1412 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 8
Lin et al.
2H), 5.14 (dq, J ) 6.0, 3.8 Hz, 2H), 2.28 (s, 3H), 2.27 (s, 3H),
1.3 (d, J ) 6.0 Hz, 6H). Anal. (C30H30O12‚H2O) C, H.
9.11 (s, 1H), 8.17 (t, J ) 5.4 Hz, 1H), 7.5 (d, J ) 15.9 Hz, 1H),
7.25 (d, J ) 15.7 Hz, 1H), 7.04-6.93 (m, 2H), 6.85-6.71 (m,
2H), 6.34 (d, J ) 15.7 Hz, 1H), 6.25 (d, J ) 15.5 Hz, 1H), 4.16
(t, J ) 5.4 Hz, 2H), 3.45 (m, 2H); FABMS m/z 384 (M - H).
Anal. (C20H19NO7‚0.5 H2O) C, H, N.
(+)-(1S,2S)-O,O-Bis(3,4-d ia cetoxycin n a m oyl)-1,2-cyclo-
h exa n ed iol (9). Reaction of (1S,2S)-cyclohexanediol as de-
scribed above provided 9 as a solid (91% yield): mp 62-64 °C
(EtOAc-hexane); [R]20 + 220° (MeOH, c ) 0.13); 1H NMR
Meth yl O,O-Bis(3,4-diacetoxycin n am oyl)-2,3-dih ydr oxy-
p r op a n oa te (18). To a solution of 2,3-dihydroxypropanoic acid
methyl ester (5.0 mmol) in anhydrous pyridine (20 mL) was
added a solution of 3,4-diacetylcaffeoyl acid chloride (5) (12.5
mmol) in toluene (30 mL), and the resulting cloudy solution
was stirred at room temperature overnight. Solvent was
removed by rotary evaporator and residue purified by flash
chromatography (ether:CHCl3), to afford 18 as a pale-white
D
(CDCl3) δ 7.55 (d, J ) 16.0 Hz, 2H), 7.36-7.3 (m, 4H), 7.17 (d,
J ) 8.3 Hz, 2H), 6.3 (d, J ) 16.0 Hz, 2H), 5.0-4.97 (m, 2H),
2.27 (s, 3H), 2.26 (s, 3H), 2.16-2.11 (m, 2H), 1.78 (m, 2H),
1.47-1.4 (m, 4H). Anal. (C32H32O12‚H2O) C, H.
O,O-Bis(3,4-d ia cetoxycin n a m oyl)-1,2-eth a n ed iol (10).
Reaction of 1,2-ethanediol as described above provided 10 as
a solid (89% yield): mp 153-156 °C (EtOAc-hexane); 1H NMR
(DMSO-d6) δ 7.72-7.64 (m, 6H), 7.31 (d, J ) 8.4 Hz, 2H), 6.7
(d, J ) 16.1 Hz, 1H), 4.43 (s, 4H). Anal. (C28H26O12) C, H.
O,O-Bis(3,4-d ia cetoxycin n a m oyl)-1,3-p r op a n ed iol (11).
Reaction of 1,3-propanediol as described above provided 11 as
a solid (91% yield): mp 194.5-196 °C (EtOAc-hexane); 1H
NMR (DMSO-d6) δ 7.7-7.62 (m, 6H), 6.09 (d, J ) 8.4 Hz, 2H),
6.66 (d, J ) 16.1 Hz, 1H), 4.47 (t, J ) 6.2 Hz, 4H), 2.283 (s,
6H), 2.278 (s, 6H), 2.04 (quintuplet, J ) 6.3 Hz, 2H). Anal.
(C29H28O12‚H2O) C, H.
N,O-Bis(3,4-d ia cetoxycin n a m oyl)-2-h yd r oxyeth yla m -
in e (12). Reaction of 2-hydroxyethylamine as described above
provided 12 as a solid (96% yield): mp 177-179.5 °C (EtOAc-
hexane); 1H NMR (CDCl3) δ 7.66 (d, J ) 16.1 Hz, 1H), 7.57 (d,
J ) 15.6 Hz, 1H), 7.42-7.32 (m, 4H), 7.21 (d, J ) 8.5 Hz, 1H),
7.18 (d, J ) 8.4 Hz, 1H), 6.38 (d, J ) 16.0 Hz, 1H), 6.34 (d, J
) 15.4 Hz, 1H), 6.00 (t, J ) 5.3 Hz, 1H), 4.36 (t, J ) 5.1 Hz,
2H), 3.71 (dt, J ) 5.1, 5.3 Hz, 2H), 2.29 (s, 3H), 2.28 (s, 3H),
2.280 (s, 3H), 2.276 (s, 3H). Anal. (C28H21NO11) C, H, N.
