Xianxing Jiang et al.
FULL PAPERS
was completed (monitored by TLC), the resulting mixture
was concentrated under reduced pressure and the residue
was purified through column chromatography on silica gel
(eluent, EtOAc/CH2Cl2 1:10) to give the optically pure prod-
uct. The enantiomeric purity of the product was determined
by using HPLC.
To a solution of the above crude product (0.3 mmol) in
3.0 mL toluene was added hydrazine hydrate (0.3 mmol,
1.0 equiv.), and the reaction mixture was stirred overnight at
room temperature. When the reaction was completed, the
mixture was concentrated under vacuum and applied to
chromatography directly to afford the desired product.
Characterization of a representative compound – (R)-JP-
Characterization of a representative compound: – (S)-2-
1
amino-1’-methyl-2’-oxospiro
N
9a: White solid; mp 3078C. H NMR (300 MHz, DMSO-d6):
line]-3-carbonitrile (6r): White solid; mp 2658C. 1H NMR
(300 MHz, DMSO-d6): d=8.25–8.28 (d, J=7.5 Hz, 1H),
7.87–7.90 (d, J=7.5 Hz, 1H), 7.52–7.68 (m, 5H), 7.37–7.41
(t, J=6.3 Hz, 1H), 7.07–7.19 (m, 3H), 6.49–6.52 (d, J=
8.1 Hz, 1H), 3.23 (s, 3H); 13C NMR (75 MHz, DMSO-d6):
d=177.5, 161.6, 144.1, 143.8, 134.3, 133.6, 129.8, 128.2, 127.9,
127.9, 125.1, 124.9, 123.9, 123.7, 123.2, 121.2, 118.9, 115.1,
109.6, 54.4, 50.9, 27.0; IR (KBr): n=3356.48, 2920.39,
2851.37, 2191.84, 1698.61, 1650.03, 1603.20, 1563.31, 1462.25,
d=8.17 (s, 1H), 7.98–8.00 (d, J=6.6 Hz, 1H), 7.73–7.79 (m,
1H), 7.46–7.55 (m, 2H), 7.14–7.23 (m, 2H), 6.79–6.95 (m,
3H), 5.67 (s, 2H), 3.17 (s, 3 H); 13C NMR (75 MHz, DMSO-
d6): d=174.6, 157.1, 154.5, 153.9, 151.6, 151.0, 132.6, 127.7,
124.2, 122.4, 122.0, 120.8, 115.6, 111.7, 106.5, 101.8, 46.7,
25.7; IR (KBr): n=3336.07, 3204.11, 2921.26, 2851.71,
1713.29, 1662.40, 1609.03, 1490.18, 1362.95, 1242.31, 1170.97,
1069.67, 755.07, 496.92 cmÀ1; HRMS (ESI): m/z=414.1199,
calcd. for C22H15N5O4 +H+: 414.1197, D=0.5 ppm (for the
other compounds see the Supporting Information).
1365.36, 1068.72, 1021.76, 808.08, 746.86 cmÀ1
; HR-MS
(ESI): m/z=376.1038, calcd. for C22H15N3O2 +Na+:
376.1056; found: D=4.9 ppm. The ee was determined by
HPLC analysis (Chiralcel AD-H, i-PrOH/hexane=30/70,
1.0 mLminÀ1, 254 nm; retention times): tminor =36.91 min,
General Methods for the Biological Studies
All compounds used in this study were synthesized in our
laboratory, all of them were dissolved in deionized water
with 5% DMSO (dimethyl sulfoxide) and further diluted
with deionized water. Control trials were performed in the
presence of corresponding concentration of DMSO to rule
out any possible non-specific action of this solvent. 3-(4,5-
tmajor =11.34 min, ee=99% (for the other compounds see the
Supporting Information).
Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
General Procedure for Synthesis of Diverse-
Structured Chiral Spirooxindole-Type
Pyranopyrimidines
(MTT) was purchased from Sigma (St. Louis, Mo.). RPMI
1640, Dulbeccoꢀs modified Eagleꢀs medium (DMEM) and
fetal bovine serum (FBS) were purchased from Gibco. An-
nexin V/PI apoptosis assay kit was purchased from Invitro-
gen-Vybrant.
