K. M. Engstrom et al. / Tetrahedron Letters 48 (2007) 1359–1362
1361
1) 2.5 eq LiOH.H2O, MeOH
O
2) H2O, CHCl3 wash
MeO2C
AcO
O
O
NH HN
N
S
OMe
3
O
3) Dowex OH- resin
4) AcOH,iPrOH distillation
5) lyophilization
OAc
OAc
6
Scheme 3. Deprotection of 6.
Yoshimatsu, K.; Iijima, A.; Nagasu, T.; Tsukahara, K.;
Kitoh, K. Sulfonamide Derivatives. U.S. Patent 5,250,549,
October 5, 1993.
After the reaction was complete, addition of 1.5 equiv of
water converted boron complex 7 into the desired prod-
uct 6. By HPLC analysis, no significant impurities or
isomers were detected in the crude reaction mixture. It
is possible that the excess equivalents of BF3 form a
complex with 1, which effectively deactivates the reactive
nitrogen functionality and prevents formation of N-
linked isomers. Aqueous sodium bicarbonate workup
quenched and removed the boron side products, while
silica gel chromatography and recrystallization from
methanol removed excess hydrolyzed 5 to give an 83%
isolated yield of 6.
4. Gordon, G.; Hagey, A. E.; Meek, K. A.; Rosenberg, S. H.
Treatment of Cancer in Pediatric Patients. International
Patent WO 2005/117903 A1, December 15, 2005.
5. Eisai Co., previously unpublished results.
6. For the synthesis of some glucuronides containing basic
functional groups, see: (a) Kim, S.; Wu, J. Y.; Zhang, Z.;
Tang, W.; Doss, G. A.; Dean, B. J.; DiNinno, F.;
Hammond, M. L. Org. Lett. 2005, 3, 411–414; (b) Liu,
C.-H.; Liu, H.; Han, X.-Y.; Wu, B.; Zhong, B.-H.; Gong,
Z.-H. Synth. Commun. 2005, 5, 701–710; (c) Stazi, F.;
Palmisano, G.; Turconi, M.; Clini, S.; Santagostino, M. J.
Org. Chem. 2004, 4, 1097–1103; (d) Kawamura, K.;
Horikiri, H.; Hayakawa, J.; Seki, C.; Yoshizawa, K.;
Umeuchi, H.; Nagase, H. Chem. Pharm. Bull. 2004, 6,
670–671; (e) Kuo, F.; Gillespie, T. A.; Kulanthaivel, P.;
Lantz, R. J.; Ma, T. W.; Nelson, D. L.; Threlkeld, P. G.;
Wheeler, W. J.; Yi, P.; Zmijweski, M. Bioorg. Med. Chem.
Lett. 2004, 13, 3481–3486; (f) Wang, Y.; Yuan, H.;
Wright, S. C.; Wang, H.; Larrick, J. W. Bioorg. Med.
Chem. 2003, 7, 1569–1576; (g) Hasuoka, A.; Nakayama,
Y.; Adachi, M.; Kamiguchi, H.; Kamiyama, K. Chem.
Pharm. Bull. 2001, 12, 1604–1608; (h) Rukhman, I.;
Yudovich, L.; Nisnevich, G.; Gutman, A. L. Tetrahedron
2001, 6, 1083–1092, and references therein; (i) Brown, R.
T.; Carter, N. E.; Mayalarp, S. P.; Scheinmann, F.
Tetrahedron 2000, 56, 7591–7594; (j) Suzuki, T.; Mabuchi,
K.; Fukazawa, N. Bioorg. Med. Chem. Lett. 1999, 5, 659–
662; (k) Dodge, J. A.; Lugar, C. W.; Cho, S.; Osborne, J.
J.; Philips, D. L.; Glasebrook, A. L.; Frolik, C. A. Bioorg.
Med. Chem. Lett. 1997, 8, 993–996.
Removal of the acetate groups and hydrolysis of the
methyl ester in 6 were accomplished using 2.5 equiv of
LiOHÆH2O in methanol (Scheme 3).7 Addition of water
and subsequent washing with chloroform removed
partially deprotected impurities if any. Treatment with
Dowex hydroxide resin adsorbed the carboxylate of 3
and filtration and washing of the resin with water re-
moved the lithium salts. The product was then recovered
from the resin by treatment with acetic acid, followed by
azeotropic removal of acetic acid with isopropanol.
Repeated lyophilization from water removed residual
solvents to give amorphous 3 in 72% isolated yield.
In summary, synthesis of the ABT-751 glucuronide 3
using the Schmidt trichloroacetimidate methodology
for the direct glucuronidation of the readily available
aglycone 1 resulted in an increase in overall yield from
16% using the linear route to 60% using this more con-
vergent route. This increase in efficiency and throughput
allowed for more rapid synthesis of the multigram quan-
tities of this metabolite required for clinical use.
7. Engstrom, K. M.; Daanen, J. F.; Wagaw, S.; Stewart, A.
O. J. Org. Chem. 2006, 71, 8378–8383.
8. Compound 5 can be synthesized on multigram scale from
1,2,3,4-tetra-O-acetyl-b-D-glucuronic acid methyl ester in
two steps: (a) Bollenback, G. N.; Long, J. W.; Benjamin,
D. G.; Lindquist, J. A. J. Am. Chem. Soc. 1955, 77, 3310–
3315; (b) Jacquinet, J. C. Carbohydr. Res. 1990, 199, 153–
181.
Acknowledgements
9. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC627190. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
10. Data for 6: 1H NMR (DMSO-d6 (2.50 ppm), 500 MHz): d
9.48 (s, 1H, NH), d 7.94 (dd, J = 4.9, 1.7 Hz, 1H), d 7.85
(s, 1H, NH), d 7.59 (d, J = 9.0 Hz, 2H),d 7.33 (d,
J = 9.2 Hz, 2H), d 7.25 (dd, J = 7.7, 1.7 Hz, 1H), d 6.96
(d, J = 9.1 Hz, 2H), d 6.88 (d, J = 9.1 Hz, 2H), d 6.70 (dd,
J = 4.9, 7.7 Hz, 1H), d 5.53 (d, J = 7.9 Hz, 1H), d 5.48 (t,
J = 9.6 Hz, 1H), d 5.07 (dd, J = 9.6, 7.8, 1H), d 5.06 (t,
J = 9.6 Hz, 1H), d 4.68 (d, J = 9.9, 1H) d 3.71 (s, 3H), d
3.65 (s, 3H), d 2.04 (s, 3H), d 2.01 (s, 3H), d 2.00 (s, 3H).
13C NMR (DMSO-d6 (39.5 ppm), 125 MHz): d 170.0,
169.8, 169.5, 167.6, 163.0, 151.4, 151.4, 145.7, 136.5, 135.3,
We would like to thank Dr. Anthony Haight and Dr.
Seble Wagaw for helpful suggestions and discussions.
References and notes
1. For a review of the importance of glucuronides in
regulation of the biological activity of pharmaceuticals,
see: Mulder, G. J. J. Annu. Rev. Pharmacol. Toxicol. 1992,
32, 25–49.
2. For reviews on the chemical synthesis of glucuronides, see:
(a) Stachulski, A. V.; Jenkins, G. A. Nat. Prod. Rep. 1998,
173–186; (b) Kaspersen, F. M.; van Boeckel, C. A. A.
Xenobiotica 1987, 17, 1451–1471.
3. Yoshino, H.; Ueda, N.; Sugumi, H.; Niijima, J.; Kotake,
Y.; Okada, T.; Koyanagi, N.; Watanabe, T.; Asada, M.;