Synthesis of Ketone Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 16 3567
2(S)-3,3-Dim eth yl-1-{2-[5-(4-h ydr oxyph en yl)pen tan oyl]-
p yr r olid in yl}p en ta n e-1,2-d ion e (5g). A mixture of 1.63 g
(3.53 mmol) of 30 and 400 mg of 10% Pd/C in 100 mL of EtOAc
was hydrogenated at 50 psi overnight. The mixture was
filtered through Celite, concentrated, and chromatographed
1.11 (s, 3H); 1.22-1.76 (m, 9H); 2.12-2.21 (m, 3H); 2.46-2.50
(m, 1H); 2.98-3.10 (m, 1H); 3.25 (br, d, 1H, J ) 13.0 Hz); 4.98
(d, 1H, J ) 5.5 Hz); 7.09-7.12 (m, 1H); 7.54-7.58 (m, 1H);
8.36 (br s, 1H); 8.49 (br s, 1H). TLC: Rf ) 0.52 (60% EtOAc/
hexane).
1
(25% EtOAc/hexane) to obtain 800 mg (61%) of 5g. H NMR
2(S)-3,3-Dim eth yl-1-[2-(6-p yr id in -3-yl-h exa n oyl)p ip er i-
d in -1-yl]p en ta n e-1,2-d ion e (11e). A mixture of 2(S)-3,3-
dimethyl-1-[2-(6-pyridin-3-yl-hex-5-ynoyl)piperidin-1-yl]pentane-
1,2-dione 37 (0.61 g, 1.59 mmol) and platinum oxide (0.1 g,
0.44 mmol) was suspended in methanol (5 mL). The reaction
mixture was placed under a hydrogen atmosphere (1 atm) and
was stirred overnight. It was filtered through Celite, concen-
trated, and purified on a silica gel column, eluting with 50%
EtOAc/hexane to yield 0.45 g (73%) of the desired product as
a clear oil. 1H NMR (CDCl3, 400 MHz): δ 0.89 (br s, 2H); 1.21
(s, 3H); 1.24 (s, 3H); 1.28-1.74 (m, 13H); 2.27 (br d, 1H, J )
13.0 Hz); 2.63 (t, 2H, J ) 7.7 Hz); 3.22 (m, 1H); 3.40 (br, d,
1H, J ) 12.8 Hz); 4.16 (t, 2H, J ) 6.4 Hz); 5.22 (d, 1H, J ) 5.4
Hz); 7.26 (m, 1H); 7.51 (d, 1H, J ) 7.7 Hz); 8.45 (s, 2H). 13C
NMR (CDCl3, 400 MHz) δ 208.4, 208.3, 167.7, 150.5, 147.5,
138.1, 136.4, 124.3, 58.0, 47.1, 44.7, 39.5, 36.1, 32.9, 31.6, 29.1,
25.5, 24.3, 23.9, 23.5, 21.2, 9.2. Anal. Calcd for C23H34N2O3‚
0.6H2O: C, 69.52; H, 8.93; N, 7.05; O, 14.50. Found: C, 69.33;
H, 8.62; N, 7.17. TLC: Rf ) 0.52 (60% EtOAc/hexane).
(CDCl3, 400 MHz): δ 0.87 (t, 3H, J ) 7.50 Hz); 1.21 (s, 6H);
1.49-1.72 (m, 4H); 1.74-1.86 (m, 2H); 1.87-1.98 (m, 2H);
2.10-2.21 (m, 1H); 2.46-2.63 (m, 4H); 3.43-3.68 (m, 3H); 4.59
(q, 1H, J ) 4.5 Hz); 6.72 (d, 2H, J ) 8.40 Hz); 7.03(d, 2H, J )
13
8.40 Hz). C NMR (CDCl3, 400 MHz): δ 208.7, 208.5, 165.9,
154.3, 132.4, 129.6, 116.6, 62.1, 47.1, 41.5, 37.8, 35.7, 31.6, 29.1,
24.6, 23.8, 23.5, 21.6, 9.1. Anal. Calcd for C22H31NO4: C, 70.75;
H, 8.37; N, 3.75. Found: C, 70.64; H, 8.44; N, 3.65. TLC: Rf )
0.45 (75% hexane/EtOAc).
