Macrocyclic Potential Protease Inhibitors
tide 27 (75 mg, 43%) as a crystalline white solid: mp 189-
7-Acet yla m in o-10-ca r b oxym et h yl-8,11-d ioxo-19-oxa -
9,12,17-t r ia za t r icyclo[14.2.1.05,18]n on a d eca -1(18),2,4,16-
tetr a en e-13-ca r boxylic Acid Meth yl Ester (30). A mixture
of the macrocycle 26 (48 mg, 0.08 mmol) and a catalytic
amount (10 mol %) of 5% palladium on carbon in acetic acid
(5 mL) and acetic anhydride (0.5 mL) was hydrogenated at
room temperature for 24 h before being filtered through a
Celite pad, and the solvents were removed. The crude residue
was taken up in CH2Cl2 (30 mL), washed with water (10 mL)
and brine (30 mL), dried over magnesium sulfate, and con-
centrated under reduced pressure to afford the acetamide free
acid 30 as a white solid (35 mg, 95%), which was used without
further purification: 90% CH2Cl2/10% MeOH (Rf 0.08); mp
135-137 °C; [R]D22 -17.6 (c 0.2, CH2Cl2); calcd for C21H24N4O8
[M+] 460.1586, found 460.1594; MS (m/z EI+, %) 460 (M+, 61),
401 (31), 279 (53), 205 (28), 167 (32), 149 (100), 57 (42); MS
(m/z CI+, %) 461 (MH+, 100), 149 (26), 279 (18), 167 (28), 149
(58), 83 (37); IR νmax (KBr) 3500-3308, 2955, 2926, 2854, 1741,
190 °C; [R]D 16.7 (c 0.12, CH2Cl2); calcd for C37H37N5O9 [M+]
22
695.2591, found 695.2586; MS (m/z EI+, %) 695 (M+, 12%), 587
(36), 219 (70), 131 (50), 91 (92), 69 (100); IR νmax (KBr) 3313,
3064, 3032, 2942, 2860, 1772, 1739, 1712, 1646 cm-1; 1H NMR
(500 MHz, CDCl3) δ 1.24-1.32 (2H, m), 1.58-1.64 (1H, m),
1.67-1.73 (1H, m), 1.76-1.78 (1H, m), 1.98-2.01 (1H, m),
2.38-2.44 (1H, m), 2.60-2.65 (1H, m), 2.96 (1H, dd, J ) 18.5,
11.5), 3.09 (1H, dd, J ) 18.5, 7.5, H), 3.46-3.50 (1H, m), 3.65
(1H, dd, J ) 13.5, 6.5), 3.66 (2H, t, J ) 5.5), 3.75 (3H, s), 4.33-
4.37 (1H, m), 4.65-4.68 (1H, m), 4.73-4.75 (1H, m), 5.10 and
5.18 (2H, AB, J ) 12.5), 5.76 (1H, d, J ) 7), 6.58 (1H, d, J )
7.5), 7.04 (1H, d, J ) 7.5), 7.17 (1H, t, J ) 8), 7.31-7.34 (6H,
m), 7.70 (2H, dd, J ) 4.5, 3), 7.86 (2H, dd, J ) 4.5, 3), 8.84
(1H, d, J ) 6); 13C NMR (125 MHz, CDCl3) δ 22.2, 25.2, 28.1,
30.7, 33.2, 36.6, 52.5, 53.4, 53.8, 54.5, 66.8, 109.3, 123.5, 124.7,
126.4, 127.2, 128.1, 128.6, 132.0, 134.2, 136.6, 139.6, 150.7,
155.4, 166.7, 169.0, 170.8, 171.5, 171.6.
