1318
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3. Germain, P.; Chambon, P.; Eichele, G.; Evans, R. M.; Lazar, M. A.; Leid, M.; de
Lera, A. R.; Lotan, R.; Mangelsdorf, D. J.; Gronemeyer, H. Pharmacol. Rev. 2006,
58, 760–772.
(3) To a solution of compound 3 (139 mg, 0.39 mmol) in THF (2 mL) were
added tBuLi (1.6 M solution in hexane, 0.29 mL, 0.47 mmol) dropwise at ꢀ78 °C
and the reaction was stirred at that temperature for 1 h, then at room
4. Laudet, V.; Gronemeyer, H. The Nuclear Receptor Facts Book; Academic Press:
San Diego, 2002.
5. Mark, M.; Ghyselinck, N.; Chambon, P. Annu. Rev. Pharmacol. Toxicol. 2006, 46,
451–480.
6. Altucci, L.; Gronemeyer, H. Nat. Rev. Cancer 2001, 1, 181–193.
7. Altucci, L.; Leibowitz, M. D.; Ogilvie, K. M.; de Lera, A. R.; Gronemeyer, H. Nat.
Rev. Drug Discov. 2007, 6, 793–810.
8. Shulman, A. I.; Mangelsdorf, D. J. N. Engl. J. Med. 2005, 353, 604–615.
9. Chawla, A.; Repa, Y. J.; Evans, R. M.; Mangelsdorf, D. J. Science 2001, 294, 1866–
1870.
10. Repa, J. J.; Mangelsdorf, D. J. Nat. Med. 2002, 8, 1243–1248.
11. (a) Das, B. C.; Smith, M. E.; Kalpana, G. V. Bioorg. Med. Chem. Lett. 2008, 18,
4177; (b) Das, B. C.; Smith, M. E.; Kalpana, G. V. Bioorg. Med. Chem. Lett. 2008,
18, 3805; (c) Das, B. C.; Evans, T. Molecular Biosystem (communicated).; (d) Das,
B. C.; Kabalka, G. W. Tetrahedron Lett. 2008, 49, 4695–4696; (e) Das, B. C.;
Mahalingam, S. M.; Evans, T.; Kabalka, G. W.; Anguiano, J.; Hema, K. Chem.
Comm. 2009, 2133; (f) Das, B. C.; Anguiano, J.; Mahalingam, S. M. Tetrahedron
Lett. 2009, 50, 5670–5672; (g) Das, B. C.; McCartin, K.; Liu, T.-C.; Peterson, R. T.;
Evans, T. PloS ONE 2010, 5; (h) Smith, M. E.; Das, B. C.; Kalpana, G. V. Cancer Cell
X.-Y.; Sanyal, S.; Mohapatra, S.; Rogler, P.; Nayak, S.; Evans, T. Tetrahedron Lett.
2011, 52, 2433–2435.
temperature for 30 min, then cooled to -78 °C again. DMF (80 lL, 0.44 mmol)
was added and the reaction was stirred for an additional 1 h at 0 °C. After that,
the reaction was quenched by aqueous saturated ammonium chloride,
extracted with ethyl acetate. The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was used in the next
step without further purification.
(4) Phosphonium salt (0.39 mmol, 218 mg), LiOH.H2O (0.5 mmol, 21 mg), and
iPrOH (3 mL) were added into a 25 mL reaction tube. The resulting mixture was
i
stirred at rt (room temperature) for 15 min. Aldehyde 4 in 1 mL of PrOH was
added to the above mixture and stirred over night. The reaction was diluted
with water, extracted with ethyl acetate. The combined organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel chromatography hexanes/ethylacetate 15:1) to give a
yellow liquid (36 mg, 18% for two steps). Compound 5. A yellow oil. 1H NMR
(CDCl3, 300 MHz) d 1.30 (s, 6H, 2CH3), 1.32 (s, 12H, 4CH3), 2.37 (d, J = 4.8 Hz,
2H, CH2), 6.47 (t, J = 4.8 Hz, 1H, CH), 6.56–6.67 (m, 2H, CH=CH), 7.17 (d,
J = 0.6 Hz, 2H, Ar), 7.32 (s, 5H, Ar), 7.35 (d, J = 7.8 Hz, 2H, Ar), 7.69 (d, J = 7.8 Hz,
2H, Ar), 7.71 (s, 1H, Ar); 13C NMR (CDCl3, 75 MHz) d 24.9, 28.5, 33.3, 39.2, 83.7,
87.1, 90.5, 121.3, 123.3, 123.6, 126.3, 127.9, 128.2, 128.7, 129.8, 130.7, 131.2,
131.6, 134.4, 134.7, 134.9, 140.2, 142.9; HRMS (EI) Calcd. for C34H36BO2 [M+H]+
requires 487.2808, found 487.2796.
