A concise stereoselective route to the lndoline spiroaminal framework of neoxaline and oxaline

Article abstract of DOI:10.1021/ol050077y

(Chemical Equation Presented) The stereoselective synthesis of tetracyclic intermediate, the indoline spiroaminal 3 for neoxaline (1) and oxaline (2), has been accomplished. The key step of the stereoselective synthesis of 3 was the Lewis acid mediated tr

Full text of DOI:10.1021/ol050077y

ORGANIC
LETTERS
2005
Vol. 7, No. 5
941-943
A Concise Stereoselective Route to the
Indoline Spiroaminal Framework of
Neoxaline and Oxaline
Toshiaki Sunazuka,†,‡,§ Tatsuya Shirahata,§ Satoshi Tsuchiya,‡ Tomoyasu Hirose,§
|
Ryuma Mori,‡ Yoshihiro Harigaya, Isao Kuwajima,§ and Satoshi O
h
mura*,†,‡,§
Kitasato Institute for Life Sciences, School of Infection Control Sciences, and
School of Pharmaceutical Sciences, Kitasato UniVersity, and The Kitasato Institute,
5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan
omura-s@kitasato.or.jp
Received January 14, 2005
ABSTRACT
The stereoselective synthesis of tetracyclic intermediate, the indoline spiroaminal 3 for neoxaline (1) and oxaline (2), has been accomplished.
The key step of the stereoselective synthesis of 3 was the Lewis acid mediated transcyclization of 4 to the diaminal 18, and the tungstate-
catalyzed oxidation of 18 to obtain the nitrone 19, which easily cyclizes to the indoline spiroaminal framework 3.
During the course of our chemical screening of microbial
metabolites, neoxaline (1)1 was isolated from the culture
broth of Aspergillus japonicus Fg-551, together with the
structurally related known compound oxaline (2)2. Neoxaline
(1) and oxaline (2) (Figure 1) are members of a novel class
of biologically active indole alkaloids, (including meleagrin3
and glandicolins4) characterized by a unique indoline spiroam-
inal framework and substitution of a 1,1-dimethylallyl
(“reverse-prenyl”) group at the benzylic ring junction. The
relative stereochemistry of 2 has been previously established
by X-ray analysis.5 Hence, the structure of 1 was determined
Figure 1. Structures of neoxaline (1) and oxaline (2).
* Corresponding author.
† Kitasato Institute for Life Sciences, Kitasato University.
by comparison with 2; however, the relative and absolute
‡ School of Infection Control Sciences, Kitasato University.
§ The Kitasato Institute.
configurations of 1 remain undefined. Compound 1 did not
present antibacterial or antifungal activity, although it did
weakly stimulate the central nervous system (dose: 100 mg/
kg, mice, p.o.). Recently, 1 and 2 were found to inhibit cell
proliferation and arrest the cell cycle during M phase in Jarkat
| School of Pharmaceutical Sciences, Kitasato University.
(1) (a) Hirano, A.; Iwai, Y.; Masuma, R.; Tei, K.; Ohmura, S. J. Antibiot.
1979, 32, 781-785. (b) Konda, Y.; Onda, M.; Hirano, A.; Ohmura, S. Chem.
Pharm. Bull. 1980, 28, 2987-2993.
(2) Steyn, P. S. Tetrahedron 1970, 26, 51-57.
(3) Nozawa, K.; Nakajima, S. J. Nat. Prod. 1979, 42, 374-377.
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kharovsky, V. G.; Baskunov, B. P. Prikl. Biokhim. I Mikrobiol. 1994, 30,
410-414.
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G.; Kruger, G. J. J. Chem. Soc., Chem. Commun. 1974, 1021-1022.
10.1021/ol050077y CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/09/2005

