LETTER
Asymmetric Synthesis of Dexoxadrol
1777
J = 7.0, 6.8, 6.8, 1.2, 1.2 Hz, 2 H), 2.41 (ddd, J = 11.4, 6.8, 6.8 Hz,
1 H), 2.63 (ddd, J = 11.4, 7.0, 7.0 Hz, 1 H), 3.20 (dd, J = 8.1, 4.6
Hz, 1 H), 3.89 (dd, J = 7.7, 7.2 Hz, 1 H), 4.04 (dd, J = 7.7, 6.3 Hz,
1 H), 4.10 (ddd, J = 7.2, 6.3, 4.6 Hz, 1 H), 4.89 (br d, J = 10.2 Hz,
1 H), 4.96 (dddd, J = 17.1, 1.4, 1.4, 1.4 Hz, 1 H), 5.10–5.19 (m,
2 H), 5.56 (ddd, J = 17.8, 9.8, 8.1 Hz, 1 H), 5.65 (dddd, J = 17.1,
2.7 Hz, 1 H), 2.86 (ddd, J = 11.3, 4.4, 2.5 Hz, 1 H), 3.08 (br d,
J = 11.8 Hz, 1 H), 3.98 (dd, J = 7.2, 7.2 Hz, 1 H), 4.06 (ddd, J = 7.2,
6.6, 4.5 Hz, 1 H), 4.18 (dd, J = 7.2, 6.6 Hz, 1 H), 7.26–7.41 (m,
6 H), 7.48–7.55 (m, 2 H), 7.54–7.61 (m, 2 H). 13C NMR (100 MHz,
CDCl3): d = 24.5, 26.4, 28.6, 46.7, 57.9, 65.9, 79.6, 109.3, 126.1,
126.2, 127.9, 128.0, 128.0, 128.1, 142.1, 142.2. HRMS (ESI+): m/z
[M + H]+ calcd for C20H24NO2: 310.1802; found: 310.1801.
10.2, 6.8, 6.8 Hz, 1 H), 7.15–7.31 (m, 6 H), 7.38–7.49 (m, 4 H). 13
C
NMR (100 MHz, CDCl3): d = 34.2, 46.3, 63.0, 66.4, 78.8, 109.8,
116.2, 118.1, 126.1, 126.2, 127.9, 128.0, 128.1, 128.1, 136.3, 136.7,
141.9, 142.1. HRMS (ESI+): m/z [M + H]+ calcd for C22H26NO2:
336.1958; found: 336.1961.
Acknowledgment
The financial support from the Spanish Ministry of Science and In-
novation, the European Regional Development Fund (CTQ2008-
00187/BQU) and the Government of Aragón (GA E-71) is acknowl-
edged.
Synthesis of 6. Benzyl chloroformate (256 mg, 1.5 mmol) was add-
ed dropwise to a solution of pure anti diastereoisomer 5 (335 mg,
1.0 mmol) and DIPEA (387 mg, 3.0 mmol) in CH2Cl2 (20 mL) at r.t.
and the resulting mixture was stirred at r.t. for 15 h. The reaction
mixture was washed with water (10 mL) and the organic layer was
dried over anhydrous MgSO4, filtered and evaporated in vacuo. Pu-
rification of the crude product by silica gel column chromatography
(CH2Cl2) afforded compound 6 (464 mg, 99%) as a colorless oil;
References and Notes
(1) Present address: Institute of Chemical Research of Catalonia
(ICIQ), Avgda. Països Catalans 16, 43007 Tarragona, Spain
(2) Hardie, W. R.; Hidalgo, J.; Halverstadt, J. F.; Allen, R. E.
J. Med. Chem. 1966, 9, 127.
(3) See for example: (a) Lasagna, L.; Pearson, J. W. Proc. Soc.
Exp. Biol. Med. 1965, 118, 352. (b) Williams, M. W.;
Williford, E. A. Jr.; Williams, C. S.; Towne, J. C. Arch. Int.
