2078
F.-D. Wang, J.-M. Yue
LETTER
To our delight, although substrate 5 has a free hydroxy at more difficult. Finally, according to the literature proce-
the chiral center and a cyano group, Spencers’ conditions dure,6 compound 6 was then converted to the target
completely converted the cis form of 5 to its trans form molecule 1a16 in 81% yield by a two-step one-pot reac-
20
{[a]D +28.7 (c 1.29, CHCl3)} without racemizing the tion. The 1H NMR data,17 melting point, as well as optical
chiral center at C-6, but it took a whole week to complete rotation18 of (R)-(+)-kavain 1a were very close to those of
the isomerization reaction at room temperature. An effort the natural product.
was thus made to modify the isomerization conditions
(Table 1) aiming to speed up the reaction. The optimum
reaction conditions were employed benzene as the solvent
In conclusion, a chiral approach for the synthesis of (R)-
(+)-kavain 1a, giving an overall yield of 25%, was com-
plete in eight steps from 2,3-O-isopropylidene-D-glycer-
at reflux; after a reaction time of nine hours the cis form
aldehyde 2. The (MeCN)2PdCl2-catalyzed isomerization
of 5 was completely transformed to its trans form in a
of the cis form of nitriles 5 to a single trans form of 5, and
yield of 80%, and the chirality at C-6 was retained as
sonochemical Blaise reaction were the key merits of this
20
judged by its optical rotation {[a]D +28.8 (c 1.37,
synthetic approach. This approach offers an efficient way
CHCl3)}. Under these optimized isomerization conditions
to synthesize optically active kava derivatives with a D7
double bond. This is also the first research work to dem-
(Table 1, entry 8), a mixture of nitriles 5 (cis/ trans = 3:1)
was conveniently converted to the pure trans form of 5 in
onstrate the absolute configuration of (R)-(+)-kavain 1a
a high yield of 91%, without having to separate the
by total synthesis from a chiral source.
isomers.12
Table 1 Optimization of the Solvents and Temperatures
Acknowledgment
Financial support from the National Scientific Foundation
(30025044) of the P. R China and the foundation from the Ministry
of Science and Technology (2002CB512807) of the P. R. China are
gratefully acknowledged.
Entry Solvents
Temperature Time (h) cis/trans
Yielda
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CHCl3
CHCl3
THF
r.t.
24
24
24
8
42:58b
20:80b
49:51b
0:100c
47:53b
25:75b
62:38b
0:100c
–
reflux
r.t.
–
–
References
reflux
r.t.
41%
–
(1) Sotheeswaran, S. Chem. Aust. 1987, 377.
(2) He, X.-G.; Lin, L.-Z.; Lian, L.-Z. Planta Med. 1997, 63, 70.
(3) (a) Gleitz, J.; Friese, J.; Beile, A.; Ameri, A.; Peters, T. Eur.
J. Pharmacol. 1996, 315, 89. (b) Seitz, U.; Ameri, A.;
Pelzer, H.; Gleitz, J.; Peters, T. Planta Med. 1997, 63, 303.
(c) Capasso, A.; Calignano, A. Acta Ther. 1988, 14, 249.
(4) Gleitz, J.; Beile, A.; Wilkens, P.; Ameri, A.; Peters, T.
Planta Med. 1997, 63, 27.
24
24
24
9
THF
reflux
r.t.
–
Benzene
Benzene
–
reflux
80%
(5) (a) Kostermans, D. Nature (London) 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) Dziadulewicz, E.; Giles, M.;
Moss, W. O.; Gallagher, T.; Harman, M.; Hursthouse, M. B.
J. Chem. Soc., Perkin Trans. 1 1989, 1793. (g) Spino, C.;
Mayes, N.; Desfossés, H.; Sotheeswaran, S. Tetrahedron
Lett. 1996, 37, 6503. (h) Pierres, C.; George, P.; Hijfte, L.
V.; Ducep, J.-B.; Hibert, M.; Mann, A. Tetrahedron Lett.
2003, 44, 3645.
(6) Smith, T. E.; Djang, M.; Velander, A. J.; Downey, C. W.;
Carroll, K. A.; Alphen, S. V. Org. Lett. 2004, 6, 2317.
(7) Blaise, E. E. C. R. Hebd. Seances Acad. Sci. 1901, 132 478..
(8) Schmid, C. R.; Bryant, J. D.; Dowlatzedah, M.; Phillips, J.
L.; Prather, D. E.; Schantz, R. D.; Sear, N. L.; Vianco, C. S.
J. Org. Chem. 1991, 56, 4056.
(9) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gennari, C.;
Raimondi, L. J. Org. Chem. 1987, 52, 4674.
(10) For a review see: Sonnet, P. E. Tetrahedron 1980, 36, 557.
(11) Yu, J. Q.; Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002,
67, 4627.
(12) Isomerization of the cis double bond: A solution of nitriles 5
(145 mg, 0.84 mmol) and bis(acetonitrile)palladium(II)
chlorine (17.5 mg, 0.07 mmol) in benzene (5 mL) was stirred
at reflux for ca. 5 h until the cis form of 5 was fully
consumed (monitored by TLC). After removal of the solvent
in vacuo, the residue was dissolved in EtOAc (50 mL) and
a The isolated yield.
b Checked by HPLC.
c Monitored by TLC
With the pure trans form of 5 in hand, the next key step
was an ultrasound-assisted Blaise reaction to prepare the
important intermediate 6. The Blaise reaction has been ne-
glected for a long time in organic synthesis due to its
shortcomings such as low yield, narrow scope, and the
competing side reactions. Fortunately, several research
groups13 recently reported that ultrasound could improve
the yield of the Blaise reaction dramatically. By simply
using Lee’s conditions13a [commercial zinc powder con-
taining ZnO (10%) and BrCH2COOEt (1.0 equiv)], the
majority of the trans form of 5 did not react, and only a
small amount of desired product was obtained after work-
up. Optimized reaction conditions14 based on Uang’s
conditions13b were thus adopted to afford, the desired
compound 6 in 70% yield, as pale yellow oil {[a]D20 +19.4
(c 1.15, CHCl3), lit.15 [a]D +20.2 (c 1.0, CHCl3)}. In
25
practice, BrCH2COOMe was used in place of
BrCH2COOEt since the latter had a Rf value very close to
that of the trans form of 5 and the desired product 6, which
made monitoring the reaction and the reaction work-up
Synlett 2005, No. 13, 2077–2079 © Thieme Stuttgart · New York