P. G. Guerrero Jr. et al. / Tetrahedron Letters 53 (2012) 5302–5305
5305
(400 MHz, d in CDCl3) 7.43 (d, J = 7.5 Hz, 1H), 7.21–7.43 (m, 6H), 7.20 (d,
J = 7.5 Hz, 1H), 6.83 (s, 1H), 2.51 (t, J = 7.5 Hz, 2H), 1.81 (s, 4H), 1.60 (quint,
J = 7.5 Hz, 2H), 1.27 (s, 6H), 1.24 (s, 6H), 1.23 (sext, J = 7.5 Hz, 2H), 0.73 (t,
J = 7.5 Hz, 3H); 13C NMR (75 MHz) 144.3, 144.2, 139.4, 135.8, 131.7, 129.5, 129.4,
129.1, 129.0, 126.9, 126.7, 126.4, 125.3, 122.2, 35.0, 34.9, 34.2, 34.1, 34.0, 31.8,
31.7, 25.0, 13.2, 8.8; HRMS (70 eV) required for C26H34TeS (M+) 508.1443,
observed 508.1456.
References and notes
1. For a most recent review of atRA chemistry see: Curley, R. W., Jr. Biochim.
Biophys. Acta 2012, 1821, 3.
2. Ramya, D.; Siddikuzzaman, M. A.; Grace, V. M. W. Immunopharmacol.
Immunotoxicol. 2012, 34, 317.
3. Withworth, J. M.; Straughn, J. M., Jr.; Atigadda, V. R.; Muccio, D. D.; Buchsbaum,
D. J. Int. J. Gynecol. Cancer 2012, 22, 191.
(E)-1-Phenylthio-2-[5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2
naphthalenyl]-1-
propene (11): To a two-neck flask under nitrogen atmosphere and magnetic
stirring bar containing a solution of (Z)-1-phenylthio-2-butyltelluro-2-[5,5,8,8-
tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl]-ethene (3) (0.75 g, 1.5 mmol)
in THF (5.0 mL) at À78 °C, n-butyllithium (1.5 mL, 1.5 mmol, 1.0 M in hexanes)
was transferred via syringe and the reaction was stirred for 10 min. Next,
dimethyl sulfate (0.20 mL, 2.0 mmol) was added and the mixture was stirred for
additional 30 min. The reaction mixture was left to reach 25 °C, diluted with
ethyl acetate (100 mL), and washed with brine (4 Â 50 mL). The organic phase
was dried under anhydrous MgSO4. After filtration, the solvent was removed
under vacuum and the crude product purified by flash chromatography in silica
gel (230–400 mesh) using hexane as mobile phase to give the pure compound
(E)-11 as yellow oil in 85% yield (0.28 g). IR (neat): 2925, 1850, 1755, 1494, 1458,
920, 689 cmÀ1 1H NMR (400 MHz, d in CDCl3) 7.12–7.41 (m, 8H), 6.55 (s, 1H),
2.25 (s, 3H), 1.67 (s, 4H), 1.27 (s, 6H), 1.24 (s, 6H); 13C NMR (75 MHz) 144.2,
144.1, 138.8, 138.4, 136.5, 128.9, 128.7, 126.5, 126.1, 123.4, 122.8, 119.6, 35.1,
34.9, 34.2, 34.0, 31.8, 31.5; GC/MS m/z required for C23H28S (M+) 336.5, observed
336.3.
4. Fields, A. L.; Soprano, D. R.; Soprano, K. J. J. Cell Biochem. 2007, 102, 886.
5. Altucci, L.; Leibowitz, M. D.; Ogilvie, K. M.; de Lera, A. R.; Gronemeyer, H. Nat.
Rev. Drug Discov. 2007, 6, 793.
6. Fontana, J. A.; Rishi, A. K. Leukemia 2002, 16, 463.
7. Dozza, B.; Papi, A.; Lucarelli, E.; Scotlandi, K.; Pierini, M.; Tresca, G.; Donati, D.;
Orlandi, M. Toxicol. In Vitro 2012, 26, 142.