Pharmacol. Ther. 1969, 178, 26. (c) Tang, A. H.; Kirch,
J. D. Anesth. Analg. 1973, 52, 577. (d) Frederickson, E. L.;
Longnecker, D. E.; Allen, G. W. Anesth. Analg. 1976, 55,
335. (e) Coan, E. J.; Collingridge, G. L. Br. J. Pharmacol.
1987, 91, 547.
(4) (a) Jacobson, A. E.; Harrison, E. A.; Mattson, M. V.;
Rafferty, M. F.; Rice, K. C.; Woods, J. H.; Winger, G.;
Solomon, R. E.; Lessor, R. A.; Silverton, J. V. J. Pharmacol.
Exp. Ther. 1987, 243, 110. (b) Thurkauf, A.; Zenk, P. C.;
Balster, R. L.; May, E. L.; George, C.; Carroll, F. I.;
Mascarella, S. W.; Rice, K. C.; Jacobson, A. E.; Mattson,
M. V. J. Med. Chem. 1988, 31, 2257.
(5) (a) Thurkauf, A.; Mattson, M. V.; Richardson, S.;
Mirsadeghi, S.; Ornstein, P. L.; Harrison, E. A. Jr.; Rice,
K. C.; Jacobson, A. E.; Monn, J. A. J. Med. Chem. 1992, 35,
1323. (b) Sax, M.; Wünsch, B. Curr. Top. Med. Chem. 2006,
6, 723. (c) Sax, M.; Ebert, K.; Schepmann, D.; Wibbeling,
B.; Wünsch, B. Bioorg. Med. Chem. 2006, 14, 5955.
(d) Sax, M.; Fröhlich, R.; Schepmann, D.; Wünsch, B. Eur.
J. Org. Chem. 2008, 6015.
25
1
[a]D +1.5 (c 1.00, CHCl3). IR (neat): 1699, 1641 cm–1. H NMR
(400 MHz, CDCl3, 333 K): d = 2.14–2.30 (m, 2 H), 3.17–3.31 (m,
2 H), 3.84 (dd, J = 8.1, 6.1 Hz, 1 H), 3.95 (dd, J = 8.1, 7.4 Hz, 1 H),
4.19–4.34 (m, 1 H), 4.38–4.52 (m, 1 H), 4.91 (br d, J = 10.2 Hz,
1 H), 4.93 (br d, J = 17.1 Hz, 1 H), 5.03 (d, J = 12.5 Hz, 1 H), 5.07
(d, J = 12.5 Hz, 1 H), 5.16 (br d, J = 17.1 Hz, 1 H), 5.19 (br d,
J = 10.5 Hz, 1 H), 5.63 (dddd, J = 17.1, 10.2, 6.8, 6.8 Hz, 1 H), 5.97
(ddd, J = 17.1, 10.5, 6.4 Hz, 1 H), 7.14–7.31 (m, 11 H), 7.39–7.45
(m, 4 H). 13C NMR (100 MHz, CDCl3, 333 K): d = 33.8, 46.0, 61.7,
67.3, 67.8, 77.6, 110.6, 116.5, 118.8, 126.1, 126.1 (×2), 127.8,
128.0, 128.0, 128.0, 128.1, 128.4, 133.4, 135.2, 136.6, 142.4, 142.5,
156.0. HRMS (ESI+): m/z [M + Na]+ calcd for C30H31NO4Na:
492.2145; found: 492.2156.
