Countering Cooperativity Using Templates
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 7 1649
1.82 (m, 3H), 1.78-1.65 (m, 4H), 1.65-1.10 (m, 15H), 0.93 (d,
J ) 6.6 Hz, 6H), 0.91 (d, J ) 6.8 Hz, 3H), 0.83 (d, J ) 6.8 Hz,
3H). HRMS m/e 587.4143 MH+; calcd for C33H55N4O5 587.4172.
Hz, 3H), 0.89 (d, J ) 6.6 Hz, 3H), 0.88 (d, J ) 6.8 Hz, 3H,
Val-âCH3), 0.86 (d, J ) 6.9 Hz, 3H, Val-âCH3). 13C NMR
(CDCl3) δ 172.4, 170.8, 157.1, 138.7, 132.9, 130.2, 129.4, 129.3,
127.2, 116.3, 72.5, 67.6, 57.9, 53.5, 52.1, 49.0, 37.3, 35.5, 34.2,
32.1, 29.1, 25.8, 25.0, 24.5, 22.4, 22.3, 18.9, 18.3. HRMS m/e
601.3183; calcd for C32H47N3O6S 601.3186.
2S-(12-{2-[Ben zen esu lfon yl-(3-m eth ylbu tyl)a m in o]-1S-
h yd r oxyeth yl}-6,10-d ioxo-2-oxa -7,11-d ia za bicyclo[12.2.2]-
octadeca-1(17),14(18),15-tr ien -8S-yl)acetam ide, 8t. 1H NMR
(500 MHz, CDCl3) δ 6.55-7.79 (m, 13H, ArH, Asn-NH2, Asn-
NH, Tyr-NH), 4.23 (m, 1H, OCH), 4.12-4.19 (m, 2H, OCH,
Asn-RCH), 4.04 (m, 1H, Tyr-RCH), 3.67 (m, 1H, CHOH), 3.40
(m, 1H, CHN), 3.02-3.25 (m, 3H, NCH2, Tyr-âCH), 2.98 (m,
1H, CHN), 2.20-2.45 (m, 4H, Tyr-âCH, Asn-âCH2, CH(CO)),
1.82-2.08 (m, 3H, CHC(O), CH2), 1.27-1.49 (m, 3H, CH, CH2),
0.79 (d, J ) 7.7 Hz, 6H (CH3)2). ESI-MS m/e 589 (M + H)+.
3-ter t-Bu tyl-1-[2R-h ydr oxy-2-(10S-isopr opyl-8,11-dioxo-
2-oxa -9,12-d ia za bicyclo[13.2.2]n on a d eca -1(18),15(19),16-
tr ien -13S-yl)-eth yl]-1-(3-m eth ylbu tyl)u r ea , 8o. A solution
of the amine 4 (12 mg, 26 µmol) and tert-butyl isocyanate (4
µL, 1.5 equiv) in DMF/THF 1:1 (1 mL) was left at room
temperature for 10 min and then evaporated to dryness under
high vacuum. The residual gum was purified by RP-HPLC,
50:50% MeCN/H2O + TFA 0.1% isocratic, tR ) 5.6 min, giving
a white powder (9 mg, 62%) after lyophilization. 1H NMR (300
MHz, CD3OH) δ 7.92 (d, J ) 9.9 Hz, 1H, Tyr-NH), 7.26 (d, J
1
) 9.2 Hz, 1H, Val-NH). H NMR, AA′XX′ system, δ 7.06 (m,
2H, J AX + J AX′ ) 8.4 Hz, ortho to CH2), 6.77 (m, 2H, J AX + J AX′
) 8.6 Hz, ortho to O), 4.28-3.96 (m, 4H, H-3, H-13), 4.09 (dd,
J ) 9.0, 5.9 Hz, 1H, Val-RH), 3.65 (m, 1H, CHOH), 3.35-3.10
(m), 3.23 (dd, J ) 10.4, 7.8 Hz, H-14), 2.38 (dd, J ) 13.5, 12.3
Hz, H-14), 2.22-2.08 (m, 2H, H-7), 1.88 (m, 1H, Val-âH), 1.80-
1.60 (m, 2H), 1.54 (m, 1H, isoamyl-CH), 1.60-1.10 (m), 1.32
1-[2-(8-Ca r b a m oylm et h yl-6,9-d ioxo-2-oxa -7,10-d ia za -
b icyclo[11.2.2]h ep t a d eca -1(16),13(17),14-t r ien -11-yl)-2-
h yd r oxyet h yl]p yr r olid in e-2-ca r b oxylic Acid [1-(1-Ca r -
b a m oyl-2-m et h yl-p r op ylca r b a m oyl)-2-m et h ylb u t yl]a m -
id e, 8u . tR ) 39.9 min (0-45% MeCN + 0.1% TFA over 50
t
(s, 9H, Bu), 0.93 (d, J ) 6.4 Hz, 3H, H-4′′), 0.92 (d, J ) 6.5
1
Hz, 3H, H-5′′), 0.90 (d, J ) 6.8 Hz, 3H, Val-γ CH3), 0.82 (d, J
) 6.9 Hz, 3H, Val-γ CH3). 13C NMR (CD3OH) δ 174.8, 172.7,
161.0, 158.3, 131.7, 131.2, 117.3, 75.5, 68.6, 58.6, 55.3, 52.8,
51.3, 47.3, 37.9, 36.8, 35.8, 33.5, 30.5, 29.7, 27.3, 25.9, 25.9,
23.0, 22.8, 19.9, 18.1. HRMS m/e 560.3940; calcd for C31H54N4O5
560.3938.
