Versatile asymmetric synthesis of the kavalactones: First synthesis of (+)-kavain

Article abstract of DOI:10.1021/ol0493960

(Equation Presented) Three asymmetric pathways to the kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates, prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings with aryl halides.

Full text of DOI:10.1021/ol0493960

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2317-2320
Versatile Asymmetric Synthesis of the
Kavalactones: First Synthesis of
(+)-Kavain
Thomas E. Smith,* Mabel Djang, Alan J. Velander, C. Wade Downey,†
Kathleen A. Carroll, and Sophie van Alphen
Department of Chemistry, Williams College, Williamstown, Massachusetts 01267
tsmith@williams.edu
Received April 1, 2004
ABSTRACT
Three asymmetric pathways to the kavalactones have been developed. The first method is chiral auxiliary-based and utilizes aldol reactions
of N-acetyl thiazolidinethiones followed by a malonate displacement/decarboxylation reaction. The second approach uses the asymmetric
catalytic Mukaiyama additions of dienolate nucleophile equivalents developed by Carreira and Sato. Finally, tin-substituted intermediates,
prepared by either of these routes, can serve as advanced general precursors of kavalactone derivatives via Pd(0)-catalyzed Stille couplings
with aryl halides.
The Kava plant (Piper methysticum) has a long and colorful
history spanning several thousand years.1 Kava has been used
by Pacific Island societies to prepare an intoxicating cer-
emonial beverage renowned for its relaxing effects and ability
to promote sociability. Modern use of Kava root, commonly
available in dietary supplements labeled “Kava Kava”, is also
for its purported anxiolytic2 and soporific qualities. Anal-
gesic,3 anesthetic, antifungal, antithrombotic,4 anticonvul-
sive,5 and muscle-relaxing6 properties also have been re-
ported.1 The psychoactive principals are a family of 15
R-pyrone derivatives known as the kavalactones that com-
prise roughly 15% of the dried rootstock. The more prevalent
of these include kavain (1, Figure 1), dihydrokavain (2), and
methysticin (3). Structurally, the kavalactones differ chiefly
with respect to their arene substitution patterns and the
presence or absence of double bonds along their carbon
backbones. Although a few of the kavalactones, such as
yangonin (5), are achiral, the majority have a single stereo-
genic center at C6 and are homochiral.
† Harvard University.
Several clinical studies indicate that the kavalactones have
a demonstrable anxiety-reducing effect.2 The pharmacologi-
cal mechanism of this anxiolysis, however, is still unclear.7
Recent warnings by the FDA and CDC of rare but severe
cases of liver injury, possibly associated with the use of kava-
(1) For a review, see: Lebot, V.; Merlin, M.; Lindstrom, L. KaVa-the
Pacific Elixir: The DefinitiVe Guide to its Ethnobotony, History, and
Chemistry; Healing Arts Press: Rochester, VT, 1997.
(2) (a) Pittler, M. H.; Ernst, E. J. Clin. Psychopharm. 2000, 20, 84. (b)
Smith, K. K.; Dharmaratne, H. R. W.; Feltenstein, M. W.; Broom, S. L.;
Roach, J. T.; Nanayakkara, N. P. D.; Khan, I. A.; Sufka, K. J Psycho-
pharmacology 2001, 155, 86.
(3) (a) Jamieson, D. D.; Duffield, P. H. Clin. Exp. Pharmacol. Physiol.
1990, 17, 495. (b) Wu, D.; Yu, L.; Nair, M. G.; DeWitt, D. L.; Ramsewak,
R. S. Phytomedicine 2002, 9, 41.
(4) Gleitz, J.; Beile, A.; Wilkens, P.; Ameri, A.; Peters, T. Planta Med.
1997, 63, 27.
(5) Schmitz, D.; Zhang, C. L.; Chatterjee, S. S.; Heinemann, U. Arch.
Pharmacol. Toxicol. 1995, 351, 348.
(6) Seitz, U.; Amerl, A.; Pelzer, H.; Gleitz, J.; Peters, T. Planta Med.
1997, 63, 303.
10.1021/ol0493960 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/16/2004

