ORGANIC
LETTERS
2009
Vol. 11, No. 1
197-199
First Total Synthesis of Hinckdentine A
Kazuhiro Higuchi, Yukihiro Sato, Mei Tsuchimochi, Kenta Sugiura,
Masatoshi Hatori, and Tomomi Kawasaki*
Meiji Pharmaceutical UniVersity, 2-522-1 Noshio Kiyose, Tokyo 204-8588, Japan
Received October 16, 2008
ABSTRACT
We have accomplished the first total synthesis of (()-hinckdentine A (1). The key steps are m-CPBA oxidation of 2-arylindole followed by
acid-mediated Mannich-type C-C bond formation of 2-hydroxyindolin-3-one, seven-membered ring closure, and regioselective tribromination.
Hinckdentine A (1) was isolated from the bryozoans Hincksi-
noflustra denticulata living in the eastern coast of Tasmania.1
Its structure and absolute configuration were determined by
single-crystal X-ray analysis. Hinckdentine A (1) has a
unique architecture containing a seven-membered lactam ring
fused to the tribromoindolo[1,2-c]quinazoline with a qua-
ternary carbon center.
derivative of hinckdentine A (1).4 Here, we report the first
total synthesis of (()-hinckdentine A (1).
Our synthetic plan for 1 is shown in Scheme 1. Bromi-
nation of the indolo[1,2-c]quinazoline core holding the
N-bulky substituent in 2 was expected to provide the desired
tribromide, thus enabling the total synthesis of 1. Further-
more, we envisioned that the hexahydroazepino[4′,5′:2,3]in-
dolo[1,2-c]tetrahydroquinazoline skeleton in 2, the central
part of this alkaloid, would be constructed by the cyclization
of aminonitrile 3, derived by pyrimidine-ring formation of
2,2-disubstituted indolin-3-one 4 followed by olefination. We
anticipated that the quaternary carbon center in 4 would be
formed from indole 6 via novel oxidation and following
Mannich-type addition of a carbon-nucleophile to the R-ke-
toiminium intermediate generated from 5.
Figure 1. Structure of Hinckdentine A.
(1) Blackman, A. J.; Hambley, T. W.; Picker, K.; Taylor, W. C.;
Thirasasana, N. Tetrahedron Lett. 1987, 28, 5561–5562.
(2) Grinev, A. N.; Kurilo, G. N.; Cherkasova, A. A.; Mashkovskii, M. D.;
Andreeva, N. I.; Sokolov, I. K. Khim.-Farm. Zh. 1978, 12, 97–101.
(3) (a) Billimoria, A. D.; Cava, M. P. J. Org. Chem. 1994, 59, 6777–
6782. (b) Barnwell, N.; Beddoes, R. L.; Mitchell, M. B.; Joule, J. A.
Heterocycles 1994, 37, 175–179. (c) Domon, L.; Coeur, C. L.; Grelard,
A.; Thie´ry, V.; Besson, T. Tetrahedron Lett. 2001, 42, 6671–6674. (d)
Koradin, C.; Dohle, W.; Rodriguez, A. L.; Schmid, B.; Knochel, P.
Tetrahedron 2003, 59, 1571–1578. (e) Mendiola, J.; Castellote, I.; Alvarez-
Builla, J.; Ferna´ndez-Gadea, J.; Go´mez, A.; Vaquero, J. J. J. Org. Chem.
2006, 71, 1254–1257. (f) Helliwell, M.; Corden, S.; Joule, J. A. Acta
Crystallogr. 2007, E63, o1993–o1995.
The framework of 1 consists of biologically important
dihydrotryptamine and dihydropyrimidine units together with
a cataleptically active indolo[1,2-c]quinazoline core,2 al-
though the biological activity of 1 has not yet appeared in
the literature. Structural and biological interests have attracted
several organic chemists to attempt the synthesis of 1.3
Although several synthetic applications were reported, the
total synthesis of 1 has not yet been realized. Recently,
McWhorter has achieved the synthesis of the 8-desbromo
(4) Liu, Y.; McWhorter, W. W. J. Am. Chem. Soc. 2003, 125, 4240–
4252.
10.1021/ol802394n CCC: $40.75
Published on Web 12/04/2008
2009 American Chemical Society