A R T I C L E S
Reid et al.
2H), 6.80 (d, J ) 8.5 Hz, 2H), 6.25 (d, J ) 1H), 5.01 (d, J ) 1H),
4.82 (m, 1H), 3.96 (t, J ) 6.1 Hz, 2H), 3.89 (m, 1H), 3.71 (s, 3H),
3.10-3.02 (m, 2H), 2.42 (t, J ) 7.4 Hz, 2H), 2.19-1.99 (m, 3H), 1.45
(s, 18H), 0.98-0.79 (m, 6H). 13C NMR (CDCl3): δ 172.4, 171.7, 171.2,
158.0, 155.6, 130.1, 127.5, 114.5, 80.2, 79.7, 66.7, 59.8, 53.2, 52.2,
37.0, 31.9, 30.8, 28.2, 28.0, 24.7, 19.1, 17.6. ISMS 537 (MH+), 559
(MNa+), 481, 437, 381.
100%). 1H NMR (300 MHz, d6-DMSO): δ 8.08 (d, J ) 9.8 Hz, 1H),
7.34 (d, J ) 9.3 Hz, 1H), 7.10 (dd, J ) 8.5, 1.9 Hz, 1H), 7.02 (dd, J
) 8.5, 1.9 Hz, 1H), 6.76 (dd, J ) 8.5, 2.4 Hz, 1H), 6.66 (dd, J ) 8.5,
2.4 Hz, 1H), 4.62 (m, 1H), 4.14-3.67 (m, 2H), 3.97 (m, 1H), 3.16
(dd, J ) 13.2, 4.0 Hz, 1H), 2.53 (apparent t J ) 12.8 Hz, 1H), 2.14
(m, 1H), 1.82 (m, 1H), 1.63 (m, 1H), 1.61-1.07 (m, 4H), 0.79 (d, J )
6.7 Hz, 3H), 0.73 (d, J ) 6.7 Hz, 3H). 1H NMR (300 MHz, CD3OD):
δ 8.35 (d, J ) 9.9 Hz, 1H tyr NH), 7.47 (d, J ) 9.3 Hz, 1H, Val-NH),
7.19 (dd, J ) 8.5, 2.2 Hz, 1H, ArH), 7.00 (dd, J ) 8.2, 2.2 Hz, 1H,
ArH), 6.85 (dd, J ) 8.4, 2.6 Hz, 1H, ArH), 6.76 (dd, J ) 8.2, 2.6 Hz,
1H, ArH), 4.87-4.76 (m, 1H, tyr RH), 4.29-4.19 (m, 1H, CH2OAr),
4.14-4.02 (m, 1H, CH2OAr), 4.00 (d, J ) 8.4 Hz, 1H, val RH (NH
exchanged)), 3.35 (dd, J ) 13.5, 4.3 Hz, 1H, tyr âH), 2.62 (dd; J )
13.5, 12.7 Hz, 1H, tyr âH), 2.20-2.07 (m, 2H, CH2CO), 1.88-1.80
(m, 2H, val âH and CH2), 1.60-1.25 (m, 3H, CH2), 0.90 (d, J ) 6.8
Hz, 3H, CH3), 0.84 (d, J ) 6.7 Hz, 3H, CH3). 13C NMR (d6-DMSO):
δ 172.9, 171.1, 170.1, 154.9, 131.3, 130.1, 129.1, 118.3, 117.2, 67.9,
56.9, 52.2, 36.5, 34.8, 31.4, 25.6, 21.6, 18.9, 18.6. 13C NMR (CD3-
OD): δ 174.93, 174.35, 172.48, 156.66, 132.56, 131.46, 130.56, 119.63,
119.40, 69.36, 59.54, 54.18, 38.50, 36.46, 32.89, 27.24, 22.84, 19.54,
19.04. HRMS m/e 362.1841 calc. for C19H26N2O5 362.1842.
4-{4-[2-(2-Amino-3-methyl-butyrylamino)-2-methoxycarbonyl-
ethyl]-phenoxy} Butyric Acid (14). The protected dipeptide derivative
(13) (380 mg, 0.71 mg) was dissolved in neat TFA (2 mL), and then
after 15 min was evaporated. The residue was purified by rp-HPLC
(22% MeCN, 78% H2O, 0.1% TFA, Rt 9.5 min) giving a white powder
1
(248 mg, 92%) after lyophilization. H NMR (300 MHz, d6-DMSO):
δ 8.81 (d, J ) 7.1 Hz, 1H), 8.06 (br s, 3H), 7.13 (d, J ) 8.6 Hz, 2H),
6.83 (d, J ) 8.6 Hz, 2H), 4.49 (m, 1H), 3.93 (t, J ) 6.4 Hz, 2H), 3.63
(m, 1H), 3.59 (s, 3H), 2.98 (dd, J ) 14.1, 5.8 Hz, 1H), 2.89 (dd, J )
14.1, 8.4 Hz, 1H), 2.36 (t, J ) 7.1 Hz, 2H), 2.10 (m, 1H), 1.95-1.85
(m, 2H), 0.94 (d, J ) 6.9 Hz, 3H), 0.90 (d, J ) 6.9 Hz, 3H). 13C NMR
(d6-DMSO): δ 174.1, 171.4, 168.2, 157.4, 130.1, 128.6, 114.3, 66.5,
57.0, 54.1, 51.9, 35.6, 30.1, 29.9, 24.3, 18.3, 17.1. ISMS 381 (MH+),
282.