Gen er a l Meth od for P r ep a r a tion of Com p ou n d s 13-
17. Diesters 8-11 or amide ester 12 (0.5 mmol) in acetone (15
mL) were refluxed (3 h) with 3 N HCl (5 mL), then cooled to
room temperature, diluted with EtOAc (100 mL), and washed
with brine. After drying (Na2SO4) samples were concentrated
and purified by either crystallization or HPLC to give the
desired products.
1
solid (2.70 g, 88% yield): mp 159-160 °C; H NMR (DMSO-
d6) δ 7.80 (d, J ) 16.1 Hz, 1H), 7.73 (d, J ) 16.2 Hz, 1H), 7.30-
7.48 (m, 6H), 6.57 (d, J ) 16.1 Hz, 1H), 6.48 (d, J ) 16.1 Hz,
1H), 5.60 (t, J ) 4.9 Hz, 1H), 4.74 (m, 2H), 3.91 (s, 3H), 2.39
(s, 12H); FABMS m/z 613 (M + H). Anal. (C30H28O14) C, H.
Meth yl N,O-Bis(3,4-d ia cetoxycin n a m oyl)ser in a te (19).
Using racemic methyl serinate hydrochloride in a procedure
similar to that described above for the synthesis of 18, product
19 was obtained as a white solid (84% yield): mp 105.5-107
°C; 1H NMR (CDCl3) δ 7.70 (d, J ) 16.0 Hz, 1H), 7.67 (d, J )
15.6 Hz, 1H), 7.29-7.40 (m, 6H), 6.55 (d, J ) 8.0 Hz, 1H), 6.50
(d, J ) 15.6 Hz, 1H), 6.44 (d, J ) 16.1 Hz, 1H), 5.11 (m, 1H),
4.69 (q, J ) 3.4 Hz, 2H), 3.90 (s, 3H), 2.38 (s, 12H); FABMS
m/z 612 (M + H). Anal. (C30H29NO13) C, H, N.
Meth yl N,O-Bis(3,4-diacetoxycin n am oyl)-L-ser in ate (20).
Using methyl L-serinate hydrochloride in a procedure similar
to that described above for the synthesis of 18, product 20 was
obtained as a white powder (76% yield). NMR spectral data
was the same as that reported above for 19. 20: [R]20D +105.5°
(CHCl3, c ) 0.56). Anal. (C30H29NO13‚0.5H2O) C, H, N.
Met h yl N,O-Bis(3,4-d ia cet oxycin n a m oyl)-D-ser in a t e
(21). Using methyl D-serinate hydrochloride in a procedure
similar to that described above for the synthesis of 18, product
21 was obtained as a white powder (81% yield). NMR spectral
data was the same as that reported above for 19. 21: [R]20
D
-108.6° (CHCl3, c ) 0.63). Anal. (C30H29NO13‚0.5H2O) C, H,
N.
(+)-(2S,3S)-O,O-Bis(3,4-d ih yd r oxycin n a m oyl)-2,3-b u -
ta n ed iol (13). Treatment of diester 8 as described above and
purification by HPLC (linear gradient, MeOH in H2O from 0%
Meth yl N,N-Bis(3,4-d ia cetoxycin n a m oyl)-2,3-d ia m in o-
p r op a n oa te (22). To a mixture of N-methylmorpholine (52.1
mmol), methyl 2,3-diaminopropanoate dihydrochloride (5.23
mmol), 3,4-diacetoxycinnamic acid (10.5 mmol), and 1-hy-
droxybenzotriazole hydrate (10.5 mmol) in CH2Cl2 (30 mL) was
added diisopropylcarbodiimide (13.60 mmol). The resulting
solution was stirred at room temperature (overnight), then
partitioned between CH2Cl2 (∼200 mL) and H2O (∼70 mL),
washed with brine, and dried (Na2SO4). Solvent was removed
by rotary evaporator and residue purified by flash column
chromatography (CHCl3 and CHCl3:EtOAc) to afford 22 as a
white crystalline solid (1.40 g, 44% yield): mp 151-152 °C;
1H NMR (DMSO-d6) δ 7.65 (d, J ) 15.8 Hz, 1H), 7.64 (d, J )
15.6 Hz, 1H), 7.26-7.34 (m, 6H), 6.54 (br s, 2H), 6.51 (d, J )
15.8 Hz, 1H), 6.41 (d, J ) 15.6 Hz, 1H), 4.85 (q, J ) 4.6 Hz,
1H), 3.92 (d, J ) 4.6 Hz, 2H), 3.89 (s, 3H), 2.39 (s, 6H), 2.38
(s, 6H); FABMS m/z 611 (M + H). Anal. (C30H30N2O12) C, H,
N.
