Organic & Biomolecular Chemistry
Communication
Notes and references
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Scheme 5 Modified synthesis of 4, (−)-triptonide, and (−)-triptonide.
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DiBAl-H in toluene gave the allylic alcohol 24 in 90% yield.
The subsequent carbonylation–lactonization sequence cata-
lyzed by Pd(OAc)2 converted 24 to the intermediate 7 in 89%
yield with 98% ee. Oxidation of 7 with CrO3 in aqueous acetic
acid (90% v/v) yielded 25 in 81% yield. The compound 25
was then demethylated with BBr3 in CH2Cl2 at −78 °C to
form the phenol 26 in 87% yield. Finally, the Friedel–Crafts
isopropylation of 26 with isopropanol in sulfuric acid afforded
the desired product 4 in 69% yield. After recrystallization, the
enantiopure compound 4 was obtained with more than 99% ee.
Presently, our novel synthesis of 4 is accomplished with
more 99% ee and excellent disastereoselectivities in 9 steps
with 13.6% total yield and 11 steps with 18.5% overall yield
through two synthetic schemes. With the compound 4 in
hand, (−)-triptonide (2) and (−)-triptolide (1) could be rapidly
synthesized according to the previously reported stategies.11a,b
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Conclusions
In summary, a novel formal synthesis of (−)-triptolide and
(−)-triptonide has been achieved based on the alternative
enantioselective synthesis of the known key building block 4
using a chiral amine-mediated asymmetric Robinson annula-
tion, stereoselective hydrogenation controlled by a chiral sub-
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strate,
Pd(II)-catalyzed
carbonylation–lactonization
and
Friedel–Crafts isopropylation as the key steps. The current syn-
thesis gave a good overall yield and high enantio- and dia-
stereo-selectivity, resulting in an efficient, elegant, and
scalable synthesis of triptolides. This work also provided a new
useful approach to the synthesis of other structurally relevant
natural products or bioactive derivatives. Further synthetic and
biological investigations in this field are currently underway in
our laboratory.
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R. M. Letcher, J. Org. Chem., 1998, 63, 6446–6447;
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J. Org. Chem., 2000, 65, 2208–2217; (d) D. Yang, X. Y. Ye,
M. Xu, W. W. Pang and K. K. Cheung, J. Am. Chem. Soc.,
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (grant no. 21372107 and
21272099).
This journal is © The Royal Society of Chemistry 2014
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