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Letters in Organic Chemistry, 2010, Vol. 7, No. 1
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inhibitors.1. 2-(alkylthio)-4,5-diphenyl-1H-imidazoles as potent
inhibitors of ACAT. J. Med. Chem., 1992, 35, 4384.
approach could be extended to the synthesis of other tubacin
analogues such as tropcin and histacin.
REFERENCES AND NOTES
[1]
For a review, see: Ropero, S.; Esteller, M. The role of histone
deacetylases (HDACs) in human cancer. Mol. Oncol., 2007, 1, 19.
(a) Wolffe, A. P. Sinful repression. Nature, 1997, 387, 16; (b)
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Cancer, 2006, 6, 38; (f) Hildmann, C.; Wegener, D.; Riester, D.;
Hempel, R.; Schober, A.; Meraner, J.; Giurato, L.; Guccione, S.;
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[2]
[10]
[11]
[3]
[12]
Preparation of 6: To a solution of 4,5-diphenyloxazole-2(3H)-
thione (1.0 g, 4.0 mmol) in DMF (5 mL), diisopropyl ethyl amine
(DIEA) (1.5 mL) was added followed after 15 min by compound 5
(1.5 g, 3.5 mmol) in DMF (5 mL). The mixture was stirred at room
temperature for 12h then poured onto water (100 mL) and extracted
with ethyl acetate (3x50 mL). The organic phase was washed with
brine and dried over anhydrous Na2SO4. The solvent was removed
in vacuo and the residue was passed through a silica gel pad
(eluting with petroleum ether: ethyl acetate = 1:1) to give mixture 6
(1.85 g, 78% yield) as a yellow oil. Preparative HPLC afforded
[4]
[5]
Weidle, U. H; Grossmann, A. Inhibition of histone deacetylases: a
new strategy to target epigenetic modifications for anticancer
treatment. Anticancer Res., 2000, 20, 1471.
pure diastereomers 6a and 6b. 6a: 1H NMR (400 MHz, CDCl3): ꢀ=
1.16 (s, 9H), 1.92-2.19 (m, 2H), 3.30-3.45 (m, 2H), 4.37-4.44
(m,1H), 4.78 (s, 2H), 5.05 (dd, 1H, J1 = 2.4, J2 = 11.6 Hz), 7.34-
For new HDAC inhibitors, see: (a) Methot, J. L.; Chakravarty, P.
K.; Chenard, M.; Close, J.; Cruz, J. C.; Dahlberg, W. K.; Fleming,
J.; Hamblett, C. L.; Hamill, J. E.; Harrington, P.; Harsch, A.;
Heidebrecht, R.; Hughes, B.; Jung, J.; Kenific, C. M.; Kral, A. M.;
Meinke, P. T.; Middleton, R. E.; Ozerova, N.; Sloman, D. L.;
Stanton, M. G.; Szewczak, A. A.; Tyagarajan, S.; Witter, D. J.;
Secrist J. P. Miller, T. A. Exploration of the internal cavity of
histone deacetylase (HDAC) with selective HDAC1/HDAC2
inhibitors (SHI-1:2). Bioorg. Med. Chem. Lett., 2008, 18, 973; (b)
Andrews, D. M.; Gibson, K. M.; Graham, M. A.; Matusiak, Z. S.;
Roberts, C. A.; Stokes, E. S. E.; Brady M. C.; Chresta, C. M.
Design and campaign synthesis of pyridine-based histone
deacetylase inhibitors. Bioorg. Med. Chem. Lett., 2008, 18, 2525 (c)
Estiu, G.; Greenberg, E.; Harrison, C. B.; Mazitschek, R.; Bradner,
J. E.; Wiest, O. On the structural origin of selectivity in class II
selective histone deacetylase inhibitors. J. Med. Chem., 2008, 51,
2898 and references cited therein.
1
7.42 (m, 16H), 7.53-7.57 (m, 2H), 7.64-7.70 (m, 6H). 6b: HNMR
(400 MHz, CDCl3): ꢀ = 1.09 (s, 9H), 1.99-2.17 (m, 2H), 3.35-3.45
(m, 2H), 4.38-4.43 (m, 1H), 4.77 (s, 2H), 5.12 (dd, 1H, J1 = 2.8, J2
= 8 Hz), 7.34-7.45 (m, 16H), 7.50-7.57 (m, 2H), 7.65-7.72 (m, 6H).
a) Rychnovsky, S. D.; Rogers, B. N.; Richardson, T.
