Method B. To a solution of carbamate 31 (0.35 g, 1.0 mmol) and
(−)-sparteine (0.28 g, 1.2 mmol) in Et2O (10 mL), at −78 ◦C, was
added dropwise s-BuLi (1.3 M, 0.92 mL, 1.2 mmol). The solution
was stirred at −78 ◦C for 5 h and then a solution of arylboronate
37 (0.37 g, 1.1 mmol) in diethyl ether (5 mL) was added dropwise
followed by MgBr2 (prepared from 1,2-dibromoethane (0.226 g,
1.2 mmol), Mg (0.048 g, 2 mmol) in Et2O (10 mL) by stirring at
rt for 4 h). The mixture was allowed to warm gradually to r.t. for
12 h while nitrogen was passed through it to remove the solvent. To
the solid residue DME (10 mL, freshly distilled from CaH2) was
added and the mixture refluxed for 12 h. The mixture was cooled
to r.t. and then treated with an aq. solution of K2CO3 (2.4 mL,
0.5 M, 1.2 mmol) and H2O2 (30%, 0.18 g, 0.16 mL, 1.4 mmol).
The mixture was stirred for 15 min at r.t. then poured into water
(10 mL) and extracted with Et2O (3 × 10 mL). The combined
extracts were washed with aq. sat. Na2S2O3, dried (Na2SO4) and
concentrated to give a yellow oil (0.68 g). The crude product was
purified twice by column chromatography (SiO2, first CH2Cl2–
Et2O and then hexanes–Et2O) to give 17 as a colourless oil (0.28 g,
0.65 mmol, 65%). The product had some impurities (ca 10%) that
were impossible to remove by column chromatography. The er of
the product, determined by chiral HPLC, was 98 : 2.
1952, vol. 2, pp. 261–329. For later developments on the synthesis
and biological activity of colchicine and its allo congeners see ref. 56.
2 F. Lits, C. R. Seances Soc. Biol. Ser Fil., 1934, 115, 1421.
3 A. P. Dustin, Bull. Acad. R. Med. Belg., 1934, 14, 487.
4 E. C. Amoroso, Nature, 1935, 135, 266.
5 A. Brossi, J. Med. Chem., 1990, 33, 2311.
6 Q. Shi, K. Chen, A. Brossi, P. Verdier-Pinard, E. Hamel, A. T. McPhail
and K.-H. Lee, Helv. Chim. Acta, 1998, 81, 1023.
7 Q. Shi, K. Chen, X. Chen, A. Brossi, P. Verdier-Pinard, E. Hamel, A. T.
McPhail, A. Tropsha and K.-H. Lee, J. Org. Chem., 1998, 63, 4018.
8 S. Bergemann, R. Brecht, F. Bu¨ttner, D. Gue´nard, R. Gust, G. Seitz,
M. T. Stubbs and S. Thoret, Bioorg. Med. Chem., 2003, 11, 1269.
9 J. Guan, X.-K. Zhu, A. Brossi, Y. Tachibana, K. F. Bastow, P. Verdier-
Pinard, E. Hamel, A. T. McPhail and K.-H. Lee, Collect. Czech. Chem.
Commun., 1999, 64, 217.
10 P. D. Davis, G. J. Dougherty, D. C. Blakey, S. M. Galbraith, G. M.
Tozer, A. L. Holder, M. A. Naylor, J. Nolan, M. R. L. Stratford, D. J.
Chaplin and S. A. Hill, Cancer Res., 2002, 62, 7247.
11 G. Micheletti, M. Poli, P. Borsotti, M. Martinelli, B. Imberti, G.
Taraboletti and R. Giavazzi, Cancer Res., 2003, 63, 1534.
12 Brues and Cohen had shown that N-acetylcolchinol was similar to
colchicine in its effect on cell division in 1936: A. M. Brues and A. V.
Cohen, Biochem. J., 1936, 30, 1363.
13 M. A. Iorio, Heterocycles, 1984, 22, 2207.
14 J. Cech and F. Santavy, Collect. Czech. Chem. Commun., 1949, 4, 532.
15 R. Brecht, F. Haenel and G. Seitz, Liebigs Ann., 1997, 2275.
16 By contrast, the synthesis of colchicine has received ample attention:
T. Graening and H.-G. Schmalz, Angew. Chem., Int. Ed., 2004, 43,
3230.
4,4,5,5-Tetramethyl-2-(3-tert-butyldimethylsilyloxyphenyl)-1,3-
dioxaborolane (37). To a solution of 4,4,5,5-tetramethyl-2-(3-
hydroxyphenyl)-1,3-dioxaborolane (0.99 g, 4.5 mmol) in DMF
(10 mL) was added imidazole (0.77 g, 11.4 mmol) followed
by TBSCl (0.82 g, 5.42 mmol). The solution was stirred at
r.t. for 12 h, then poured into water (100 mL) and extracted
with Et2O (2 × 20 mL). The combined extracts were dried
(Na2SO4), concentrated in vacuo and the residue purified by
column chromatography (SiO2, hexanes–Et2O) to give silyl ether
37 (1.25 g, 3.75 mmol, 83%) as a colourless oil that solidified
after storing a few days in a refrigerator: mp 37–38 ◦C. IR (film):
m = 3047 s, 2950 s, 2931 s, 2859 s, 1574 s, 1487 m, 1422 s, 1356 s,
17 J. W. Cook, J. Jack, J. D. Loudon, G. L. Buchanan and J. MacMillan,
J. Chem. Soc., 1951, 1397.
18 H. Rapoport, A. R. Williams and M. E. Cisney, J. Am. Chem. Soc.,
1951, 73, 1414.