(b) General procedure for the synthesis of compounds 7 and 8.
12. (a) Groziak, M. P. In Progress in Heterocyclic Chemistry; Gribble, G. C., Gilchrist, T.
L., Eds.; Pergamon: Oxford, 2000; Vol. 12, pp 1–21; (b) Morin, C. Tetrahedron
1994, 50, 12521–12569; (c) Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23,
346; (d) Matterson, D. S. Tetrahedron 1989, 45, 1859; (e) Tian, Z.-Q.; Brown, B.
B.; Mack, D. P.; Hutton, C. A.; Bartlett, P. A. J. Org. Chem. 1997, 62, 514; (f) Leung,
D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2003, 63, 1144; (g) Kabalka, G. W.;
Das, B. C.; Das, S. Tetrahedron Lett. 2001, 42, 7145–7146; (h) Zhong, Y.; Wu, Y.;
Liu, R.; Chuang, P.; Das, B.C.; Evans, T.; He, J.C. PloS ONE 2011, 6, e27945,
R.; Mackay, H.; Chavda, S.; Babu, B.; O’Brien, E. L.; Risinger, A. L.; Susan, L.;
Mooberry, S. L.; Lee, Moses J. Med. Chem. 2010, 53, 325–334.
13. Das, B. C.; Mahalingam, S. M.; Evans, T. Tetrahedron Lett. 2009, 50, 3031–
3034.
14. Zhang, C.; Zhemg, G.; Fang, L.; Li, Y. Synlett 2006, 475.
15. Vallin, Karl S. A.; Wensbo, Posaric David; Hamersak, Zdenko; Svensson, Mats
A.; Minidis, Alexander B. E. J. Org. Chem. 2009, 74, 9328.
16. Liang, G.-B.; Feng, D. D. Tetrahedron Lett. 1996, 37, 6627–6630.
17. (a) General procedure of synthesis of 5:
(1) At 0 °C, To a 50 mL RBF were added aldehyde 4 (0.7 mmol, 200 mg), NaH2PO4
(1 mmol, 120 mg), 2-methyl-2-buene (1 mL), and tBuOH (3 mL). At 0 °C, NaClO2
(1.4 mmol, 127 mg) was added to the above mixtrue and then stirred at rt over
night. The reaction mixture was diluted by water, extracted with EA (3 ꢁ 15 mL).
The combined organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was purified by silicagel chromatography hexanes/
ethylacetate (4:1)to give a yellow solid 6 (140 mg, 60%).
(2) Acid 6 (0.073 mmol, 22 mg), CDI (14 mg, 0.087 mmol) and DMF were added
into a 10 mL reaction tube. The reaction mixture was stirred at rt for around
30 min. Amidoxime (18 mg, 0.087 mmol) was added to the above mixture and
the reaction was then heated to reflux over night. After cooling to rt, the reaction
mixture was poured into water, and extracted with ethyl acetate. The combined
organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by silica gel chromatography hexanes/ethyl acetate (10:1)
to give a yellow solid 7 (28 mg, 80%).