Method A: The corresponding chiral spiro[oxindole-3,4’-pyr-
anochromene] (0.3 mmol) was dissolved in 2.0 mL Ac2O
and 1.0 mL pyridine, and then stirred for about 3 h at 608C.
When the reaction was completed, the solution was concen-
trated under vacuum. The residue was then dissolved in dry
CH2Cl2, and washed with water several times. The organic
phase was dried over anhydrous Na2SO4 and concentrated
under vacuum. The crude product was purified via flash
chromalography.
Characterization of a representative compound – (R)-JP-
8b: White solid; mp 1808C. 1H NMR (300 MHz, CDCl3):
d=7.81–7.84 (d, J=7.8 Hz, 1H), 7.65–7.72 (t, J=7.5 Hz,
1H), 7.37–7.44 (m, 2H), 6.84–6.91 (m, 3H), 5.85–5.98 (m,
1H), 5.44–5.50 (d, J=17.4 Hz, 1H), 5.28–5.31 (d, J=
10.2 Hz, 1H), 4.44–4.46 (d, J=5.1 Hz, 2H), 3.76 (s, 3H),
Acknowledgements
We are grateful for the grants from the National Natural Sci-
ence Foundation of China (Nos. 20932003 and 90813012), the
Key National S&T Program “Major New Drug Develop-
ment” of the Ministry of Science and Technology of China
(2012ZX09504-001-003), and the Fundamental Research
Funds for the Central Universities of China (860618).
2.66 (s, 3H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3): d= References
173.1, 158.2, 156.8, 156.1, 152.8, 152.5, 136.2, 134.0, 130.7,
130.6, 125.0, 122.8, 118.1, 117.2, 115.3, 112.2, 111.6, 111.4,
110.7, 101.4, 95.9, 55.8, 50.1, 43.4; IR (KBr): n=3426.82,
2932.24, 2228.53, 1725.95, 1680.34, 1608.38, 1372.60, 1289.94,
[1] R. Kneller, Nat. Rev. Drug Discovery 2010, 9, 867.
[2] a) K. Ding, Y. Lu, Z. Nikolovska-Coleska, G. Wang, S.
Qiu, S. Shangary, W. Gao, D. Qin, J. Stuckey, K. Kra-
jewski, P. P. Roller, S. Wang, J. Med. Chem. 2006, 49,
3432; b) V. V. Vintonyak, K. Warburg, H. Kruse, S.
Grimme, K. Hꢃbel, D. Rauh, H. Waldmann, Angew.
Chem. 2010, 122, 6038; Angew. Chem. Int. Ed. 2010, 49,
5902.
[3] Selected for examples, see: a) J. J. Badillo, N. V.
Hanhan, A. K . Franz, Curr. Opin. Drug Discov. Devel.
2010, 13, 758; b) F. Zhou, Y. L. Liu, J. Zhou, Adv.
Synth. Catal. 2010, 352, 1381; c) W. B. Chen, Z. J. Wu,
Q. L. Pei, L. F. Cun, X. M. Zhang, W. C. Yuan, Org.
Lett. 2010, 12, 3132; d) C. V. Galliford, K. A. Scheidt,
Angew. Chem. 2007, 119, 8902; Angew. Chem. Int. Ed.
1200.78, 1072.40, 965.39, 761.79 cmÀ1; HR-MS
ACTHUNRTGNE(GNU ESI): m/z=
534.1287 calcd. for C28H21N3O7 +Na+: 534.1272; D=2.9 ppm
(for the other compounds see the Supporting Information).
Method B: The corresponding chiral spiro[oxindole-3,4’-
pyranochromene] (0.6 mmol) was added to 3.0 mL triethyl
orthoformate and 1.0 mL acetic acid, and then stirred for
about 5 h at 908C. When the reaction was completed, the
mixture was concentrated under vacuum. The residue was
then dissolved in dry CH2Cl2, and washed with water several
times. The organic phase was dried over anhydrous Na2SO4
and concentrated under vacuum. The crude product was
used directly without further purification.
924
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 917 – 925