1
1651 cm-1; H NMR (500 MHz, CDCl3) δ 2.01 (3H, s), 2.34-
Met h yl (7S,10S,13S)-7-(Acet yla m in o)-10-b en zyl-8,11-
d ioxo-19-oxa -9,12,17-tr ia za tr icyclo[14.2.1.06,18]n on a d eca -
1(18),2,4,16-tetr a en e-13-ca r boxyla te (28). A solution of the
macrocycle 25 (44 mg, 0.08 mmol) in acetic acid (5 mL) and
acetic anhydride (0.5 mL) was hydrogenated at room temper-
ature (H2 ) 1 atm) over a catalytic amount (10 mol %) of 5%
palladium on carbon. After 48 h, the mixture was filtered
through a Celite pad and the solvents evaporated. The crude
residue was taken up in CH2Cl2 (30 mL), washed with a
potassium bicarbonate solution (2 × 30 mL) and brine (30 mL),
dried over magnesium sulfate, and evaporated to afford the
acetamido derivative 28 as a white solid (33 mg, 85%), which
was used without further purification: 90% CH2Cl2/10%
MeOH (Rf 0.5); [R]D22 -12.5 (c 0.2, CH2Cl2); calcd for C26H28N4O6
[M+] 492.2009, found 492.2021; MS (m/z EI+, %) 492 (M+,
100%), 449 (15), 433 (18), 174 (56), 120 (73), 91 (76); IR νmax
(film) 3286, 3063, 3031, 2952, 2928, 1741, 1634 cm-1; 1H NMR
(500 MHz, CDCl3) δ 2.28-2.34 (1H, m), 2.46-2.50 (1H, m),
2.86-2.98 (3H, m), 3.10 (1H, dd, J ) 14.0, 6.5), 3.36 (1H, dd,
J ) 13.5, 6.5), 3.42 (1H, dd, J ) 13.5, 2.5), 3.68 (3H, s), 4.51-
4.55 (1H, m), 4.62-4.68 (2H, m), 5.98 (1H, d, J ) 8.5), 6.49
(1H, d, J ) 6.5), 6.99 (1H, dd, J ) 7.5, 2.5), 7.03 (1H, d, J )
7.5), 7.08-7.17 (4H, m), 7.16 (1H, t, J ) 8), 7.25 (1H, d, J )
8), 8.63 (1H, d, J ) 5.5); 13C NMR (125 MHz, CDCl3) δ 23.3,
24.8, 25.1, 32.8, 37.4, 52.5, 53.4, 53.6, 54.3, 109.4, 124.7, 126.0,
127.0, 127.4, 128.7, 129.2, 136.1, 139.6, 150.6, 165.8, 169.6,
170.3, 170.6, 171.2.
2.39 (1H, m), 2.58-2.62 (1H, m), 2.61 (1H, dd, J ) 17.5, 4.5),
2.94 (1H, dd, J ) 19, 11.5), 3.02 (1H, dd, J ) 17.5, 5), 3.04
(1H, dd, J ) 19.0, 8), 3.28 (1H, dd, J ) 14, 6), 3.64-3.66 (1H,
m), 3.68 (3H, s), 4.51-4.54 (1H, m), 4.83-4.87 (1H, m), 5.01-
5.04 (1H, m), 6.63 (1H, s), 6.99 (1H, d, J ) 7.5), 7.20 (1H, t, J
) 8), 7.32 (1H, d, J ) 8.5), 7.52 (1H, d, J ) 8.5), 9.64 (1H, d,
J ) 4.5); 13C NMR (125 MHz, CDCl3) δ 23.3, 24.4, 24.7, 33.0,
35.3, 49.6, 52.5, 53.0, 53.8, 109.6, 124.9, 126.3, 127.2, 139.6,
150.9, 167.5, 170.4, 171.0, 171.2, 171.4, 174.8.
(7S,10S,13S)-7-(Acetyla m in o)-10-ben zyl-8,11-d ioxo-19-
oxa-9,12,17-tr iazatr icyclo[14.2.1.06,18]n on adeca-1(18),2,4,16-
tetr a en e-13-ca r boxa m id e (29). Lithium hydroxide mono-
hydrate (5 mg, 0.12 mmol) was added to a suspension of
macrocycle 28 (39.4 mg, 0.08 mmol) in 2 mL of 1/1 acetonitrile/
water, and the resulting yellow solution was stirred for 90 min
at room temperature. The solvents were evaporated, and the
residue was partitioned between ethyl acetate (3 × 10 mL)
and water (10 mL). The pH of the aqueous layer was adjusted
to 2 with 1 M HCl, extracted with ethyl acetate (4 × 3 mL),
and washed with brine (10 mL). The combined organic phases
were dried over magnesium sulfate and concentrated to give
37 mg (96%) of the corresponding acid as a white powder that
was used directly. To a solution of the acid (5 mg, 0.12 mmol)
in THF (13 mL) were added N-hydroxybenzotriazole (16 mg,
0.105 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodi-
imide hydrochloride (EDCI) (13.5 mg, 0.07 mmol). This
mixture was stirred at room temperature for 1 h, 25% aqueous
ammonia (24.5 mg, 27 µL, 0.07 mmol) was added slowly and
the reaction stirred for an additional 2 h at room temperature.
