1630
J. J. Topczewski, D. F. Wiemer / Tetrahedron Letters 52 (2011) 1628–1630
base-induced fragmentation, it was decided to protect the C-3 hy-
droxyl group. Treatment of aldehyde 16 with excess MOMCl and
diisopropylethylamine resulted in the quantitative formation of
acetal 17. When the HWE condensation was attempted with the
fully protected aldehyde 17 and KHMDS as base, olefination was
facile and stilbene 19 was isolated in good yield. Stilbene 19 was
treated with TsOH in methanol, resulting in the hydrolysis of all
five MOM acetal groups to afford vedelianin (1) along with a signif-
icant amount of partially hydrolyzed materials.13 The 1H and 13C
NMR spectra of the synthetic vedelianin are in excellent agreement
with those reported for the natural product.1 Furthermore, the spe-
cific rotation of the synthetic material matched both the sign and
magnitude reported for vedelianin (lit.1 +37, observed +35.3, for
material of 90% ee by HPLC), which indicates that compound 1
has been prepared as the naturally occurring antipode. Based on
the known absolute stereochemistry of aldehyde 10,5g ultimately
generated by Shi epoxidation, the absolute stereochemistry of
(+)-vedelianin now can be assigned as the (2S,3R,4aR,9aR)-isomer.
In conclusion, we have accomplished the first total synthesis of
(+)-vedelianin in 18 steps from vanillin. In addition, this work rep-
resents a more direct synthesis of the related compound schwein-
furthin G. Finally, aldehydes 10, 11, 16, and 17 can serve as key
intermediates in further efforts to delineate structure–activity
relationships and in the synthesis of mechanistic probes to uncover
vedelianin’s unique, and as yet unidentified, mechanism of anti-
proliferative activity.
References and notes
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in 2000 as NSC# 720065. Personal communication from Dr. John A. Beutler,
NCI–Frederick.
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6. While this reaction could be conducted by addition of n-BuLi to the aryl halide,
more reproducible yields were obtained through addition of the aryl halide to a
solution of the n-BuLi.
Acknowledgments
7. (a) Wang, Z.; Shi, Y. J. Org. Chem. 1998, 63, 3099–3104; (b) Shi, Y. Acc. Chem. Res.
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We thank Dr. John A. Beutler (NCI–Frederick), Dr. Odile Thois-
son, and Dr. Françoise Gueritte (ISCN CNRS, Gif-sur-Yvette, France)
for sharing data on the activity of (+)-vedelianin in the NCI 60 cell
line screen, Dr. John G. Kodet for providing the initial vanillin
derivative, and Dr. Nolan R. Mente for providing phosphonate 18.
Financial support in the form of an ACS Division of Medicinal
Chemistry predoctoral fellowship (to J.J.T.), a Shriner Fellowship
from the University of Iowa (to J.J.T.), from the Roy J. Carver Char-
itable Trust, and the NIH (R41CA126020 via Terpenoid Therapeu-
tics, Inc.) is gratefully acknowledged.
R
based on the literature precedents above, and confirmed by direct
comparison of compound 10 with material prepared by other means.5g Single
crystal diffraction analyses of both trans-fused5h and cis-fused5i
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controls the stereochemistry of the ring fusion in the tricyclic product..
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Supplementary data
12. (a) Prantz, K.; Mulzer, J. Chem. Rev. 2010, 110, 3741–3766; (b) Green, J. C.;
Pettus, T. R. R. J. Am. Chem. Soc. 2011, 133, 1603–1608.
Experimental procedures and/or spectral data for compounds 1,
5–11, 13–17, and 19 are available. Supplementary data associated
with this article can be found, in the online version, at doi:10.1016/
13. Hydrolysis of the C-2 and C-3 MOM groups proceeds significantly more slowly
then hydrolysis of the phenolic MOM groups. Based on TLC analysis of the
reaction mixture, we hypothesize that the partially hydrolyzed material is a
mixture of vedelianin derivatives that still carry MOM groups at C-2 and/or
C-3.