8. Armstrong, R. B.; Ashenfelter, K. O.; Eckholff, C.; Levin, A. A.; Shapiro, S. S.
General and Reproductive Toxicology of Retinoids. In The Retinoids Biology
Chemistry and Medicine, second ed.; Raven Press Ltd: New York, 1994; pp 545–
572.
9. Loeliger, P.; Bollag, W.; Mayer, H. Eur. J. Med. Chem. 1980, 15, 9.
10. Agarwal, C.; Chandraratna, R. T.; Teng, M.; Nagpal, S.; Rorke, E. A.; Eckert, R. L.
Cell Growth Differ. 1996, 7, 521.
11. Pignatello, M. A.; Kauffman, F. C.; Levin, A. A. Toxicol. Appl. Pharmacol. 2002,
178, 186.
12. West, M. R.; Page, J. M.; Turner, D. M.; Wood, E. J.; Holland, D. B.; Cunliffe, W. J.;
Rupniak, H. T. J. Invest. Dermatol. 1992, 99, 95.
13. Stricklandca, S.; Breitma, T. R.; Frickel, F.; Nurrenbach, A.; Hadicke, E.; Sporn, M.
B. Cancer Res. 1983, 43, 4283.
14. Corbeil, J.; Rapaport, E.; Richman, D. D.; Looney, D. J. J. Clin. Invest. 1981, 1994,
93.
15. Wu, K.; Dupre, E.; Kim, H.; Tin, U. C.; Bissonnette, R. P.; Lamp, W. W.; Brown, P.
H. Breast Cancer Res. Treat. 2006, 96, 147.
16. Benbrook, D. M.; Madler, M. M.; Spruce, L. W.; Birckbichler, P. J.; Nelson, E. C.;
Subramanian, S.; Weerasekare, G. M.; Gale, J. B.; Patterson, M. K., Jr.; Wang, B.;
Wang, W.; Lu, S.; Rowland, T. C.; DiSivestro, P.; Lindamood, C., III; Hill, D. L.;
Berlin, K. D. J. Med. Chem. 1997, 40, 3567.
4-[(1E)-2-(5,5,8,8-tetramethyl-5,6,7,8 tetrahydro-2-naphthalenyl)]-1-phenyl-1-
propene (2) (Temarotene): To a two-neck flask under nitrogen atmosphere and
magnetic stirring bar containing
a solution of (E)-1-Phenylthio-2-[5,5,8,8-
tetramethyl-5,6,7,8-tetrahydro-2 naphthalenyl]-1-propene (11) (0.34 g,
1.0 mmol) in THF (8 mL) and NiCl2(dppe) (0.026 g, 0.05 mmol) was added
dropwise via syringe the C6H5ZnBr (4 mL, 2 mmol, 0.5 M in THF) and the
mixture was stirred for 2.5 h under reflux. The reaction mixture was left to reach
25 °C, diluted with ethyl acetate (100 mL) and washed with brine (5 Â 50 mL).
The organic phase was dried under anhydrous MgSO4. After filtration, the
solvent was removed under vacuum and the crude product purified by flash
chromatography in silica gel (230–400 mesh) using hexane as mobile phase to
give the pure temarotene 2 as yellow oil in 55% yield (0.16 g). IR (neat) 2925,
17. Gianni, M.; Ponzanelli, I.; Mologni, L.; Reichert, U.; Rambaldi, A.; Terao, M.;
Garattini, E. Cell Death Differ. 2000, 7, 447.
1607, 1458, 922 cmÀ1 1H NMR (400 MHz, d in CDCl3) 7.43 (d, J = 7.5 Hz, 1H),
;
18. Wetherall, N. T.; Taylor, C. M. Eur. J. Cancer Clin. Oncol. 1986, 22, 53.
19. Flanagan, J. L.; Willhite, C. C.; Ferm, V. H. J. Natl. Cancer Inst. 1987, 78, 533.
20. Wright, J. J. US 4431,669; February 14, 1984; Chem. Abstr. 1984, 100, 210217k.
21. (a) Bollag, W.; Ott, F. Eur. J. Cancer Clin. Oncol. 1987, 23, 131; (b) Lasnitzki, I.;
Bollag, W. Eur. J. Cancer Clin. Oncol. 1987, 23, 861; (c) Halliday, G. M.; Ho, K. K.-
L.; Barnetson, R. S. C. J. Invest. Dermatol 1992, 99, 835.