After evaporation, the residue was taken up in CH2Cl2 (10 mL)
and washed with saturated sodium bicarbonate solution (3 ×
30 mL). The organic layer was washed with brine (10 mL) and
dried over magnesium sulfate. The solvent was evaporated to
give a white solid, which was subjected to chromatography over
silica (95% CH2Cl2/5% MeOH) to afford the acetamido primary
amide 29 as a white solid (19.4 mg, 58%): 90% CH2Cl2/10%
Meth yl (7S,10S,13S)-7-(Acetyla m in o)-10-(4′-p h th a lim i-
dobutyl)-8,11-dioxo-19-oxa-9,12,17-triazatricyclo [14.2.1.06,18]-
n on a d eca -1(18),2,4,16-tetr a en e-13-ca r boxyla te (31). Mac-
rocycle 27 (52 mg, 0.08 mmol) was reacted under an atmosphere
of hydrogen for 24 h, according to the procedure above, to give
the acetamide 31 as a white solid (36 mg, 75%), which was
used without further purification: 90% CH2Cl2/10% MeOH (Rf
22
0.65); mp 168-170 °C; [R]D -14.0 (c 0.2, CH2Cl2); calcd for
C
31H33N5O3 [M+] 603.2334; found 603.2329; MS (m/z EI+, %)
603 (M+, 100), 560 (21), 559 (23), 546 (25), 257 (37), 244 (61),
22
MeOH (Rf 0.4); mp 152-154 °C; [R]D -9.1 (c 0.2, CH2Cl2);
231 (76), 187 (45), 174 (63), 160 (54), 146 (43), 84 (75); IR νmax
calcd for C25H27N5O5 [M+] 477.1999, found 477.2012; MS (m/z
EI+, %) 477 (M+, 81), 433 (100), 341 (51), 299 (69), 286 (82),
258 (55), 216 (91), 174 (63), 120 (68), 91 (84); MS (m/z CI+, %)
478 (MH+, 76), 461 (74), 433 (100), 286 (34), 258 (39), 216 (30),
187 (29), 120 (64), 91 (80); IR νmax (KBr) 3410, 3297, 3062,
3031, 2924, 2852, 1665, 1651 cm-1; 1H NMR (500 MHz, CDCl3)
δ 1.82 (3H, s), 2.03-2.06 (1H, m), 2.40-2.46 (1H, m), 2.73 (1H,
ddd, J ) 18.5, 7, 5), 2.97-3.01 (1H, m), 2.93 (1H, dd, J ) 14.5,
5), 3.01 (1H, dd, J ) 14.5, 7), 3.19 (1H, dd, J ) 13.5, 2), 3.34
(1H, dd, J ) 13.5, 9), 4.25 (1H, dt, J ) 6.5, 5), 4.51-4.54 (2H,
m), 5.42 (1H, s), 5.60 (1H, d, J ) 6), 6.40-6.42 (2H, m), 6.85-
6.87 (1H, m), 6.98 (1H, d, J ) 7.5), 7.08-7.10 (5H, m), 7.67
(1H, d, J ) 8), 8.75 (1H, d, J ) 7.5); 13C NMR (125 MHz,
CDCl3) δ 23.3, 24.9, 25.1, 32.8, 37.2, 53.1, 53.7, 56.3, 109.8,
125.1, 126.7, 127.1, 127.7, 128.8, 129.2, 135.6, 138.9, 150.7,
(KBr) 3327, 2925, 2853, 1772, 1741, 1711, 1684, 1640 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.19-1.25 (2H, m), 1.61-1.63
(1H, m), 1.70-1.74 (1H, m), 1.99 (3H, s), 1.81-1.84 (1H, m),
2.02-2.13 (1H, m), 2.45-2.49 (2H, m), 2.57-2.63 (1H, m),
2.94-2.99 (1H, m), 3.14-3.16 (1H, m), 3.65-3.71 (1H, m),
3.73-3.75 (1H, m), 3.67 (2H, t, J ) 7.0), 3.76 (3H, s), 4.33-
4.37 (1H, m), 4.66 (1H, td, J ) 6, 3), 4.93 (1H, td, J ) 6.5, 2),
6.41 (1H, d, J ) 6.5), 6.56 (1H, d, J ) 7.5), 7.10 (1H, d, J )
7.0), 7.23 (1H, t, J ) 8), 7.36 (1H, d, J ) 7.5), 7.76 (2H, dd, J
) 5.5, 3), 7.92 (2H, dd, J ) 5.5, 3), 9.11 (1H, d, J ) 6); 13C
NMR (125 MHz, CDCl3) δ 22.1, 23.3, 24.9, 25.0, 28.0, 29.7,
32.8, 36.3, 52.4, 53.2, 53.3, 54.0, 109.3, 123.5, 124.6, 126.4,
127.4, 131.8, 134.3, 139.8, 150.7, 166.7, 169.1, 169.4, 171.3,
171.4, 171.5. Anal. Calcd for C31H33N5O3: C, 61.68; H, 5.51;
N, 11.60. Found: C, 61.6; H, 5.4; N, 11.7.
J . Org. Chem, Vol. 67, No. 14, 2002 4891