 4.89-4.99 (m, 1 H), 4.63-4.70 (m, 1 H), 4.42-4.48 (m, 1 H), 3.76 (s, 3 H), 2.86 (q, J = 4.8 Hz, 1 H), 2.18-2.28 (m, 1 H), 2.11-2.18 (m, 1 H), 2.02-2.11 (m, 1 H), 1.92-2.02 (m, 2 H), 1.75-1.87 (m, 2 H), 1.61-1.75 (m, 3 H), 1.48-1.53 (m, 1 H), 1.26 (d, J = 6.4 Hz, 3 H), 0.89-1.00 (m, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 166.43, 153.91, 151.97, 151.09, 137.78, 130.17, 119.89, 116.89, 114.80, 79.08, 72.04, 71.91, 55.87, 50.24, 40.33, 39.72, 35.63, 34.58, 32.01, 26.51, 20.93. IR (film, neat): 3475, 2929, 2846, 2364, 1714, 1506, 1457, 1355, 1260, 1228, 1038, 974, 825 cm-¹. HRMS: m/z [M]+ calcd for C23H30O5: 386.2093; found: 386.2090.
Synthesis of (+)-Brefeldin A (1): To a solution of 14 (8 mg, 0.02 mmol) in MeCN-H2O (4:1, 0.2 mL) was added CAN (ceric ammonium nitrate; 22 mg, 0.040 mmol) in MeCN-H2O (4:1, 0.1 mL) at 0 ˚C. The reaction mixture was warmed to r.t. and stirred for 1 h. A solution of sat. aq NH4Cl (2.5 mL) was added. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over MgSO4, filtered, concentrated in vacuo, and the residue was purified by silica gel chroma-tography (CH2Cl2-MeOH, 20:1) to give 1 (4.8 mg, 84%) as a white solid; mp 202-204 ˚C; R f 0.23 (CH2Cl2-MeOH, 10:1); [α]²² D +86.6 (c 0.9, MeOH). ¹H NMR (400 MHz, CD3OD): δ = 7.49 (dd, J = 15.6, 3.0 Hz, 1 H), 5.85 (dd, J = 15.6, 1.9 Hz, 1 H), 5.79 (ddd, J = 15.2, 10.2, 4.7 Hz, 1 H), 5.20 (dd, J = 15.0, 9.6 Hz, 1 H), 4.75-4.83 (m, 1 H), 4.18-4.25 (m, 1 H), 4.01-4.07 (m, 1 H), 2.39 (q, J = 8.7 Hz, 1 H), 2.12 (ddd, J = 13.6, 8.6, 5.4 Hz, 1 H), 1.96-2.06 (m, 3 H), 1.72-1.92 (m, 6 H), 1.52-1.63 (m, 2 H), 1.40-1.48 (m, 1 H), 1.27 (d, J = 6.3 Hz, 3 H), 0.85-1.00 (m, 1 H). ¹³C NMR (100 MHz, CD3OD): δ = 168.38, 155.12, 138.13, 131.41, 117.78, 76.63, 73.21, 72.98, 53.18, 45.46, 44.09, 41.85, 34.99, 32.97, 28.01, 21.06. IR (film, neat): 3364, 2972, 2927, 2857, 1715, 1442, 1255, 1111, 1077, 1000, 975 cm-¹. HRMS: m/z [M]+ calcd for C16H24O4: 280.1675; found: 280.1681.