19 J. S. Sawyer and T. L. Macdonald, Tetrahedron Lett., 1988, 29, 4839.
20 Banwell and co-workers performed an oxidative phenolic coupling
using lead tetraacetate as a key step in their synthesis of colchicine:
M. G. Banwell, J. N. Lambert, M. F. Mackay and R. J. Greenwood,
J. Chem. Soc., Chem. Commun., 1992, 974.
21 M. Leblanc and K. Fagnou, Org. Lett., 2005, 7, 2849.
22 A. V. Vorogushin, A. V. Predeus, W. D. Wulff and H.-J. Hansen, J. Org.
Chem., 2003, 68, 5826.
23 T. Keenan, D. R. Yaeger, N. L. Courage, C. T. Rollins, M. E. Pavone,
V. M. Rivera, W. Yang, T. Guo, J. F. Amara, T. Clackson, M. Gilman
and D. A. Holt, Bioorg. Med. Chem., 1998, 6, 1309.
24 D. B. Cordes, T. M. Nguyen, T. J. Kwong, J. T. Suri, R. T. Luibrand
and B. Singaram, Eur. J. Org. Chem., 2005, 5289.
1
1314 s, 1235 s, 1145 s, 969 s, 838 s cm−1. H NMR (500 MHz,
CDCl3): dH = 7.40 (1H, d, J 7.2, CH), 7.24 (1H, t, J 7.7, C5H),
7.27 (1H, s, C2H), 6.93 (1H, dd, J 1.6, 8.0), 1.35 (12H, s, 4 ×
CH3), 1.00 (9H, s, C(CH3)3), 0.21 (6H, s, (CH3)2Si). 13C NMR
(75 MHz, CDCl3): dC = 155.3 (C3), 130.7 (br, C1), 129.0 (CH),
127.9 (CH), 126.3 (CH), 123.0 (CH), 83.9 (2 × C(CH3)2), 25.9
(C(CH3)3), 25.0 (4 × CH3CO), 18.3(C(CH3)3), −4.2 (Si(CH3)2).
11B NMR (80 MHz, CDCl3): d = 30.8 ppm. HRMS (ES): m/z
calcd for C18H31BO3Si (M + H)+: 335.2208 Found: 335.2224.
Anal. calcd for C18H31BO3Si: C, 64.66; H, 9.35%. Found: C, 64.4;
H, 9.5%.
25 Asymmetric reduction of 14 with (+)-B-chlorodiisopinyl-
campheylborane (er > 98 : 2) was reported by Holt and co-workers
(see ref. 23).
26 E. J. Corey, R. K. Bakshi and S. Shibata, J. Am. Chem. Soc., 1987, 109,
5551.
27 E. J. Corey and C. J. Helal, Angew. Chem., Int. Ed., 1998, 37, 1987.
28 K.-J. Haack, S. Hasiguchi, A. Fujii, T. Ikariya and R. Noyori, Angew.
Chem., Int. Ed., 1997, 36, 285.
29 R. Noyori and T. Ohkuma, Angew. Chem., Int. Ed., 2001, 40, 40.
30 M. Kitamura and R. Noyori, in Ruthenium in Organic Synthesis, ed.
S.-I. Murahashi, VCH Weinheim, 2004, p. 3.
31 B. Lal, B. N. Pramanik, M. S. Manhas and A. K. Bose, Tetrahedron
Lett., 1977, 18, 1977.
32 A. Saito, K. Saito, A. Tanaka and T. Oritani, Tetrahedron Lett., 1997,
38, 3955.
33 M. C. Viaud and P. Rollin, Synthesis, 1990, 130.
Acknowledgements
34 A. McKillop, A. G. Turrell, D. W. Young and E. C. Taylor, J. Am.
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35 E. C. Taylor, J. G. Andrade, G. J. H. Rall and A. McKillop, J. Am.
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38 Y. Kita, H. Tohma, K. Hatanaka, T. Takada, S. Fujita, S. Mitoh, H.
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39 H. Hamamoto, G. Anilkumar, H. Tohma and Y. Kita, Chem.–Eur. J.,
2002, 8, 5377.
We thank the EPSRC and AstraZeneca Pharmaceuticals for
generous financial support. We also thank Colin Kilner for X-
ray structure determinations, Tanya Marinko-Covell for mass
spectrometry, Simon Barrett for NMR spectroscopy and James
Titchmarsh for chiral HPLC.
References
1 For a comprehensive summary of the early biological studies on
colchicine see: J. W. Cook and J. D. Loudon, The Alkaloids, ed.
R. H. F. Manske and H. L. Holmes, Academic Press, New York,
40 T. Takada, M. Arisawa, M. Gyoten, R. Hamada, H. Tohma and Y.
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2206 | Org. Biomol. Chem., 2006, 4, 2193–2207
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