(3) Compound 7 (20 mg, 0.042 mmol), LiOH (8 mg, 0.36 mmol) were added into
a 10 mL reaction tube. A mixed solvent THF/H2O (2:1) 1 mL was added and the
reaction mixture was stirred at rt over night. After acidified by 1 N HCl, the
mixture was extracted with EA. The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel
chromatography hexanes/ethylacetate (4:1) to give a yellow solid 8 (6 mg, 33%).
Compound 7. A yellow solid. mp 136–138 °C. 1H NMR (CDCl3, 300 MHz): d 1.39
(s, 6H, 2CH3), 1.46 (t, J = 7.2 Hz, 3H, CH3), 2.48 (d, J = 4.8 Hz, 2H, CH2), 4.45 (q,
J = 7.2 Hz, 2H, CH2), 6.61 (t, J = 4.8 Hz, 1H, C@CH), 7.41–7.43 (m, 3H, Ar), 7.53 (d,
J = 8.1 Hz, 1H, Ar), 7.64–7.67 (m, 2H, Ar), 8.14 (dd, J1,2 = 8.1, 1.8 Hz, 1H, Ar), 8.21
(1) Phenyl acetylene (102 mg, 1.0 mmol) was added into THF (3 mL) in a 25 mL
reaction tube under N2. The reaction temperature was cooled to -78 °C
followed by adding tBuLi (1.6 M solution in hexane, 0.625 mL, 1.0 mmol). After
1 h, Bromide (127 mg, 0.5 mmol) in THF (1 mL) was added and the reaction
was stirred at ꢀ78 °C for additional 1 h. The reaction was then quenched by
saturated NH4Cl solution, extracted with EA. The combined organic layers were
washed by brine, water, dried over Na2SO4, and filtered. After evaporation of
the organic solvent, the residue was purified by silica gel chromatography
hexanes/ethylacetate (4:1) to give a yellow solid 2 (140 mg, 79%).
(2) To a solution of compound 2 (139 mg, 0.39 mmol) in DCM (4 mL) were
added MsCl and Et3N at 0 °C. The reaction temperature was maintained at 0 °C
for around 10 min. The ice-water bath was removed and the reaction was
heated to reflux for 3 h. The reaction was diluted with aqueous saturated
ammonium chloride and then extracted with EA. The combined organic layers
were washed with brine, dried over Na2SO4, and filtered. The solvent was
removed in vacuo and the residue was purified by silica gel chromatography
(ethyl acetate/:hexane, 1:10) to give the product 3 as a colorless oil (58 mg,
29%).
(d, J = 8.4 Hz, 2H, Ar), 8.29 (d, J = 8.4 Hz, 2H, Ar), 8.60 (d, J = 1.8 Hz, 1H, Ar); 13
C
NMR (CDCl3, 75 MHz) d 14.7, 28.8, 34.3, 39.2, 61.7, 87.0, 91.9, 121.1, 122.6, 123.6,
125.1, 125.7, 127.9, 128.4, 128.8, 128.9, 130.4, 131.5, 132.1, 132.9, 133.1, 135.7,
149.5, 166.4, 168.7, 176.5.
Compound 8. A yellow solid. mp 156–158 °C. 1H NMR (CDCl3, 300 MHz) d 1.39 (s,
6H, 2CH3), 2.47 (d, J = 4.8 Hz, 2H, CH2), 6.61 (t, J = 4.8 Hz, 1H, C@CH), 7.41–7.45
(m, 3H, Ar), 7.53 (d, J = 8.1 Hz, 1H, Ar), 7.65–7.68 (m, 2H, Ar), 8.14 (dd, J1,2 = 8.1,
1.8 Hz, 1H, Ar), 8.28 (d, J = 8.4 Hz, 2H, Ar), 8.34 (d, J = 8.4 Hz, 2H, Ar), 8.60 (d,
J = 1.8 Hz, 1H, Ar); 13C NMR (CDCl3, 75 MHz): d 28.3, 33.9, 38.8, 86.6, 91.5, 120.7,
122.1, 123.2, 124.7, 125.3, 127.6, 128.1, 128.5130.7, 131.4, 131.7, 132.0, 132.5,
135.3, 149.1, 168.1, 170.6, 176.2.