2(S)-1-(3,3-Dim eth yl-2-oxop en ta n oyl)p ip er id in e-2-ca r -
both ioic Acid P yr id in -2-yl Ester (34). A mixture of 2(S)-
1-(3,3-dimethyl-2-oxopentanoyl)piperidine-2-carboxylic acid 33
(6.3 g, 24.7 mmol), N,N′-dicyclohexylcarbodiimide (7.6 g, 37.0
mmol), 2-mercaptopyridine (3.02 g, 27.2 mmol), and 4-(dim-
ethylamino)pyridine (0.91 g, 7.41 mmol) was suspended in
methylene chloride (300 mL) and stirred at room temperature
overnight. The reaction mixture was filtered through Celite,
and the organic phase was concentrated in vacuo to yield a
clear oil. The oil was purified on a silica gel column (25-35%
EtOAc/hexane) to provide 8 g (83%) of the desired product as
Refer en ces
1
a yellow solid. H NMR (CDCl3, 400 MHz): δ 0.92 (t, 3H, J )
(1) Harding, M. W.; Galat, A.; Uehling, D. E.; Schreiber, S. L. A
7.5 Hz); 1.26 (s, 3H); 1.31 (s, 3H); 1.66-1.84 (m, 7H); 2.45-
2.48 (m, 1H); 3.34-3.41 (m, 1H); 3.46-3.50 (m, 1H); 5.50 (d,
1H, J ) 5.5 Hz); 7.34 (dd, 1H, J ) 1.0, 7.5 Hz); 7.61 (d, 1H, J
) 8.0 Hz); 7.78 (dt, 1H, J ) 2.0, 8.0 Hz); 8.66-8.68 (m, 1H).
TLC: Rf ) 0.65 (10% EtOAc/hexane).
receptor for the immunosuppressant FK506 is
a cis-trans
peptidyl-prolyl isomerase. Nature 1989, 341, 758-760.
(2) Siekierka, J . J .; Hung, S. H.; Poe, M.; Lin, C. S.; Sigal, N. H. A
cytosolic binding protein for the immunosuppressant FK506 has
peptidyl-prolyl isomerase activity but is distinct from cyclophi-
lin. Nature 1989, 341, 755-757.
2(S)-3,3-Dim eth yl-1-[2-(6-tr im eth ylsilan yl-h ex-5-yn oyl)-
piper idin -1-yl]pen tan e-1,2-dion e (35). 2(S)-1-(3,3-Dimethyl-
2-oxopentanoyl)piperidine-2-carbothioic acid pyridin-2-yl ester
34 (1.5 g, 4.30 mmol) was dissolved in anhydrous THF (20 mL),
cooled to 0 °C, and treated with freshly prepared (5-trimeth-
ylsilyl-pent-1-ynyl)magnesium bromide (8 mL). The reaction
mixture was allowed to stir for 4 h. The reaction mixture was
washed with saturated ammonium chloride. The organic phase
was dried, concentrated, and purified on a silica gel column
(25% EtOAc/hexane) to provide 1.35 g (83%) of desired product
(3) Galat, A. Peptidylproline cis-trans-isomerases: immunophilins.
Eur. J . Biochem. 1993, 216, 689-707.
(4) Hamilton, G. S.; Steiner, J . P. Immunophilins: Beyond Immu-
nosuppression. J . Med. Chem. 1998, 41, 5119-5143.
(5) Schreiber, S. L. Chemistry and biology of the immunophilins
and their immunosuppressant ligands. Science 1991, 251, 283-
287.
(6) Steiner, J . P.; Dawson, T. M.; Fotuhi, M.; Glatt, C. E.; Snowman,
A. M.; Cohen, N.; Snyder, S. H. High brain densities of the
immunophilin FKBP colocalized with calcineurin. Nature 1992,
358, 584-587.
(7) Lyons, W. E.; George, E. B.; Dawson, T. M.; Steiner, J . P.;
Snyder, S. H. Immunosuppressant FK506 promotes neurite
outgrowth in cultures of PC12 cells and sensory ganglia. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 3191-3195.
(8) Snyder, S. H.; Sabatini, D. M. Immunophilins in the nervous
system. Nat. Med. 1995, 1, 32-37.
(9) Gold, B. G.; Storm-Dickerson, T.; Austin, D. R. The immuno-
suppressant FK506 increases functional recovery and nerve
regeneration in rat sciatic nerve. J . Neurosci. 1995, 15, 7509-
7516.
(10) Snyder, S. H.; Sabatini, D. M.; Lai, M. M.; Steiner, J . P.;
Hamilton, G. S.; Suzdak, P. D. Neural actions of immunophilin
ligands. Trends Pharmacol. Sci. 1998, 19, 21-26.
