Journal of the American Chemical Society
Communication
potassium hydroxide and reduction of the ketone moiety with
sodium borohydride were carried out in one pot in methanol to
give phenol 25. Initial attempts at oxidative dearomatization of
25 using iodobenzene diacetate in methanol, however, resulted
in decomposition of the substrate. Since the tertiary amine
moiety appeared to react with the oxidant under these
conditions, we decided to protect it as an ammonium salt.
Treatment of 25 with methanolic hydrogen chloride followed
by oxidation with iodobenzene diacetate gave the desired ortho-
quinone monoketal 26. Upon heating 26 under an ethylene
atmosphere, the desired Diels−Alder reaction proceeded
smoothly to give 27 with complete control of stereochemistry.
Finally, manipulations of the functional groups on the bicyclo
[2.2.2] system were performed (Scheme 5). Protection of the
group gave lepenine (2), which was identical in all respects to
natural lepenine.12b
In summary, we have achieved the straightforward
asymmetric synthesis of lepenine, the first member of the
denudatine-type alkaloids that succumbed to total synthesis.
Our synthesis features an effective construction of the complex
hexacyclic system via a tethered intramolecular Diels−Alder
reaction, an intramolecular Mannich reaction, and a Diels−
Alder reaction between an ortho-quinone monoketal and
ethylene. Another key feature of the synthesis is a chirality
transfer from L-lactic acid methyl ester via a Claisen
rearrangement.
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Scheme 5. Total Synthesis of Lepenine
Experimental details, characterization data, and NMR spectra.
This material is available free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
Numbers 20002004, 25221301, Platform for Drug Discovery,
Informatics, and Structural Life Science (MEXT), Mochida
Memorial Foundation for Medical and Pharmaceutical
Research, and the Uehara Memorial Foundation. Y.N. and
Y.H. were supported by research fellowships from JSPS.
REFERENCES
■
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