Configurational assignment of polyene macrolide antibiotics using
[13C]acetonide analysis. Acc. Chem. Res., 1998, 31, 9; (b) Lira, R.;
Roush, W. R. Stereoselective synthesis of the C91)-C(19) fragment
of Tetrafibricin. Org. Lett., 2007, 9, 533; (c) Migita, A.; Shichijo,
Y.; Oguri, H.; Watanabe, M.; Tokiwano, T.; Oikawa, H. Stereo-
controlled synthesis of prelasalocid, a key precursor proposed in
the biosynthesis of polyether antibiotic lasalocid A. Tetrahedron
Lett., 2008, 49, 1021; The stereo-chemistry of diol 6a was
determined to be syn by 1H and 13C NMR analyses of the
corresponding acetonide 7a. Preparation of 7a and 7b: To a stirred
solution of 6a (or 6b) (0.2 g, 0.3 mmol) in acetone (10 mL) was
added 2,2-dimethoxypropane (1.0 mL, 10 mmol), TsOH (0.01 g,
0.05 mmol) and the mixture was left to stir at room temperature for
~24 h. Acetone was evaporated under reduced pressure, and the
residue was dissolved in ethyl acetate (20 mL), washed with
saturated NaHCO3 solution (5 mL), brine (5 mL) and dried on
anhydrous Na2SO4. The solution was concentrated and the residue
was purified by column chromatography to give the desired ketal
7a (or 7b). 7a (0.18 g, 80% yield). 1H NMR (400 MHz, CDCl3): ꢀ
= 1.09 (s, 9H), 1.52 (s, 3H), 1.58 (s, 3H), 1.63 (m, 1H), 1.99 (m,
1H), 3.39-3.41 (m, 2H), 4.37-4.44 (m, 1H), 4.76 (s, 2H), 4.95 (dd,
1H, J1 = 11.6, J2 = 2.4 Hz), 7.30-7.45 (m, 16H), 7.55-7.57 (m, 2H),
[13]
[6]
[7]
(a) Haggarty, S. J.; Koeller, M. K.; Wong, J. C.; Butcher, R. A.;
Schreiber, S. L. Multidimensional chemical genetic analysis of
diversity oriented synthesis-derived deacetylase inhibitors using
cell-based assays. Chem. Biol., 2003, 10, 383; (b) Wong, J. C.;
Hong, R.; Schreiber, S. L. Structural biasing elements for in-cell
histone deacetylase paralog selectivity. J. Am. Chem. Soc., 2003,
125, 5586.
(a) Hideshima, T.; Bradner. J. E.; Wong, J.; Chauhan, D.;
Richardson, P.; Schreiber, S. L.; Anderson, K.C. Small-molecule
inhibition of proteasome and aggresome function induces
synergistic antitumor activity in multiple myeloma. Proc. Natl.
Acad. Sci. USA, 2005, 102, 8567; (b) Itoh, Y.; Suzuki, T.;
Kouketsu, A.; Suzuki, N.; Maeda, S.; Yoshida, M.; Nakagawa, H.;
Miyata, N. Design, synthesis, structure--selectivity relationship,
and effect on human cancer cells of a novel series of histone
deacetylase 6-selective inhibitors. J. Med. Chem., 2007, 50, 5425.
(a) Sternson, S. M.; Wong, J. C.; Grozinger, C. M.; Schreiber, S. L.
Synthesis of 7200 small molecules based on a subsstructural
analysis of the histone deacetylase inhibitors trichostatin and
troposin. Org. Lett., 2001, 3, 4239; (b) Schreiber, S. L.; Sternson, S.
M.; Wong, J. C.; Grozinger, C. M.; Haggarty, S. J. US patent
2004/0072849.
7.64-7.72 (m, 6H). 13C NMR (100 MHz, CDCl3): ꢀ= 158.2, 146.4,
139.8, 139.7, 135.6, 134.7, 132.7, 131.3, 128.9, 127.9, 127.8, 127.7,
127.4, 127.1, 126.9, 125.5, 125.3, 125.1, 98.8, 70.4, 67.9, 64.5,
1
37.3, 37.0, 29.3, 26.1, 19.1, 18.5. 7b (0.16 g, 76% yield). HNMR
(400 MHz, CDCl3): ꢀ= 1.09 (s, 9H), 1.47 (s, 6H), 2.07-2.26 (m,
2H), 3.39-3.57 (m, 2H), 4.37-4.40 (m, 1H), 4.76 (s, 2H), 4.93-4.97
(m, 1H), 7.32-7.45 (m, 16H), 7.53-7.59 (m, 2H), 7.64-7.73 (m, 6H).
13C NMR (100 MHz, CDCl3): ꢀ = 158.3, 146.3, 139.7, 139.6, 135.5,
134.7, 132.7, 131.3, 128.9, 128.1, 127.9, 127.8, 127.7, 127.6, 127.4,
127.2, 127.1, 126.9, 125.6, 125.5, 125.4, 125.3, 125.2, 125.1, 124.7,
100.5, 67.4, 65.6, 64.4, 38.0, 36.8, 26.0, 24.2, 24.1, 18.5.
[8]
[9]
(a) Racherla, U. S.; Brown, H. C. Chiral synthsis via organoboranes.
27. Remarkably rapid and exceptionally enantioselective
(approaching 100%ee) allylboration of representative aldehydes at
-100.degree under new, salt-free conditions. J. Org. Chem., 1991,
56, 401; (b) Racherla, U. S.; Liao, Y.; Brown, H. C. Chiral synthsis
6
29.3 ppm
O
4
O
H
6
O
O
98.8 ppm
19.1 ppm
4
100.5 ppm
24.2 ppm
H
via
allylborations of representative heterocyclic aldehydes at
100.degree.C under new, salt-free conditions. J. Org. Chem., 1992,
organoboranes.
36.
Exceptionally
enantioselective
7b
-
7a
24.1 ppm