(11) Hamilton, G. S.; Steiner, J . P. Neuroimmunophilin ligands as
novel therapeutics for the treatment of degenerative disorders
of the nervous system. Curr. Pharm. Des. 1997, 3, 405-428.
(12) Hamilton, G. S.; Huang, W.; Connolly, M. A.; Ross, D. T.; Guo,
H.; Valentine, H. L.; Suzdak, P. D.; Steiner, J . P. FKBP12-
binding domain analogues of FK506 are potent, nonimmuno-
suppressive neurotrophic agents in vitro and promote recovery
in a mouse model of Parkinson’s Disease. Bioorg. Med. Chem.
Lett. 1997, 7, 1785-1790.
(13) Kofron, J . L.; Kuzmic, P.; Kishore, V.; Colon-Bonilla, E.; Rich,
D. H. Determination of kinetic constants for peptidylprolyl cis-
trans isomerases by an improved spectrophotometric assay.
Biochemistry 1991, 30, 6127.
(14) Steiner, J . P.; Hamilton, G. S.; Ross, D. T.; Valentine, H. L.; Guo,
H.; Connolly, M. A.; Liang, S.; Ramsey, C.; Li, J .-H.; Huang, W.;
Howorth, P.; Soni, R.; Fuller, M.; Sauer, H.; Nowotnick, A.;
Suzdak, P. D. Neurotrophic immunophilin ligands stimulate
structural and functional recovery in neurodegenerative animal
models. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 2019-2024.
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1
as a clear oil. H NMR (CDCl3, 400 MHz): δ 0.75 (t, 3H, J )
7.5 Hz); 1.08 (s, 3H); 1.11 (s, 3H); 1.22-1.76 (m, 9H); 2.12-
2.21 (m, 3H); 2.46-2.50 (m, 1H); 2.98-3.10 (m, 1H); 3.25 (br
d, 1H, J ) 13.0 Hz); 4.98 (d, 1H, J ) 5.5 Hz). TLC: Rf ) 0.65
(10% EtOAc/hexane).
2(S)-1-(2-Hex-5-yn oylp ip er id in -1-yl)-3,3-d im eth ylp en -
ta n e-1,2-d ion e (36). 2(S)-3,3-Dimethyl-1-[2-(6-trimethylsila-
nyl-hex-5-ynoyl)piperidin-1-yl]pentane-1,2-dione 35 (0.5 g, 1.32
mmol) was dissolved in anhydrous THF (5 mL), cooled to -78
°C, and treated with tetrabutylammonium fluoride (1.0 M, 6.6
mL). The reaction mixture was allowed to stir for 2 h. The
reaction mixture was diluted with EtOAc (100 mL) and washed
with water. The organic phase was dried, concentrated, and
purified on a silica gel column (25% EtOAc/hexane) to provide
0.3 g (75%) of the desired product as a clear oil. 1H NMR
(CDCl3, 400 MHz): δ 0.75 (t, 3H, J ) 7.5 Hz); 1.08 (s, 3H);
1.11 (s, 3H); 1.22-1.76 (m, 10H); 2.12-2.21 (m, 3H); 2.46-
2.50 (m, 1H); 2.98-3.10 (m, 1H); 3.25 (br d, 1H, J ) 13.0 Hz);
4.98 (d, 1H, J ) 5.5 Hz). TLC: Rf ) 0.45 (10% EtOAc/hexane).
2(S)-3,3-Dim eth yl-1-[2-(6-p yr id in -3-yl-h ex-5-yn oyl)p ip -
er id in -1-yl]p en ta n e-1,2-d ion e (37). A mixture of 2(S)-1-(2-
hex-5-ynoylpiperidin-1-yl)-3,3-dimethylpentane-1,2-dione 36
(0.85 g, 2.78 mmol), 3-iodopyridine (0.63 g, 3.06 mmol), and
triethylamine (0.37 g, 3.64 mmol) was dissolved in methylene
chloride (25 mL) and allowed to stir for 5 min at room
temperature. (PPh3)2PdCl2 (0.2 g, 0.28 mmol) and copper iodide
(0.04 g, 0.21 mmol) were added to the reaction mixture and
stirred for an additional hour. The mixture was refluxed at
50 °C overnight. The organic phase was concentrated and
purified on a silica gel column (60% EtOAc/hexane) to provide
0.6 g (61%) of the desired product as a yellow oil. 1H NMR
(CDCl3, 400 MHz): δ 0.75 (t, 3H, J ) 7.5 Hz); 1.08 (s, 3H);