344
J. Boukouvalas, M. Pouliot
LETTER
MeO
HO
HO
Br
Br
OMe
OMe
b
a
O
O
O
O
O
O
5
6
7
c
X
HO
MeO
MeO
X
O
O
X
O
OH
OMe
OMe
e
d
X
O
O
O
O
O
O
10 X = H
2 X = Br
9
8
X
f
X
HO
MeO
Scheme 1 Reagents and conditions: (a) 2,6-lutidine, n-Bu2BOTf, p-anisaldehyde, THF, –78 °C to –20 °C, 45 min, 64%; (b) p-methoxyphe-
nyl-boronic acid, AsPh3, Ag2O, PdCl2(PhCN)2, THF, H2O, 23 °C, 20 h, 86%; (c) Dess–Martin periodinane, CH2Cl2, 23 °C, 15 h, 89%;
(d) TBSOTf, p-anisaldehyde, i-Pr2NEt, CH2Cl2, 23 °C, 1 h; DBU, 23 °C, 2 h, 94%; (e) BBr3, CH2Cl2, –78 °C to 23 °C, 20 h, 93%; (f) Br2, KBr,
dioxane, H2O, 23 °C, 1 h, 98%.
Riendeau, D.; Rodger, I.; Tagari, P.; Thérien, M.; Vickers,
P.; Wong, E.; Xu, L.-J.; Young, R. N.; Zamboni, R.; Boyce,
S.; Rupniak, N.; Forrest, M.; Visco, D.; Patrick, D. Bioorg.
Med. Chem. Lett. 1999, 9, 1773.
Next, exposure of 9 to boron tribromide accomplished
removal of all three methyl groups to furnish lactone 10
with high efficiency.13 Bromination of 10 with Br2/KBr14
delivered cadiolide B as an amorphous orange solid
(6) Jas, G. Synthesis 1991, 965.
(7) Jefford, C. W.; Jaggi, D.; Boukouvalas, J. J. Chem. Soc.,
Chem. Commun. 1988, 1595.
1
whose H NMR and 13C NMR properties were in full
agreement with those reported for the natural product.1
(8) Compound 6: yellow oil. 1H NMR (300 MHz, CDCl3): d =
3.66 (br s, 1 H), 3.79 (s, 3 H), 4.82 (s, 2 H), 5.62 (s, 1 H), 6.89
(d, J = 8.7 Hz, 2 H), 7.38 (d, J = 8.7 Hz, 2 H). 13C NMR (75
MHz, CDCl3): d = 55.2, 69.0, 73.4, 114.1, 127.1, 132.1,
132.4, 139.3, 159.6, 170.2. Anal. Calcd for C12H11BrO4: C,
48.19; H, 3.71. Found: C, 48.13; H, 3.57.
In conclusion, the first synthesis of cadiolide B has been
accomplished in concise and efficient fashion (6 steps,
42% overall yield) by a new, inherently flexible pathway
that is especially attractive for generating libraries of
analogues for biological evaluation.
(9) Ruel, F. S.; Braun, M. P.; Johnson, C. R. Org. Synth.,
Collect. Vol. 75 1998, 69.
(10) See also: Uenishi, J.; Beau, J.-M.; Armstrong, R. W.; Kishi,
Y. J. Am. Chem. Soc. 1987, 109, 4756.
Acknowledgment
We thank NSERC (Canada), Merck Frosst Canada and Eisai Re-
search Institute (MA, USA) for financial support. We also thank
NSERC for a postgraduate scholarship to M. Pouliot.
(11) Compound 7: white solid; mp 90–92 °C. 1H NMR (300
MHz, CDCl3): d = 3.78 (s, 3 H), 3.82 (s, 3 H), 4.15 (d, J = 9.8
Hz, 1 H), 5.03 (d, J = 16.9 Hz, 1 H), 5.22 (d, J = 16.9 Hz, 1
H), 5.79 (d, J = 9.8 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 2 H), 6.93
(d, J = 8.8 Hz, 2 H), 7.29 (d, J = 8.8 Hz, 2 H), 7.38 (d, J = 8.6
Hz, 2 H). 13C NMR (75 MHz, CDCl3): d = 55.2, 55.3, 68.4,
70.8, 114.1, 114.6, 122.4, 124.8, 127.7, 129.2, 133.4, 156.8,
159.3, 161.6, 174.6. HRMS: m/z calcd for C19H18O5:
326.1154; found: 326.1158.
References
(1) Smith, C. J.; Hettich, R. L.; Jompa, J.; Tahir, A.; Buchanan,
M. V.; Ireland, C. M. J. Org. Chem. 1998, 63, 4147.
(2) Miao, S.; Andersen, R. J. J. Org. Chem. 1991, 56, 6275.
(3) Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeau, M.
Tetrahedron Lett. 1998, 39, 7665.
(4) (a) Carroll, A. R.; Healy, P. C.; Quinn, R. J.; Tranter, C. J. J.
Org. Chem. 1999, 64, 2680. (b) Ortega, M. J.; Zubía, E.;
Ocaña, J. M.; Naranjo, S.; Salvá, J. Tetrahedron 2000, 56,
3963.
(5) Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson, S.;
Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson, A.
W.; Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser, M.;
Kargman, S.; Kennedy, B.; Leblanc, Y.; Léger, S.; Mancini,
J.; O’Neill, G. P.; Ouellet, M.; Percival, M. D.; Perrier, H.;
Compound 8: yellow solid; mp 166–167 °C. 1H NMR (300
MHz, CDCl3): d = 3.79 (s, 3 H), 3.85 (s, 3 H), 5.30 (s, 2 H),
6.84 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 7.36 (d,
J = 8.8 Hz, 2 H), 7.91 (d, J = 8.8 Hz, 2 H). 13C NMR (75
MHz, CDCl3): d = 55.3, 55.5, 70.3, 114.1, 114.6, 121.4,
123.4, 128.7, 129.6, 132.0, 159.7, 162.4, 164.6, 171.1,
190.1. Anal. Calcd for C19H16BrO5: C, 70.36; H, 4.97.
Found: C, 70.12; H, 5.02.
(12) Compound 9: yellow solid; 189–190 °C. 1H NMR (300
MHz, CDCl3): d = 3.79 (s, 3 H), 3.81 (s, 3 H), 3.84 (s, 3 H),
6.23 (s, 1 H), 6.84 (d, J = 8.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz,
2 H), 6.92 (d, J = 8.6 Hz, 2 H), 7.36 (d, J = 8.6 Hz, 2 H), 7.80
(d, J = 8.6 Hz, 4 H). 13C NMR (75 MHz, CDCl3): d = 55.2,
Synlett 2005, No. 2, 343–345 © Thieme Stuttgart · New York