was reacted with Bu-SO2-Cl to give compound 2c in 90%
yield.
Intermediate 3 was assembled by alkylating dimethoxy-
phenol with 3,3-dimethylacrylate in CH3SO3H to make
lactone 11 in 40% yield using a procedure of isolation
simpler than that previously reported (Scheme 3).18-20 The
aldehydes 14a,b (not shown in Scheme 4), which were
further oxidized to acids 15a,b in an overall yield of 30-
33% determined from the starting materials 12a,b. Removal
of the Boc group in 15a,b with TFA/CH2Cl2 produced the
final linear precursors 16a,b.23 Cyclization of 16a,b to give
cyclic prodrugs 1a,b was done using HBTU and DIEA in a
highly dilute solution of DMF. Compounds 1a,b were
purified by column chromatography to give a 9-12% yield.24
In summary, we have developed a strategy to prepare
cyclic prodrugs of Aggrastat and its analogue via a modified
phenylpropionic acid linker with the aim of balancing the
solubility and hydrophobicity of the cyclic prodrugs to obtain
optimal physicochemical properties for membrane perme-
ation through the intestinal mucosa. These cyclic prodrugs
Scheme 3a
(22) Typical procedure: Compound 2c (1.44 g, 2.67 mmol) was
dissolved in dry dichloromethane (DCM) (10.0 mL), and the solution was
cooled to 0 °C. To this clear solution was added 1,3-dicyclohexylcarbo-
diimide (DCC) (0.66 g, 3.2 mmol), and the reaction mixture was stirred at
0 °C for 10 min. Compound 3 (0.945 g, 2.67 mmol) in dry DCM (5.0 mL)
was added to the reaction followed by the addition of DMAP (0.39 g, 3.2
mmol). The reaction mixture was stirred for 2 h at 0 °C and for 20 h at
room temperature. The resulting white precipitate was removed by filtration.
Solvent removal with a rotary evaporator gave a yellow oil residue, which
was dissolved in ethyl acetate (30 mL). The ethyl acetate solution was
washed with 5% aqueous NaHCO3, 5% aqueous citric acid, H2O, and brine.
The organic layer was dried over MgSO4 and concentrated under reduced
pressure to give a light yellow oil, which was purified on a silica gel column
(50:50, ethyl acetate/hexane) to give the light yellow oil product 12a (1.71
g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.25 (d, 2 H, J ) 8.5 Hz), 6.88 (d,
2 H, J ) 8.6 Hz), 6.37 (d, 1 H, J ) 2.6 Hz), 5.86 (d, 1 H, J ) 2.6 Hz), 4.96
(d, 1 H, 9 Hz), 4.50 (m, 1 H), 4.15 (m, 2 H), 3.95 (t, 2 H, J ) 6.4 Hz), 3.81
(s, 3 H), 3.72 (s, 3 H), 3.47 (t, 2 H, J ) 7.2 Hz), 3.32 (dd, 1 H, J ) 4.9,
4.8 Hz), 3.10 (dd, 1 H, J ) 7.9, 7.9 Hz), 2.80 (t, 2 H, J ) 8.1 Hz), 2.70 (t,
2 H, J ) 13.0 Hz), 2.08 (m, 2 H), 1.61-1.82 (m, 8 H), 1.47 (s, 8 H), 1.42
(s, 9 H), 1.30 (m, 5 H), 1.13 (m, 2 H), 0.87 (s, 9 H), 0.87 (t, 3 H, J ) 7.3
Hz), 0.00 (s, 6 H); MS (FAB) m/z 775 (M+ - Boc). Data for 12b: 1H
NMR (400 MHz, CDCl3) δ 7.25 (d, 2 H, J ) 8.5 Hz), 6.87 (d, 2 H, J )
8.6 Hz), 6.37 (d, 1 H, J ) 2.6 Hz), 5.86 (d, 1 H, J ) 2.6 Hz), 4.93 (d, 1
H, 9 Hz), 4.51 (m, 1 H), 4.15 (m, 2 H), 3.95 (t, 2 H, J ) 6.4 Hz), 3.80 (s,
3 H), 3.73 (s, 3 H), 3.47 (t, 2 H, J ) 7.2 Hz), 3.34 (dd, 1 H, J ) 4.9, 4.8
Hz), 3.08 (dd, 1 H, J ) 7.8, 7.8 Hz), 2.80 (t, 2 H, J ) 8.1 Hz), 2.70 (t, 2
H, J ) 13.0 Hz), 2.07 (m, 2 H), 1.82 (m, 2 H), 1.70 (m, 2 H), 1.61 (m, 4
H), 1.47 (s, 8 H), 1.41 (s, 9 H), 1.30 (m, 1 H), 1.13 (m, 2 H), 0.86 (s, 9 H),
0.86 (t, 3 H, J ) 8.0 Hz), 0.00 (s, 6 H); MS (FAB) m/z 647 (M+ - Boc -
TBDMS + 1).