min). H NMR (H2O/D2O, 8:2) δ 8.69 (br s, 1H, Ile-NH), 8.22
(d, J ) 7.23 Hz, 1H, Val-NH), 7.71 (d, J ) 9.8 Hz, 1H, 10′-
NH), 7.65 (br s, 1H), 7.47 (br s, 1H,), 7.21 (d, J ) 8.8 Hz, 1H,
Asn-NH), 7.20 (dd, J ) 2.1, 8.4 Hz, 1H, H17′), 7.15 (dd, J )
2.2, 8.4 Hz, 1H, H14′), 7.09 (br s, 1H), 7.00 (dd, J ) 2.7, 8.4
Hz, 1H, H16′), 6.95 (dd, J ) 2.7, 8.4 Hz, 1H, H15′), 6.72 (br s,
1H), 4.42-4.48 (m, 1H, H-3′), 4.29-4.38 (m, 3H, Asn-RCH, Ile-
RCH, and H-3′), 4.22-4.29 (m, 1H), 4.19 (m, 1H, Val-RCH),
4.10-4.16 (m, 2H, Pro-RCH and H-2), 3.8 (m, 1H, Pro-δCH),
3.15-3.28 (m, 3H), 3.12 (dd, J ) 3.5, 5.6 Hz, 1H, H-12′), 2.78
(dd, J ) 13.5, 13.5 Hz, 1H, H-12′), 2.55 (m, 1H), 2.42-2.51
(m, 3H), 2.29 (ddd, J ) 16.2, 7.6, 3.6 Hz, 1H), 2.19 (m, 1H),
1.98-2.14 (m, 6H), 1.89-1.98 (m, 1H), 1.51-1.61 (m, 1H),
1.20-1.30 (m, 1H), 1.02 (d, J ) 6.8 Hz, 6H), 0.98 (d, J ) 6.8
Hz, 3H), 0.94 (t, 3H, J ) 7.4 Hz). 13C NMR (H2O/D2O, 8:2) δ
10.59, 15.06, 18.21, 18.69, 23.08, 24.25, 24.98, 30.04, 30.23,
31.50, 35.63, 36.51, 38.86, 50.51, 53.84, 55.49, 58.19, 59.18,
59.74, 68.42, 68.78, 78.50, 114.98, 117.23, 117.83, 129.45,
131.27, 132.44, 156.90, 158.00, 171.93, 173.71, 174.50, 176.13.
ESI-MS m/e 688 (M + H+).
2-[3-[2R-Hyd r oxy-2-(10S-isop r op yl-8,11-d ioxo-2-oxa -9,-
12-d ia za -b icyclo[13.2.2]n on a d eca -1(18),15(19),16-t r ien -
13-yl)-et h yl]-3-(3-m et h ylb u t yl)u r eid o]-3-m et h ylb u t yr ic
Acid , 8p . This urea derivative was prepared in two steps from
the amine (7, n ) 5) and valine methyl ester isocyanate46 in
THF, followed by hydrolysis of the methyl ester with NaOH.