22. (a) Howard, W. B.; Willhite, C. C.; Sharma, R. P. Teratology 1987, 36, 303; (b)
Willhite, C. C.; Dawson, M. I. Toxicol. Appl. Pharmacol. 1990, 103, 324.
23. Deloux, L.; Srebnik, M.; Saba, M. J. Org. Chem. 1995, 60, 3276.
24. Anding, A. L.; Nieves, N. J.; Abzianidze, V. V.; Collins, M. D.; Curley, R. W., Jr.;
Clagett-Dame, M. Chem. Res. Toxicol. 2011, 24, 1853.
25. (a) Dawson, M. I.; Derdzinski, K.; Hobbs, P. D.; Chan, R. L. C.; Rhee, S. W.;
Yasuda, D. J. Org. Chem. 1984, 49, 5265; (b) Boehm, M. F.; Lin, Z.; Bade, B. A.;
White, S. K.; Mais, D. E.; Berger, E.; Suto, C. M.; Goldman, M. E.; Heyman, R. A. J.
Med. Chem. 1994, 37, 2930.
26. (a) Hanefeld, W.; Jung, M. Liebigs Ann. Chem. 1994, 59; (b) Hanefeld, W.; Jung,
M. Liebigs Ann. Chem. 1994, 331.
7.33–7.35 (m, 4H), 7.29 (d, J = 7.5 Hz, 2H), 7.24 (m, 1H), 6.78 (s, 1H), 2.25 (s, 3H),
1.69 (s, 4H), 1.31 (s, 6H), 1.27 (s, 6H); 13C NMR (75 MHz) 144.8, 144.1, 141.0,
138.6, 137.6, 129.1, 128.1, 127.0, 126.7, 126.4, 124.1, 123.5, 35.2, 34.1, 40.1, 31.9,
17.4; HRMS (70 eV) required for C23H28 (M+) 304.2191, observed 304.2182.
2-[4-(1E)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propen-
1yl]phenyl-4,4-dimethyl-2-oxazoline (13): To a two-neck flask under nitrogen
atmosphere and magnetic stirring bar containing a solution of (E)-1-phenylthio-
2-[5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl]-1-propene 11
(0.34 g, 1.0 mmol) in THF (8.0 mL) and Ni(dppe)Cl2 (0.026 g, 0.05 mmol) was
added dropwise via syringe the 2-(4-bromophenyl zinc)-4,4-dimethyl-2-
oxazoline 12 (2.0 mmol) [prepared separately by addition of dry ZnBr2 (0.45 g,
2.0 mmol) to
a solution of 2-(4-bromophenyl magnesium)-4,4-dimethyl
oxazoline33 (2.0 mmol) in THF (4.0 mL) at 0 °C and the mixture was stirred for
30 min] and the reaction stirred for 5 h under reflux. After cooling the mixture
was diluted with ethyl acetate (100 mL) and washed with brine (5 Â 50 mL). The
organic phase was dried under anhydrous MgSO4. After filtration, the solvent
was removed under vacuum and the crude product purified by flash
chromatography in silica gel (230–400 mesh) and hexane/ethyl acetate (9:1 v/
v) as mobile phase to give the pure compound (E)-13 in 63% (0.25 g). IR (neat)
27. Wang, Z.; Campagna, S.; Yang, K.; Xu, G.; Pierce, M. E.; Fortunak, J. M.;
Confalone, P. N. J. Org. Chem. 2000, 65, 1889.
28. Bruson, H. A.; Kroeger, J. W. J. Am. Chem. Soc. 1940, 62, 36.
29. Kawasoko, C. Y.; Nazario, C. E. D.; Santana, A. S.; Viana, L. H.; Hurtado, G. R.;
Marques, F. A.; Frensch, G.; de Oliveira, P. R.; Guerrero, P. G., Jr.; Carvalho, D. B.;
Baroni, A. C. M. Tetrahedron Lett. 2011, 52, 6067.