a Reagents and conditions: (a) CH3SO3H, 70 °C, 3 h, 40%; (b)
LiAlH4, THF, 70%; (c) TBDMS-Cl, Et3N, CH2Cl2, 78%.
alkylation method using H2SO4 in toluene that was previously
used to make linker 1c produced only a 20% yield of
compound 11. Increasing the reaction temperature or time
failed to improve this yield. Lactone 11 was then reduced
to a diol in 70% yield using LiAlH4 in THF. The primary
alcohol was selectively protected by a TBDMS group using
a standard procedure to give compound 3 in 78% yield.13,21
The syntheses of cyclic prodrugs 1a and 1b were initialized
by coupling linker 3 and compounds 2c and 2d to yield
intermediates 12a (73%) and 12b (67%), respectively.22 The
TBDMS-protected group was removed using AcOH/H2O in
THF; the resulting alcohols 13a,b were oxidized to yield
(14) Wang, B.; Nimkar, K.; Wang, W.; Zhang, H.; Shan, D.; Gudmunds-
son, O. S.; Gangwar, S.; Siahaan, T. J.; Borchardt, R. T. J. Pept. Res. 1999,
53, 370.
(15) Gudmundsson, O. S.; Nimkar, K.; Gangwar, S.; Siahaan, T. J.;
Borchardt, R. T. Pharm. Res. 1999, 16, 16.
(16) Hartman, G. D.; Egberston, M. S.; Halczenko, W. Laswell, W. L.;
Duggan, M. E.; Smith, R. L.; Naylor, A. M.; Manno, P. D.; Lynch, R. J.;
Zhang, G.; Chang, C. T.; Gould, R. J. J. Med. Chem. 1992, 35, 4640.
(17) Egberston M. S.; Chang, C. T.; Duggan, M. E.; Gould, R. J.;
Halczenko, W.; Hartman, G. D.; Laswell, W. L.; Lynch, J. J.; Lynch, Jr.;
R. J.; Manno, P. D.; Naylor, A. M.; Prugh, J. D.; Ramjit, D. R.; Sitko, G.
R.; Smith, R. S.; Turchi, L. M.; Zhang, G. J. Med. Chem. 1994, 37, 2537.
(18) Carpino, L. A.; Triolo, A. S.; Berglund, R. A. J. Org. Chem. 1989,
54, 3303.
(23) Data for 15a: 1H NMR (400 MHz, CDCl3) δ 7.23 (d, 2 H, J ) 8.3
Hz), 6.87 (d, 2 H, J ) 8.3 Hz), 6.36 (d, 1 H, J ) 2.4 Hz), 5.92 (d, 1 H, J
) 2.5 Hz), 5.21 (d, 1 H, J ) 8.9 Hz), 4.48 (m, 1 H), 3.93 (t, 2 H, J ) 6.3
Hz), 3.80 (s, 3 H), 3.72 (s, 3 H), 3.28 (dd, 1 H, J ) 4.7, 4.7 Hz), 3.15 (dd,
1 H, J ) 7.5, 7.3 Hz), 2.87 (q, 2 H, J ) 5.8, 4.7 Hz), 2.78 (t, 2 H, J ) 7.3
Hz), 2.68 (t, 2H, J ) 11.0 Hz), 1.76 (m, 7 H), 1.67 (m, 2 H), 1.52 (m, 8
H), 1.47 (s, 9 H), 1.32-1.45 (m, 5 H), 1.12 (m, 2 H), 0.84 (t, 3 H, J ) 7.4
Hz); MS (FAB) m/z 677 (M+ - Boc + 2). Data for 15b: 1H NMR (400
MHz, CDCl3) δ 7.25 (d, 2 H, J ) 8.4 Hz), 6.88 (d, 2 H, J ) 8.6 Hz), 6.37
(d, 1 H, J ) 2.7 Hz), 5.92 (d, 1 H, J ) 2.5 Hz), 5.15 (d, 1 H, J ) 8.9 Hz),
4.48 (m, 1 H), 3.94 (t, 2 H, J ) 6.3 Hz), 3.81 (s, 3 H), 3.72 (s, 3 H), 3.30
(dd, 1 H, J ) 4.7, 4.7 Hz), 3.10 (dd, 1 H, J ) 7.7, 7.6 Hz), 2.88 (q, 2 H,