cells.6 Compounds 1 and 2 bind to tublin at, or near, the
colchicine binding site, which results in inhibition of tubulin
polymerization.6 The highly complex indoline spiroaminal
framework of the neoxalines was recognized as an attractive
target for total synthesis. In conjunction with our continuing
structural and synthetic studies of important bioregulatory
products,7 we report herein the concise stereoselective
synthesis of the indoline spiroaminal framework 3 of 1 and
2.
Scheme 2 a
Retrosynthetic analysis of the indoline spiroaminal frame-
work 3 is shown in Scheme 1.
Scheme 1
a Boc ) tert-butoxycarbonyl, DMAP ) 4-dimethylaminopyridi
ne, TBAF ) tetrabutylammonium fluoride, N-PSP ) N-phenyl-
selenophthalimide, PPTS ) pyridinium p-toluenesulfonate.
mixture (1:1) of 3-selenylated furoindolines 10 and 11.12
Treatment of each compound with methyl triflate and
prenyltri(n-butyl)stannane13 introduced the reverse prenyl
group to the desired position to give compounds 12 and 13,
respectively, with either stereochemistry14 (Scheme 2).
BOC deprotection (TMSI, CH3CN) of 12, reprotection
with Alloc group, methyl ester hydrolysis, and condensation
with glycine amide 14, afforded 15. Subsequent deprotection
of the Alloc group gave 4 in high yield (Scheme 3).
We anticipated that the spiroaminal framework 3 could
be prepared from furoindoline 4 via oxidative transcycliza-
tion. Compound 4 would be obtained via condensation of
glycine amide with 5, generated from the chiral indole lactic
acid derivative 6, according to the procedure of Marsden et
al.8 Compound 6 would be prepared via alkylation of
commercially available indole 7 with chiral epoxide 8. The
first step of the synthesis, regioselective alkylation9 of indole
7 with chiral epoxide 810 was examined. Initially SnCl4 was
used, however in low yield(52%). Using a Sc(OTf)3 gave
complex mixture, Cu(OTf)3 in 21% yield. Yb(OTf)3 proved
the most efficient and afforded indole lactic acid ester 6 in
77% yield (Scheme 2). Silylation of the secondary hydroxy
group, followed by Boc protection of the R-amino group and
desilylation, afforded the alcohol 9.
Scheme 3 a
Next, selenylation-induced ring closure with N-phenyl-
selenophthalimide (N-PSP)11 provided the separable diastereo
(6) Koizumi, Y.; Arai, M.; Tomoda, H.; Ohmura, S. Biochim. Biophys.
Acta-Mol. Cell Res. 2004, in press.
(7) Sunazuka, T.; Hirose, T.; Shirahata, T.; Harigaya, Y.; Hayashi, M.;
Komiyama, K.; Ohmura, S.; Smith, A. B., III. J. Am. Chem. Soc. 2000, 122,
2122-2123.
a TMSI ) trimethylsilyl iodide, Alloc ) allyloxycarbonyl, DCC
) dicyclohexylcarbodiimide, HOBt ) 1-hydroxybenzotriazole.
(8) (a) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.;
Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953-
11963. (b) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem.
Soc. 1994, 116, 11143-11144.
Treatment of aminal 4 with AlMe3 in CH2Cl2 at 0 °C
facilitated transcyclization to afford diaminal 18, through the
(9) Akita, H.; Kawaguchi, T.; Enoki, Y.; Oishi, T. Chem. Pharm. Bull.
1990, 38, 323-328.
942
Org. Lett., Vol. 7, No. 5, 2005

MeOH (5:1)) afforded the desired indoline spiroaminal
framework 3 (Scheme 4). Compound 3 is a versatile
intermediate for the synthesis of the neoxaline family of
compounds.
Scheme 4
In summary, we describe a concise route to the indoline
spiroaminal framework of neoxaline and oxaline via nitrone
intermediate. Efforts to complete the total syntheses of
neoxaline and oxaline using this synthetic approach are
currently underway.
Acknowledgment. This work was supported by the Grant
of the 21st Century COE Program, Ministry of Education,
Culture, Sports, Science and Technology (MEXT), and a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture, Japan, and the Japan
Keirin Association.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL050077Y
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(12) In Marsden’s case8 Bis(BOC)tryptophan methyl ester reacted with
N-phenylselenophthalimide and p-TsOH to give a 78% yield of 3-selenylated
pyrroindole as a 9:1 mixture of diastereomers. On the other hand, N-BOC
indolelactic acid 9 gave a 1:1 mixtire of 3-selenylated furoindoline. The
difference of these selectivity is due to the nucleophilicity between N-BOC
of bis(BOC)tryptophan and the hydroxyl group of 9.
(13) Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Org. Synth. 1993, 71,
118-124.
(14) The 3a-8a cis-configuration in compound 13 was determined by
NOE proton correlations using a de-Boc compound of 13. The NOE
experimental details for the stereochemistry are given in the Supporting
Information.
iminium intermediate 17, in 76% yield. Subsequent tungstate-
catalyzed oxidation15 of 18 gave nitrone 19, which was then
treated with silica gel (CHCl3-MeOH-i-Pr2NEt) to afford
spiroaminal 20. Methylation of 20 (TMSCHN2, benzene/
(10) Schaus, S. E.; Brandes, D. B.; Larrow, J. F.; Tokunaga, M.; Hansen,
K. B.; Gould, A. E.; Furrow, M. E.; Jacobsen, E. N. J. Am. Chem. Soc.
2002, 124, 1307-1315.
(15) (a) Murahashi, S.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S.
J. Org. Chem. 1990, 55, 1736-1744. (b) Murahashi, S.; Oda, T.; Sugahara,
T.; Masui, Y. J. Org. Chem. 1990, 55, 1744-1749.
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