Our first approach to a general asymmetric synthesis of
the kavalactones utilizes acetate aldol reactions based upon
thiazolidinethione chiral auxiliaries (Scheme 1).13 The tita-
nium enolate of valine-derived N-acetyl thiazolidinethione
7 was reacted with cinnamaldehyde or dihydrocinnamalde-
hyde to give aldol adducts 8a13c and 8b, respectively. Similar
reactions with an analogous tributyltin-substituted aldehyde
led to protodestannylated products. Use of the original Nagao
tin triflate enolization conditions13a,b alleviated this problem.
Although tin-based aldol reactions of this type generally give
higher levels of diastereocontrol, the titanium counterparts
provide useful yields of purified major diastereomers with
less expense and operational complexity. The boron-based
system very recently reported by Sammakia would also be
an attractive option here.13e
Critical to the efficiency of our plan was the discovery
that the thiazolidinethione auxiliaries can be displaced by a
carbon nucleophile without the need for protection of the
free hydroxyl group. Thus, treatment of aldol adducts 8a-c
with the potassium salt of monoethyl malonate and MgCl2
in the presence of imidazole led to â-ketoesters 9a-c. The
intermediacy of acyl imidazolides is presumed.14 This direct
homologation of thiazolidinethione aldol adducts represents
a powerful method for the preparation of polyacetate
fragments.
Figure 1. Representative kavalactones from P. methysticum.
containing dietary supplements, further accentuate the need
for additional studies on the individual kavalactones and
structural analogues.8
Lactonization of the δ-hydroxy-â-ketoesters (9) is smoothly
accomplished with potassium carbonate in methanol. Al-
though it is possible to isolate and purify the polar â-keto-
lactone intermediates (10), we have found it more efficient
to simply remove the methanol solvent in vacuo and then
carry out the standard enol ether formations in the same pot
to afford the kavalactone products. In this fashion, the first
asymmetric synthesis of (+)-kavain (1) was completed in
64% overall yield in three steps from cinnamaldehyde.
In an effort to devise a synthesis that would provide rapid
access to the entire family of kavalactones and structural
Although mixtures of the kavalactones are readily available
from the crude extract of cultivated Kava, large quantities
of isolated enantiopure kavalactones are not.9 Similarly,
although racemic syntheses of the kavalactones are numer-
ous,10 no generally applicable asymmetric synthesis has been
developed. Enantioselective reductions of â-ketoester inter-
mediates have led to the preparation of (+)-7,8-dihydroka-
viain (2), but these methods currently are not amenable to
the synthesis of kavalactones having C7-C8 unsaturation.11
Somewhat surprisingly, no enantioselective synthesis of (+)-
kavain has been reported to date.12
Scheme 1. Chiral-Auxiliary-Based Synthesis of Kavalactones
2318
Org. Lett., Vol. 6, No. 14, 2004

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
Org. Lett., Vol. 6, No. 14, 2004
2319

Scheme 3. Carreira’s Catalytic Asymmetric Dienolate
Scheme 4. Asymmetric Catalysis-Based Synthesis of the
Additions to Aldehydesa
Kavalactones
a As reported in ref 22a.
In conclusion, we have developed three simple and
efficient approaches to the asymmetric synthesis of the
kavalactones and have completed the first enantioselective
synthesis of (+)-kavain.
the products of the asymmetric Mukaiyama aldol reactions
developed by Carreira22 (Scheme 3) and Sato23 can be
transformed directly into the kavalactone ring system in a
single pot (Scheme 4). Although we have only tested our
lactonization/methylation process on racemic substrates,24 use
of the Carreira catalyst would render this an extremely
efficient enantioselective route to the kavalactones.
Acknowledgment. This research was supported by the
Petroleum Research Fund, administered by the American
Chemical Society (36453-GB1), the National Science Foun-
dation (CHE-0237658), and Williams College. We are
grateful to Dr. Franc¸ois Be´land of SiliCycle, Inc. for
providing samples of functionalized silica gels, functionalized
TLC plates, and analysis of tin scavenging experiments. We
thank Mr. James P. Sieradzki for preliminary studies.
(16) Although the coupling reactions proceeded more rapidly with tri-
2-furylphosphine, small amounts of furyl-substituted kavalactones were
observed as a result of phosphorous-to-palladium aryl migration (Kong,
K.-C.; Cheng, C.-H. J. Am. Chem. Soc. 1991, 113, 6313). This problem
was alleviated by the use of tris(o-methoxyphenyl)phosphine.
(17) The 7,8-dihydrokavalactone derivatives are available from these
coupled products via selective catalytic hydrogenation (ref 10e).
(18) The tributyltin iodide byproducts of these coupling reactions could
not be completely removed by chromatography using normal silica gel.
However, simply stirring for 1 h with a slurry of triamine-functionalized
silica gel (SiliCycle, Si-Triamine) succeeded in scavenging 95% of the
residual tin contaminants. Chromatography with diol-functionalized silica
gel (SiliCycle, Si-Diol) was also required to achieve clean chromatographic
separation of tin-substituted aldol adduct 8c.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0493960
(19) (a) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org.
Lett. 2002, 4, 1127. (b) Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am.
Chem. Soc. 2003, 125, 8706.
(20) (a) Crimmins, M. T.; Chaudhary, K. Org. Lett. 2000, 2, 775. (b)
Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894.
(21) The final diastereomeric possibility is accessible via the correspond-
ing oxazolidinone: Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C.
W. J. Am. Chem. Soc. 2002, 124, 392.
(22) (a) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117,
12360. (b) Kim, Y.; Singer, R. A.; Carreira, E. M. Angew. Chem., Int. Ed.
1998, 37, 1261. (c) Kru¨ger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998,
120, 837.
(23) (a) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pharm.
Bull. 1994, 42, 839. (b) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C.
Heterocycles 1995, 41, 1435. (c) DeRosa, M.; Soriente, A.; Scettri, A.
Tetrahedron: Asymmetry 2000, 11, 3187.
(24) Racemic 28 was prepared from 26 using TiCl4 as the Lewis acid.
2320
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