2923, 1847, 1635, 1610, 1417, 920 cmÀ1 1H NMR (400 MHz, d in CDCl3) 7.95 (d,
;
J = 7.5 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.50 (s, 1H), 7.16 (s, 1H), 7.10 (s, 1H), 6.75
(s, 1H), 4.10 (s, 1H), 1.95 (s, 3H), 1.71 (s, 4H), 1.38 (s, 6H), 1.30 (s, 6H), 1.25 (s,
6H); 13C NMR (75 MHz) 162.0, 149.2, 144.2, 143.2, 138.1, 132.7, 128.0, 126.8,
116.2, 79.0, 67.5, 35.1, 33.9, 31.9, 28.4, 19.9; Anal. Calcd for C28H35NO: C, 76.19;
H, 8.73, Found C, 76.34; H, 8.90.
30. Bleicher, L. S.; Cosford, N. D. P.; Herbaut, A.; McCallum, J.; McDonald, I. A. J. Org.
Chem. 1998, 63, 1109.
31. Dabdoub, M. J.; Dabdoub, V. B.; Pereira, M. A.; Baroni, A. C. M.; Marques, F. A.;
de Oliveira, P. R.; Guerrero, P. G., Jr. Tetrahedron Lett. 2010, 51, 5141.
32. Experimental procedures for the synthesis of selected compounds: (Z)-1-Phenylthio-
2-butyltelluro-2-[5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl]-ethene
(3): To a two-neck flask under nitrogen atmosphere and magnetic stirring
containing elemental tellurium (0.19 g, 1.5 mmol) in THF (6.0 mL) at 0 °C, n-
butyllithium (1.5 mmol, 1.5 mL, 1.0 M in hexanes) was added dropwise. The
mixture was stirred for 10 min at room temperature. Next, water (4.0 mL)
4-[(1E)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)-1-propen-
1yl]benzoic acid (1) (TTNPB): A solution containing (E)-13, (2.0 g, 5.0 mol) and
hydrochloric acid (65 mL, 3 N) was refluxed for 3 h. Next, the reaction was
cooled to 0 °C when a white precipitate formed. After filtration, the white
crystals were washed with water (2 Â 30 mL) and the solid crude product was
recrystallized from acetic acid, furnishing the pure TTNPB 1 in 85% yield (0.31 g).
mp 240–24 °C (lit. mp 239–240 °C)24
309 nm);24 IR (Nujol) 1680, 1604, 1567, 795 cmÀ1
;
UV (DMSO) kmax 312 nm (lit. kmax
;
1H NMR (400 MHz, d in
followed by
a
solution of 1-thiophenyl-2-[5,5,8,8-tetramethyl-5,6,7,8-
CDCl3) 7.95 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 7.5 Hz, 2H), 7.50 (s, 1H), 7.31 (s, 2H),
6.89 (s, 1H), 2.25 (s, 3H), 1.65 (s, 4H), 1.28 (s, 6H), 1.24 (s, 6H); 13C NMR (75 MHz)
167.7, 144.8, 144.5, 142.9, 140.7, 139.6, 129.7, 129.6, 129.2, 126.9, 126.1, 124.2,
123.9, 35.2, 35.0, 34.5, 34.3, 32.1, 32.0, 17.9; Anal. Calcd for C24H28O2: C, 82.74;
H, 8.45, Found C, 83.02; H, 8.78.
tetrahydro-2-naphthalenyl] ethyne 9 (0.48 g 1.5 mmol) in THF (5.0 mL) was
transferred via syringe and the reaction mixture refluxed for 2.0 h. After cooling,
the mixture was diluted with ethyl acetate (100 mL) and washed with brine
(3 Â 50 mL). The organic phase was dried under anhydrous MgSO4. After
filtration, the solvent was removed under vacuum and the crude product was
purified by flash chromatography in silica gel (230–400 mesh) using hexane as
mobile phase, furnishing the pure compound (Z)-3 as yellow oil in 80% yield
33. The magnesium reagent 2-(4-bromophenyl magnesium)-4,4-dimethyl
xazoline was generated in situ as described by Meyers, A. I.; Temple, D. L.;
Haidukewych, D.; Mihelich, E. D. J. Org. Chem. 1974, 39, 2787.
(0.40 g). IR (neat): 3011, 2923, 1847, 1755, 1490, 1458, 920 cmÀ1 1H NMR
;