8-Isopropyl-6,9-dioxo-2-oxa-7,10-diaza-bicyclo[11.2.2]heptadeca-
1(16),13(17),14-triene-11-carboxylic Acid Methyl Ester (15). The
zwitterion (14) (30 mg, 0.079 mmol) and BOP (45 mg, 0.10 mmol,
1.2 equiv) were dissolved in DMF (8 mL) and stirred at room
temperature for 5 min. DIPEA (100 µL, 0.56 mmol) was added, and
stirring was continued overnight. The solvent was evaporated, and the
residue was dissolved in EtOAc and washed with 2 M HCl, NaHCO3,
brine, dried over MgSO4, and evaporated. The residue was purified by
rp-HPLC (38% MeCN, 62% H2O, 0.1% TFA, Rt 6.0 min) giving a
white powder (17 mg, 59%) after lyophilization. 1H NMR (300 MHz,
CDCl3): δ 7.14-7.07 (m, 1H), 6.95-6.81 (m, 3H), 5.79 (d, J ) 10.2
Hz, 1H), 5.54 (d, J ) 8.5 Hz, 1H), 5.10 (m, 1H), 4.51 (m, 1H), 4.28
(m, 1H), 3.82 (s, 3H), 3.66 (t, J ) 8.2 Hz, 2H), 3.46 (dd, J ) 13.7, 6.4
Hz, 1H), 2.58 (dd, J ) 13.7, 11.3 Hz, 1H), 2.32-2.26 (m, 2H), 2.13-
1.84 (m, 2H), 1.73 (m, 1H), 0.82 (apparent t, J ) 6.5 Hz, 6H). 13C
NMR (CDCl3): δ 172.1, 170.9, 170.7, 159.0, 131.9, 130.0, 128.0, 118.2,
115.7, 67.7, 58.8, 52.6, 51.7, 38.0, 31.9, 30.7, 24.8, 18.8, 18.4.
8-Isopropyl-6,9-dioxo-2-oxa-7,10-diaza-bicyclo[11.2.2]heptadeca-
1(16),13(17),14-triene-11-carboxylic Acid (1). The methyl ester (15)
(17 mg, 0.047 mmol) was dissolved in MeOH (3 mL), and then LiOH‚
H2O (10 mg in water (1 mL)) was added. The solution was stirred at
room temperature for 1 h, and was then acidified with TFA (1 drop).
The solvent was evaporated, and the residue was purified by rp-HPLC
(27% MeCN, 73% H2O, 0.1% TFA, Rt 6.5 min) giving a white powder
(15 mg, 92%) after lyophilization. 1H NMR (300 MHz, d6-DMSO): δ
7.87 (d, J ) 9.9 Hz, 1H, Tyr-NH), 6.75 (d, J ) 9.1 Hz, 1H, Val-NH),
7.03-6.94 (m, 2H), 6.73-6.67 (m, 2H), 4.74 (m, 1H, Tyr RCH), 4.29
(m, 1H), 4.15 (m, 2H), 3.63 (dd, J ) 9.1, 8.1 Hz, 1H, Val RCH), 3.20
(dd, J ) 13.2, 5.6 Hz, 1H), 2.54 (dd, J ) 13.2, 12.6 Hz, 1H), 2.29 (m,
1H), 1.95-1.74 (m, 2H), 1.65 (m, 1H), 1.54 (m, 1H), 0.73 (d, J ) 6.7
10S-Isopropyl-8,11-dioxo-2-oxa-9,12-diaza-bicyclo[13.2.2]nona-
deca-1(18),15(19),16-triene-13S-carboxylic Acid (3). H NMR (300
1
MHz, d6-DMSO): δ 8.12 (d, J ) 9.5 Hz, 1H, Tyr-NH), 7.25 (d, J )
9.1 Hz, 1H, Val NH), AA′XX′ system, 7.06 (m, 2H, JAX + JAX′ ) 8.5
Hz, ortho to CH2), 6.73 (m, 2H, JAX + JAX′ ) 8.5 Hz, ortho to O),
4.62 (m, 1H, Tyr-RCH), 4.24-4.01 (m, 2H, OCH2), 3.97 (dd, J ) 9.1,
7.8 Hz, Val-RCH), 3.13 (dd, J ) 13.5, 4.2 Hz, Tyr-âCH), 2.57 (dd, J
) 13.5, 12.7 Hz, Tyr-âCH), 2.19-2.06 (m, 1H, H-7′), 1.95-1.84 (m,
1H, H-7′), 1.78 (m, 1H, Val-âCH), 1.65-0.90 (e, 6H, H-4′, H-5′ and
H-6′), 0.80 (d, J ) 6.7 Hz, Val-γCH3), 0.72 (d, J ) 6.7 Hz, 3H, Val-
γCH3). 13C NMR (CD3OD): δ 174.6, 174.5, 172.7, 158.8, 131.3, 130.7,
117.6, 68.7, 59.1, 54.1, 38.1, 35.9, 33.2, 31.1, 26.3, 26.1, 19.6, 18.8.