Synthesis of 7. A solution of compound 6 (469 mg, 1.0 mmol) in
CH2Cl2 (20 mL) was added dropwise to a solution of Grubb’s first
generation catalyst (82 mg, 0.10 mmol) in CH2Cl2 (20 mL) at r.t.
and the resulting solution was stirred at r.t. for 2 h. The solvent was
evaporated in vacuo and the residue was purified by silica gel col-
umn chromatography (Et2O–hexanes, 1:2), to afford compound 7
(436 mg, 99%) as a colorless oil; [a]D25 –140.9 (c 1.00, CHCl3). IR
(neat): 1702, 1655 cm–1. 1H NMR (300 MHz, CDCl3, 333 K): d =
1.91 (br d, J = 17.2 Hz, 1 H), 2.04–2.28 (m, 1 H), 2.85–3.13 (m,
1 H), 3.83–4.04 (m, 1 H), 3.96–4.24 (m, 2 H), 4.22 (ddd, J = 6.6,
6.6, 6.6 Hz, 1 H), 4.37–4.63 (m, 1 H), 5.08 (d, J = 12.3 Hz, 1 H),
5.13 (d, J = 12.3 Hz, 1 H), 5.82–5.95 (m, 2 H), 7.17–7.38 (m, 11 H),
7.40–7.56 (m, 4 H). 13C NMR (75 MHz, CDCl3, 333 K): d = 24.6,
38.4, 54.0, 67.3, 67.8, 78.6, 110.3, 125.2, 126.2 (×2), 127.0, 127.0,
127.8, 127.9, 127.9, 128.0, 128.1, 128.5, 136.6, 142.4, 142.4, 155.4.
HRMS (ESI+): m/z [M + Na]+ calcd for C28H27NO4Na: 464.1832;
found: 464.1850.
(6) See for example (a) Etayo, P.; Badorrey, R.; Díaz-de-
Villegas, M. D.; Gálvez, J. A. Synlett 2006, 2799.
(b) Etayo, P.; Badorrey, R.; Díaz-de-Villegas, M. D.;
Gálvez, J. A. Tetrahedron: Asymmetry 2007, 18, 2812.
(c) Etayo, P.; Badorrey, R.; Díaz-de-Villegas, M. D.;
Gálvez, J. A. J. Org. Chem. 2008, 73, 8594. (d) Etayo, P.;
Badorrey, R.; Díaz-de-Villegas, M. D.; Gálvez, J. A. Eur. J.
Org. Chem. 2008, 3474. (e) Badorrey, R.; Portaña, E.; Díaz-
de-Villegas, M. D.; Gálvez, J. A. Org. Biomol. Chem. 2009,
7, 2912.
Synthesis of 1. 10% Pd/C (15 mg) was added to a solution of com-
pound 7 (221 mg, 0.50 mmol) in EtOH (10 mL) and the mixture was
vigorously stirred overnight at r.t. under an atmospheric pressure of
H2. After completion of the reaction, the catalyst was removed by
filtration on Celite and the filtrate was evaporated in vacuo. The res-
idue was dissolved in CH2Cl2 (20 mL) and washed with 2.0 N aque-
ous NaOH (10 mL). The organic layer was dried over anhydrous
MgSO4, filtered and evaporated in vacuo to afford compound 1 (152
mg, 99%) as a colorless oil; [a]D25 +36.6 (c 1.00, CHCl3). IR (neat):
3334 cm–1. 1H NMR (400 MHz, CDCl3): d = 1.11 (dddd, J = 12.4,
12.4, 12.4, 3.9 Hz, 1 H), 1.22–1.52 (m, 3 H), 1.52–1.67 (m, 1 H),
1.62–1.81 (m, 2 H), 1.77–1.90 (m, 1 H), 2.62 (ddd, J = 11.8, 11.3,
(7) Sydorenko, N.; Hsung, R. P.; Vera, E. L. Org. Lett. 2006, 8,
2611.
(8) (a) Díez, R.; Badorrey, R.; Díaz-de-Villegas, M. D.; Gálvez,
J. A. Eur. J. Org. Chem. 2007, 2114. (b) Allepuz, A. C.;
Badorrey, R.; Díaz-de-Villegas, M. D.; Gálvez, J. A. Eur. J.
Org. Chem. 2009, 6172. (c) Badorrey, R.; Díaz-de-Villegas,
M. D.; Gálvez, J. Tetrahedron: Asymmetry 2009, 20, 2226.
Synlett 2010, No. 12, 1775–1778 © Thieme Stuttgart · New York