First total synthesis of hinckdentine a

Article abstract of DOI:10.1021/ol802394n

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 regioselecti

Full text of DOI:10.1021/ol802394n

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
kawasaki@my-pharm.ac.jp
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.
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6782. (b) Barnwell, N.; Beddoes, R. L.; Mitchell, M. B.; Joule, J. A.
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A.; Thie´ry, V.; Besson, T. Tetrahedron Lett. 2001, 42, 6671–6674. (d)
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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

to afford 2-aryl-2-allylindolin-3-one 10a in 98% yield (entry
1). In addition, a modified Petasis-boronic acid-Mannich
reaction13 with allylboronic ester gave 10a in 98% yield
(entry 2). Alkylation with silylketenacetal and silylenolates
also furnished carbonyl compounds 10b, 10c, and 10d,
respectively (entries 3-5). The addition of N-methyl indole
also worked efficiently with camphorsulfonic acid to provide
10e in 98% yield (entry 6).
Scheme 1. Retrosynthetic Analysis for Hinckdentine A (1)
Table 1. Mannich-Type Reaction of 8
Several preparative methods for 2,2-disubstituted indolin-
3-ones are well-known, for example, rearrangement of 2,3-
dihydroxyindolines,5 rearrangement of 2,3-disubstituted in-
dolin-3-ols,6 alkylation of 2-arylindolin-3-ones,7 oxidative
rearrangement of 2,3-disubstituted indoles,8 cyclization of
o-azidophenyl alkylketones,9 and so on.10 Recently, Koba-
yashi’s group has disclosed the acid-mediated substitution
of 2-alcohoxyindolin-3-one with aromatic, organosilicon, and
organoboron compounds as carbon-nucleophiles.11 This is
a fascinating methodology as a direct preparative tool of 2,2-
disubstituted indolin-3-one.
At the beginning of the synthesis of 1, we studied the
Mannich-type reaction of 2-hydroxyindolin-3-one 8 with
several carbon-nucleophiles via an indoleninium intermedi-
ate. Initially, preparation of 8 was carried out by PMB
protection of 2-(2-nitirophenyl)indole 712 and m-CPBA
oxidation in 85% yield (Scheme 2).
With 2,2-disubstituted indolin-3-one 10d in hand, we then
constructed the pyrimidine ring and introduced the side chain
at the 3 position of 10d to convert into 15 (Scheme 3).
Scheme 2. Oxidation of 2-Arylindole
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W. W. J. Org. Chem. 2003, 68, 2618–2622.
We explored the reaction of 2-hydroxyindolin-3-one 8 with
various carbon-nucleophiles under acidic conditions (Table
1). When 8 was treated with allyltrimethylsilane and TiCl4
in CH2Cl2 at 0 °C, the desired reaction proceeded successfully
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Org. Lett., Vol. 11, No. 1, 2009

aminonitrile16 afforded lactam 18 in 66% yield. Finally,
bromination on both aromatic rings of 18 was accomplished
by treatment with NBS to produce the desired tribromide.
Because of the bulkiness of Boc group on the quinazoline
nitrogen, a fourth bromination did not take place. Depro-
tection of the N-Boc group followed by TPAP oxidation of
tetrahydropyrimidine gave hinckdentine A (1). The spectro-
scopic data of synthetic 1 were consistent with those of the
natural product.1
Scheme 3. Synthesis of 15
Scheme 4. Total Synthesis of Hinckdentine A (1)
Initially, NaBH4 reduction of aldehyde 10c followed by TBS
protection of alcohol provided 11 (89%). After the removal
of the PMB group with DDQ, the nitro group was reduced
with zinc in AcOH-CH2Cl2 to afford aniline 12 in 67% two-
step yield. The formation of the dihydropyrimidine ring
within 13 was achieved by the treatment of 12 with
trimethylorthoformate in the presence of PPTS in 86%
yield.14 Horner-Wadsworth-Emmons olefination of 13 with
phosphonate 14 in the presence of NaH followed by
magnesium reduction of olefin and imine moieties gave 15
in 77% yield. The stereochemistry of 15 was confirmed by
NOE experiments.15
In conclusion, we have accomplished the first total
synthesis of (()-hinckdentine A (1). As a key step for the
construction of a quaternary carbon center, Mannich-type
C-C bond formation to 2-hydroxyindolin-3-one under acidic
conditions was successfully achieved. Further application of
this methodology to the synthesis of other alkaloids and the
enantioselective preparation of 2,2-disubstituted indolin-3-
one are now under investigation in our laboratory.
We performed transformation of 15 to hinckdentine A (1)
through lactamization to build the core of 1 and regioselective
tribromination by the following procedure (Scheme 4). The
secondary amino group in 15 was protected by a Boc group,
and then the silylether was deprotected by HF·pyridine to
furnish alcohol 16. The conversion of 16 to mesylate
followed by substitution with NaN3 provided azide 17 in 86%
yield. The reduction of azide 17 using the Staudinger protocol
and the subsequent ruthenium-catalyzed lactamization of
Acknowledgment. We thank N. Eguchi, T. Koseki, and
S. Kubota of the Analytical Center of our University for
microanalysis, NMR, and mass spectral measurements.
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T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 6630–
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Kawasaki, T. Heterocycles 2007, 73, 641–650.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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OL802394N
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(15) See Supporting Information.
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