reaction. Recent studies by Evans19 and Crimmins20 have
elevated the utility of thiazolidinethione auxiliaries as applied
to propionate aldol reactions (Scheme 2). Three of the four
Table 1. Stille Couplings of Tin-Substituted Kavalactones
Scheme 2. Representative Aldol Reactions of N-Propionyl
Thiazolidinethiones
analogues, we have prepared vinylstannane 11 as a common
advanced precursor. In several unoptimized initial experi-
ments (Table 1), Stille couplings15 with three appropriate aryl
iodides provided (+)-kavain (1), (+)-5,6-dihydroyangonin
(12), and (+)-methysticin (3).16 This coupling strategy
circumvents the difficulties associated with the preparation
of electron-rich cinnamaldehyde derivatives and their di-
minished reactivity in aldol reactions and allows for the rapid
generation of aryl-substituted kavain analogues.17,18 A comple-
mentary Suzuki coupling approach is currently under inves-
tigation.
possible diastereomeric products can now be accessed with
appropriate selection of enolization conditions.21 The catalytic
asymmetric variant of this process is particularly elegant.19b
We prepared the known cinnamaldehyde adducts of the
phenylalanine-derived thiazolidinethiones (19-22) and sub-
jected them to our reaction conditions (Table 2). Gratifyingly,
Having demonstrated the utility of the aldol/trans-acylation
sequence, we chose to explore the scope of this interesting
(7) (a) Davies, L. P.; Drew, C. A.; Duffield, P.; Johnston, G.; Jamieson,
D. Pharmacol. Toxicol. 1992, 7, 120. (b) Jussofie, A.; Schmiz, A.; Hiemke,
C. Psychopharmacology 1994, 116, 469. (c) Seitz, U.; Schule, A. L.; Gleitz,
J. Planta Med. 1997, 63, 548. (d) Boonen, G.; Ha¨berlein, H. Planta Med.
1998, 64, 504. (e) Baum, S. S.; Hill, R.; Rommelspacher, H. Prog. Neuro-
Psychopharmacol. Biol. Psychiatry. 1998, 22, 1105. (f) Yuan, C.-S.; Dey,
L.; Wang, A. B.; Mehendale, S.; Xie, J.-T.; Aung, H. H.; Ang-Lee, M. K.
Planta Med. 2002, 68, 1092.
Table 2. Malonate Displacements of Thiazolidinethionesa
(8) Stickel, F.; Baumu¨ller, H.-M.; Seitz, K.; Vasilakis, D.; Seitz, G.; Seitz,
H. K.; Schuppan, D. J. Hepatol. 2003, 39, 62.
(9) Ha¨berlein, H.; Boonen, G.; Beck, M. A. Planta Med. 1997, 63, 63.
(10) (a) Kostermans, D. Nature 1950, 166, 788. (b) Fowler, E. M. F.;
Henbest, H. B. J. Chem. Soc. 1950, 3642. (c) Klohs, M. W.; Keller, F.;
Williams, R. E. J. Org. Chem. 1959, 24, 1829. (d) Izawa, T.; Mukaiyama,
T. Chem. Lett. 1975, 161. (e) Israili, Z. H.; Smissman, E. E. J. Org. Chem.
1976, 41, 4070. (f) Reffstrup, T.; Boll, P. M. Acta Chem. Scand. B 1976,
30, 613. (g) Dziadulewicz, E.; Giles, M.; Moss, W. O.; Gallagher, T.;
Harman, M.; Hursthouse, M. B. J. Chem. Soc., Perkin Trans. 1 1989, 1793.
(11) (a) Spino, C.; Mayes, N.; Desfosse´s, H.; Sotheeswaran, S. Tetra-
hedron Lett. 1996, 37, 6503. (b) McCleary, J.; Sun, L.; Chen, S. U.S. Patent
6,677,462, 2004; Chem. Abstr. 2003, 133055.
(12) A hetero Diels-Alder approach was used to produce kavain in 13%
ee: Togni, A. Organometallics 1990, 9, 3106.
(13) (a) Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. J.
Chem. Soc., Chem. Commun. 1985, 1418. (b) Nagao, Y.; Hagiwara, Y.;
Kumagai, T.; Ochiai, M.; Inoue, T.; Hashimoto, K.; Fujita, E. J. Org. Chem.
1986, 51, 2391. (c) Gonza´lez, AÄ .; Aiguade´, J.; Urp´ı, F.; Vilarrasa, J.
Tetrahedron Lett. 1996, 37, 8949. (d) Guz, N. R.; Phillips, A. J. Org. Lett.
2002, 4, 2253. (e) Zhang, Y.; Phillips, A. J.; Sammakia, T. Org. Lett. 2004,
6, 23.
a Conditions: potassium ethyl malonate (2 equiv), MgCl2 (1 equiv), imid.
(1 equiv), THF, rt, overnight.
(14) (a) Nagao, Y.; Matsunaga, H.; Kumagai, T.; Inoue, Y.; Miwa, Y.;
Taga, T. J. Chem. Soc., Chem Commun. 1992, 437. (b) Brooks, D. W.; Lu,
L. D-L.; Masamune, S. Angew. Chem., Int. Ed. Engl. 1979, 18, 72. (c)
Gage, J. R.; Kelly, R. C.; Hewitt; B. D. U.S. Patent 6,077,963, 2000; Chem.
Abstr. 1999, 194136.
(15) For a review see: Farina, V.; Krishnamurthy, V.; Scott, W. J. The
Stille Reaction; John Wiley & Sons: New York, 1998.
the expected â-ketoester products (23-25) were produced,
albeit in moderate yields.
Finally, as a complementary alternative to this chiral
auxiliary-based approach, we also have demonstrated that
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