Meth yl N,N-Bis(3,4-m eth oxycin n a m oyl)-2,3-d ia m in o-
p r op a n oa te (23). Using 3,4-dimethoxycinnamic acid in a
procedure similar to that described above for the synthesis of
22, product 23 was obtained as a pale solid (67% yield): mp
125-126 °C; 1H NMR (DMSO-d6) δ 7.65 (d, J ) 15.6 Hz, 1H),
7.64 (d, J ) 15.5 Hz, 1H), 7.23 (d, J ) 6.8 Hz, 1H), 6.90-7.13
(m, 6H), 6.62 (t, J ) 6.7 Hz, 1H), 6.45 (d, J ) 15.6 Hz, 1H),
6.37 (d, J ) 15.5 Hz, 1H), 4.90 (q, J ) 6.6 Hz, 1H), 3.98 (s,
12H), 3.92 (m, 2H), 3.88 (s, 3H); FABMS m/z 499 (M + H).
Anal. (C26H30N2O8) C, H, N.
to 100% MeOH over 30 min) provided 13 as a white solid (73%
1
yield): [R]20 +98° (MeOH, c ) 0.13); H NMR (DMSO-d6) δ
D
7.47 (d, J ) 16.0 Hz, 2H), 7.03-6.96 (m, 4H), 6.73 (d, J ) 8.1
Hz, 2H), 6.24 (d, J ) 15.9 Hz, 2H), 5.05 (dq, J ) 6.0, 3.8 Hz,
2H), 1.21 (d, J ) 6.0 Hz, 6H); FABMS m/z 413 (M - H). Anal.
(C22H22O8‚H2O) C, H.
(+)-(1S,2S)-O,O-Bis(3,4-d ih yd r oxycin n a m oyl)-1,2-cy-
cloh exa n ed iol (14). Treatment of diester 9 as described above
provided 14 as a solid (88% yield): mp 216-218 °C (EtOAc-
CHCl3); [R]20D +373° (MeOH, c ) 0.18); 1H NMR (DMSO-d6) δ
7.42 (d, J ) 15.9 Hz, 2H), 6.98-6.92 (m, 4H), 6.7 (d, J ) 8.1
Hz, 2H), 6.16 (d, J ) 15.9 Hz, 2H), 4.9 (m, 2H), 1.98 (m, 2H),
1.68 (m, 2H), 1.4 (m, 4H); FABMS m/z 439 (M - H). Anal.
(C24H24O8‚11/4 H2O) C, H.
O,O-Bis(3,4-d ih yd r oxycin n a m oyl)-1,2-eth a n ed iol (15).
Treatment of diester 10 as described above provided 15 as a
solid (89% yield): mp > 330 °C (MeOH-CHCl3); 1H NMR
(DMSO-d6) δ 9.61 (s, 2H), 9.13 (s, 2H), 7.5 (d, J ) 15.9 Hz,
2H), 7.04-6.99 (m, 4H), 6.75 (d, J ) 8.1 Hz, 2H), 6.29 (d, J )
15.9 Hz, 1H), 4.37 (s, 4H); FABMS m/z 385 (M - H). Anal.
(C20H18O8‚H2O) C, H.
O,O-Bis(3,4-dih ydr oxycin n am oyl)-1,3-pr opan ediol (16).
Treatment of diester 11 as described above provided 16 as a
1
solid (83% yield): mp 205-207 °C (MeOH-CHCl3); H NMR
(DMSO-d6) δ 7.48 (d, J ) 5.9 Hz, 2H), 7.03 (d, J ) 1.8 Hz,
2H), 6.97 (dd, J ) 8.2, 1.8 Hz, 2H), 6.68 (d, J ) 8.1 Hz, 2H),
6.24 (d, J ) 15.9 Hz, 2H), 4.21 (t, J ) 6.2 Hz, 4H), 2.0 (t, J )
6.1 Hz, 2H); FABMS m/z 399 (M - H). Anal. (C21H20O8‚H2O)
C, H.
Gen er a l P r oced u r e for Dem eth yla tion of Com p ou n d s
18, 22, a n d 23 To P r ovid e P r od u cts 24-26, Resp ectively.
A suspension of methyl ester (0.4 mmol) and lithium iodide
(3.2 mmol) in pyridine (3 mL) was stirred at reflux (1 h).
Pyridine was removed, and the residue was taken up in H2O
(30 mL), acidified with 6 N HCl (to pH 3), extracted with
N,O-Bis(3,4-d ih yd r oxycin n a m oyl)-2-h yd r oxyeth yla m -
in e (17). Treatment of diester 12 as described above provided
17 as a solid (88% yield): mp 214-215.5 °C (MeOH-CHCl3);
1H NMR (DMSO-d6) δ 9.59 (s, 1H), 9.35 (s, 1H), 9.14 (s, 1H),