J ) 5.8, 4.7 Hz), 2.80 (t, 2 H, J ) 8.1 Hz), 2.70 (t, 2H, J ) 12.0 Hz), 1.81
(m, 2 H), 1.71 (m, 3 H), 1.60 (m, 2 H), 1.54 (d, 6 H, J ) 9.3 Hz), 1.47 (s,
9 H), 1.35-1.45 (m, 4 H), 1.25 (m, 2 H), 1.14 (m, 3 H), 0.84 (t, 3 H, J )
7.4 Hz); MS (FAB) m/z 763 (M+ + 1). Data for 16a: 1H NMR (400 MHz,
DMSO-d6) δ 11.7 (br, 1 H), 8.45 (br, 1 H), 8.10 (br, 1 H), 7.90 (d, 1 H, 9.3
Hz), 7.30 (d, 2 H, J ) 8.5 Hz), 6.88 (d, 2 H, J ) 8.5 Hz), 6.46 (d, 1 H, J
) 2.4 Hz), 5.94 (d, 1 H, J ) 2.3 Hz), 4.27 (m, 1 H), 3.99 (t, 2 H, J ) 6.1
Hz), 3.78 (s, 3 H), 3.68 (s, 3 H), 3.40 (m, 2 H), 3.28 (d, 2 H, J ) 9.3 Hz),
3.20 (dd, 1 H, J ) 4.7, 4.7 Hz), 2.85 (m, 3 H), 2.70 (m, 2 H), 2.60 (m, 2
H), 1.80 (d, 2 H, J ) 10.0 Hz), 1.70 (m, 2 H), 1.52 (m, 1 H), 1.39 (s, 6 H),
1.20-1.35 (m, 5 H), 1.12 (m, 2 H), 0.75 (t, 3 H, J ) 7.2 Hz); MS (FAB)
m/z 677 (M+ + 1). Data for 16b: 1H NMR (400 Hz, CDCl3) δ 8.89 (m, 1
H), 8.20 (m, 1 H), 7.26 (d, 2 H, J ) 8.4 Hz), 6.86 (d, 2 H, J ) 8.4 Hz),
6.36 (d, 1 H, J ) 2.4 Hz), 5.87 (d, 1 H, 2.4 Hz), 5.50 (m, 1 H), 4.48 (m,
1 H), 3.99 (t, 2 H, J ) 6.0 Hz), 3.80 (s, 3 H), 3.72 (s, 3 H), 3.40 (m, 2 H),
3.29 (dd, 2 H, J ) 4.7, 4.7 Hz), 3.15 (dd, 1 H, J ) 7.5, 7.3 Hz), 2.85 (m,
5 H), 2.70 (m, 2 H), 1.80 (m, 2 H), 1.60 (m, 2 H), 1.50 (d, 6 H, J ) 8.7
Hz), 1.41 (m, 5 H), 1.30 (m, 2 H), 0.87 (t, 3 H, J ) 7.2 Hz); MS (FAB)
m/z 663 (M+ + 1).
(19) Experimental procedure: Methanesulfonic acid (50 mL) was
heated to 70 °C in an oil bath, and methyl 3,3-dimethylacrylate (5.7 g,
50.0 mmol) and 3,5-dimethoxyl phenol (6.65 g, 40.0 mmol) were added
all at once with stirring. Stirring was continued at 70 °C for 3 h, and the
reaction mixture was diluted to 500 mL with water and extracted with ethyl
acetate (3 × 50 mL). The extracts were washed with water, saturated
NaHCO3, and NaCl solutions and dried over MgSO4. Solvent removal with
a rotary evaporator gave a brown solid, which was purified on a silica gel
column (15:85, ethyl acetate/hexane) to give the light brown solid product
1
11 (3.78 g, 40%). H NMR (400 MHz, CDCl3) δ 6.26 (d, 2 H, J ) 10.3
Hz), 3.82 (s, 3 H), 3.79 (s, 3 H), 2.59 (s, 2 H), 1.42 (s, 6 H); MS (FAB)
m/z 237 (M+ + 1).
(20) Amsberry, K. L.; Borchardt, R. T. J. Org. Chem. 1990, 55, 5867.
(21) Data for 3: 1H NMR (400 MHz, CDCl3) δ 6.23 (br, 1 H), 6.06 (d,
2 H, J ) 2.6 Hz), 5.98 (d, 1 H, J ) 2.6 Hz), 3.74 (s, 3 H), 3.72 (s, 3 H),
3.60 (t, 2 H, J ) 6.8 Hz), 2.05 (t, 2 H, J ) 6.8 Hz), 1.53 (s, 6 H), 0.86 (s,
9 H), 0.01 (s, 6 H); MS (FAB) m/z 355 (M+ + 1).
Org. Lett., Vol. 4, No. 4, 2002
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