The solution was acidified with TFA and purified by RP-HPLC
50:50% MeCN/H2O + TFA 0.1% isocratic, tR ) 6.0 min, giving
1
a white powder after lyophilization. H NMR (300 MHz, CD3-
CN) δ AA′XX′ system, 7.06 (m, 2H, J AX + J AX′ ) 8.5 Hz, ortho
to CH2), 6.77 (m, 2H, J AX + J AX′ ) 8.5 Hz, ortho to CH2), 6.45
(d, J ) 9.7 Hz, 1H, H-12), 6.19 (d, J ) 8.7 Hz, 1H, H-9), 6.13
(br, 1H, urea NH), 4.24 (ddd, J ) 12.0, 6.0, 4.0 Hz, 1H, H-3),
4.15-3.98 (m, 3H, H-3, H-10, H-13), 3.69 (m, 1H, CHOH),
3.44-3.13 (m, 3H), 3.08 (dd, J ) 13.7, 3.9 Hz, 1H), 2.45-2.00
(m, also H2O peak), 1.9-1.78 (m, 1H), 1.71-1.00 (m), 0.98 (d,
J ) 6.9 Hz, 3H), 0.95 (d, J ) 6.9 Hz, 3H), 0.92 (d, J ) 6.5 Hz,
6H), 0.84 (d, J ) 6.8 Hz, 3H), 0.76 (d, J ) 6.8 Hz, 3H). 13C
NMR (CD3CN) δ 174.6, 172.5, 171.6, 161.1, 157.8, 131.6, 131.3,
117.0, 74.9, 68.4, 60.4, 57.7, 54.6, 52.3, 47.4, 37.6, 36.2, 35.7,
33.2, 30.7, 29.9, 26.8, 25.6, 25.6, 22.9, 22.8, 19.8, 19.7, 18.4,
18.1. ISMS m/e 605.4 MH+; calcd for C32H53N4O7 605.4.
N-[2R-H yd r oxy-2-(8S-isop r op yl-6,9-d ioxo-2-oxa -7,10-
d ia za -bicyclo[11.2.2]h ep ta d eca -1(16),13(17),14-tr ien -11S-
yl)-eth yl]-N-(3-m eth ylbu tyl)ben zen esu lfon a m id e, 8q. 1H
NMR (500 MHz, CDCl3) δ 6.66-7.73 (m, 10H, ArH, Val-NH),
7.62 (d, J ) 9.2 Hz, 1H, Tyr-NH), 4.3 (m, 1H, OCH), 4.18 (m,
1H, OCH), 4.05 (m, 1H, Tyr-RCH), 3.69 (m, 1H, CHOH), 3.50
(m, 1H, Val-RCH), 3.25-3.34 (m, 2H, CHN, NCH), 3.18 (m,
1H, Tyr-âCH), 3.07 (m, 1H, NCH), 2.92 (m, 1H, CHN), 2.3-
2.37 (m, 2H, Tyr-âCH, CHC(O)), 2.05 (m, 1H, CHC(O)), 1.78-
1.96 (m, 2H, CH2), 1.60 (m, 1H, Val-âCH), 1.44 (m, 1H, CH),
1.22-1.37 (m, 2H, CH2), 0.77 (d, J ) 7.3 Hz, 6H (CH3)2), 0.69
(d, J ) 6.7 Hz, 3H, CH3), 0.67 (d, J ) 6.7 Hz, 3H, CH3). ISMS
m/z 574 (M + H)+.
11S-Am in o-8S-sec-bu tyl-2-oxa -6,9-d ia za bicyclo[11.2.2]-
h ep ta d eca -1(16),13(17),14-tr ien e-7,10-d ion e (2).25 1H NMR
(300 MHz, CD3OH) δ 7.79 (broad m, 1H, NHCH2), 7.22 (d, J
) 7.8 Hz, 1H, Ile-NH), 7.23 (dd, J ) 8.4, 2.1 Hz, 1H, ArH),
6.97-6.79 (m, 3H, ArH), 4.41-4.31 (m, 1H, H-3), 4.28-4.16
(m, 1H, H-3), 4.08 (dd, J ) 10.7, 7.0 Hz, 1H, Tyr-RCH), 3.60-
3.45 (m, 1H, H-5), 3.47 (t, J ) 7.5 Hz, 1H, Ile-RCH), 3.28 (dd,
J ) 12.4, 7.0 Hz, 1H, Tyr-âCH), 2.86-2.75 (m, 1H, H5), 2.70
(dd, J ) 12.4, 10.7 Hz, 1H, Tyr-âCH), 2.30-2.09 (m, 1H, H-4),
1.83-1.69 (m, 1H, H-4), 1.60-1.39 (m, 2H, Ile-âCH and Ile-
γCH2), 1.01-0.88 (m, 1H, Ile-γCH2), 0.83 (t, J ) 7.2 Hz, 3H,
Ile-δCH3), 0.75 (d, J ) 6.8 Hz, 3H, Ile-γC3). 13C NMR (CD3-
OH) δ 171.5, 168.6, 160.0, 132.2, 130.4, 128.2, 118.8, 118.7,
68.6, 59.8, 56.0, 40.0, 38.0, 37.5, 27.6, 26.2, 14.9, 11.7. ISMS
m/z 334 (MH+).
