ORGANIC
LETTERS
2
006
Vol. 8, No. 23
239-5242
Substrate-Directed Stereoselectivity in
Vicinal Diamine-Catalyzed Synthesis of
Warfarin
5
Hyunwoo Kim, Cindy Yen, Philippa Preston, and Jik Chin*
Department of Chemistry, UniVersity of Toronto, 80 St. Geroge Street,
Toronto, ON, M5S 3H6 Canada
Received August 11, 2006
ABSTRACT
A new mechanism involving a diimine intermediate is proposed for vicinal diamine-catalyzed synthesis of warfarin. Decreasing the NCCN
dihedral angle by varying the diamine results in an increase in the enantioselectivity of warfarin synthesis.
4
There has been much recent interest in developing stereo-
However, the mechanism provided in the study leads one
to predict the sense of stereoselectivity for the reaction that
selective organocatalysts for making new carbon-carbon
1
-3
4
6
bonds.
In an elegant and innovative study, a chiral
is opposite to the one observed. Our interest in finding the
imidazolidine (1) was used as a catalyst for stereoselective
coupling of 4-hydroxycoumarin (2) and trans-4-phenyl-3-
buten-2-one (3) to make warfarin (4), a widely prescribed
correct mechanism and the origin of stereoselectivity led us
(
3) For selected organocatalytic conjugate additions to R,â-unsaturated
aldehydes, see: (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc.
002, 124, 1172-1173. (b) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem.
5
anticoagulant used for treating thrombosis (Scheme 1).
2
Soc. 2002, 124, 7894-7895. (c) Brown, S. P.; Goodwin, N. C.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2003, 125, 1192-1194. (d) Huang, Y.; Walji,
A. M.; Larsen, C. H.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
15051-15053. (e) Wang, W.; Li, H.; Wang, J. Org. Lett. 2005, 7, 1637-
1639. (f) King, H. D.; Meng, Z.; Denhart, D.; Mattson, R.; Kimura, R.;
Wu, D.; Gao, Q.; Macor, J. E. Org. Lett. 2005, 7, 3437-3440. (g) Xie,
J.-W.; Yue, L.; Xue, D.; Ma, X.-L.; Chen, Y.-C.; Wu, Y.; Zhu, J.; Deng,
J.-G. Chem. Commun. 2006, 1563-1565.
(
1) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-
5
175. (b) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719-724. (c)
List, B. Acc. Chem. Res. 2004, 37, 548-557. (d) Allemann, C.; Gordillo,
R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. Acc. Chem. Res. 2004,
3
5
5
7, 558-569. (e) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37, 570-
79. (f) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37,
80-591.
(
2) For selected organocatalytic conjugate additions to R,â-unsaturated
(4) Halland, N.; Hansen, T.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2003, 42, 4955-4957.
ketones, see: (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975-2978.
b) Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67,
331-8338. (c) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem.,
(
8
(5) For stereoselective warfarin synthesis, see: (a) Demir, A. S.; Tanyeli,
C.; G u¨ lbeyaz, V.; Akg u¨ n, H. Turk. J. Chem. 1996, 20, 139-145. (b)
Robinson, A.; Li, H.-Y.; Feaster, J. Tetrahedron Lett. 1996, 37, 8321-
8324. (c) Cravotto, G.; Nano, G. M.; Palmisano, G.; Tagliapietra, S.
Tetradedron: Asymmetry 2001, 12, 707-709.
Int. Ed. 2003, 42, 661-665. (d) Melchiorre, P.; Jørgensen, K. A. J. Org.
Chem. 2003, 68, 4151-4157. (e) Halland, N.; Aburel, P. S.; Jørgensen, K.
A. Angew. Chem., Int. Ed. 2004, 43, 1272-1277. (f) Fonseca, M. T. H.;
List, B. Angew. Chem., Int. Ed. 2004, 43, 3958-3960. (g) Peelen, T. J.;
Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598-11599. (h)
Yang, J. W.; Fonseca, M. T. H.; List, B. J. Am. Chem. Soc. 2005, 127,
5036-15037. (i) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.;
Masui, R.; Shoji, M. J. Am. Chem. Soc. 2005, 127, 16028-16029. (j) Prieto,
A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897-3900.
(6) In Figure 1 (right) of the original report,4 the (R,R) form of the
imidazolidine catalyst forms an aminal intermediate with the ketone
substrate. According to this figure, hydroxycoumarin is expected to attack
from the Si face since the Re face is blocked. This leads one to predict that
the (R,R) form of the catalyst would give the S form of warfarin in conflict
with the experimental result (Table 1 of the original report).
1
1
0.1021/ol062000v CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/11/2006