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.
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Org. Lett., Vol. 7, No. 5, 2005