2-Acetyla m in o-4-m eth ylp en ta n oic Acid {1-[1-Ben zyl-
3-(8-sec-bu tyl-7,10-d ioxo-2-oxa -6,9-d ia za -bicyclo[11.2.2]-
h eptadeca-1(16),13(17),14-tr ien -11S-ylam in o)-2R-h ydr oxy-
p r op ylca r ba m oyl]-2-m eth ylp r op yl}a m id e, 10a . Ac-Leu-
Val-Phe-COCH2Br24 was reduced to the bromohydrin and
cyclized to the epoxide 9 under the conditions reported for 5a
and 6a , respectively. Epoxide ring opening with the macrocy-
clic amine 2 in DMF, 70 °C, 24 h, gave 10a as a white powder
after HPLC (tR ) 55 min, Waters Delta-Pak cartridge (C18, 5
µm, 100 Å, 8 mm × 100 mm)), using a linear gradient from
H2O + 0.1% TFA to 55% MeCN + 0.1% TFA over 50 min at a
N-[2S-Hyd r oxy-2-(10S-isop r op yl-8,11-d ioxo-2-oxa -9,12-
d ia za -bicyclo[13.2.2]n on a d eca -1(18),15(19),16-tr ien -13-yl-
)et h yl]-N-(3-m et h ylb u t yl)b en zen esu lfon a m id e, 8s. tR
)
1
14.8 min. H NMR (600 MHz, CDCl3) δ 7.83 (m, 2H, ortho to
SO2), 7.63 (m, 1H, para to SO2), 7.55 (m, 2H, meta to SO2). 1H
NMR AA′XX′ system, δ 7.05 (m, 2H, J AX + J AX′ ) 8.5 Hz, ortho
to CH2), 6.83 (m, 2H, J AX + J AX′ ) 8.5 Hz, ortho to O), 5.79 (d,
J ) 8.4 Hz, 1H), 5.69 (d, J ) 9.5 Hz, 1H), 4.32-4.22 (m, 2H,
H-3, H-13), 4.16 (m, 1H, H-13), 3.96 (dd, J ) 8.3, 6.2 Hz, 1H,
Val-RCH), 3.90 (m, 1H, CHOH), 3.30-3.15 (m, 4H, CH2NCH2),
3.00 (dd, J ) 14.0, 4.2 Hz, H-14), 2.68 (dd, J ) 14.0, 12.5 Hz,
1H, H-14), 2.25 (m, 1H), 1.95-1.15 (e, 10H), 0.90 (d, J ) 6.6
1
flow rate of 2 mL/min. H NMR (500 MHz, CD3OH) δ 8.30 (d,
J ) 6.1 Hz, 1H, Leu-NH), 7.85 (m, 1H, NH), 7.73 (d, J ) 5.8
Hz, 1H, Val-NH), 7.70 (m, 1H, Phe-NH), 7.34 (d, J ) 7.6 Hz,
1H, Ile-NH), 6.80-7.30 (m, 9H, ArH), 4.38 (m, 1H, H3′), 4.20-
4.26 (m, 2H, Leu-RCH, H3′), 4.13 (m, 2H, Tyr-RCH, Phe-RCH),
3.81 (m, 2H, Val-RCH, H2), 3.54 (m, 1H, H5′), 3.45 (m, 1H,
Ile-RCH), 3.39 (dd, J H12′H12′ ) 12.1 Hz, J H11′H12′ ) 7.0 Hz, 1H,