ISMS: m/z 377 (MH+). HRMS m/e 376.1998 calc. for C20H28N2O5
376.1998.
11-Isopropyl-9,12-dioxo-2-oxa-10,13-diaza-bicyclo[14.2.2]eicosa-
1
1(19),16(20),17-triene-14-carboxylic Acid (4). H NMR (500 MHz,
d6-DMSO): δ 8.07 (d, J ) 9.3 Hz, 1H, Tyr-NH), 7.34 (d, J ) 9.3 Hz,
1H, Val-NH), 7.08 (d, J ) 8.5 Hz, 2H), 6.72 (d, J ) 8.5 Hz, 2H), 4.54
(m, 1H), 4.09 (m, 1H), 4.06-3.95 (m, 2H), 3.09 (dd, J ) 13.6, 3.7
Hz, 1H), 2.63 (dd, J ) 13.6, 12.4 Hz, 1H), 2.04 (m, 1H), 1.84 (m,
1H), 1.75 (m, 1H), 1.60 (m, 1H), 1.52 (m, 1H), 1.43-1.23 (m, 3H),
1.20-1.04 (m, 2H), 0.93 (m, 1H), 0.81 (d, J ) 6.8 Hz, 3H), 0.74 (d,
J ) 6.8 Hz, 3H). ISMS 391 (MH+), 781 (2MH+).
12-Isopropyl-10,13-dioxo-2-oxa-11,14-diaza-bicyclo[15.2.2]-
1
heneicosa-1(20),17(21),18-triene-15-carboxylic Acid (5). H NMR
(300 MHz, d6-DMSO): δ 8.24 (d, J ) 8.9 Hz, 1H, Tyr-NH), 7.44 (d,
J ) 9.2 Hz, 1H, Val-NH), 7.11 (d, J ) 8.2 Hz, 2H), 6.74 (d, J ) 8.2
Hz, 2H), 4.49 (m, 1H), 4.20-3.94 (m, 3H), 3.07 (dd, J ) 14.0, 3.0
Hz, 1H), 2.69 (dd, J ) 14.0, 12.5 Hz, 1H), 2.11 (m, 1H), 1.91 (m,
1H), 1.77 (m, 1H), 1.60-1.42 (m, 2H), 1.42-1.31 (m, 2H), 1.31-
1.10 (m, 2H), 0.98 (m, 1H), 0.84 (d, J ) 6.8 Hz, 3H), 0.78 (d, J ) 6.8
Hz, 3H). ISMS 405 (MH+), 809 (2MH+).
1
Hz, 3H), 0.68 (d, J ) 6.7 Hz, 3H). ISMS 349 (MH+). H NMR (500
MHz, 90% H2O/10%D2O): δ 7.98 (d, J ) 10.0 Hz, 1H), 7.18-7.12
(m, 2H), 7.03 (dd, J ) 8.5, 2.1 Hz, 1H), 6.89 (dd, J ) 8.5, 2.7 Hz,
1H), 6.81 (dd, J ) 8.5, 2.7 Hz, 1H), 4.39 (m, 1H), 4.26 (m, 1H), 3.57
(apparent t, J ) 9.1 Hz, 1H), 3.41 (dd, J ) 13.7, 6.1 Hz, 1H), 2.65
(dd, J ) 13.2, 12.0 Hz, 1H), 2.45 (m, 1H), 2.19 (m, 1H), 1.99-1.92
(m, 2H), 1.66 (m, 1H), 0.77 (d, J ) 6.7 Hz, 3H), 0.71 (d, J ) 6.7 Hz,
3H).
15-Isopropyl-13,16-dioxo-2-oxa-14,17-diaza-bicyclo[18.2.2]tetracosa-
1
1(23),20(24),21-triene-18-carboxylic Acid (6). H NMR (300 MHz,
d6-DMSO): δ 8.26 (d, J ) 8.6 Hz, 1H, Tyr-NH), 7.62 (d, J ) 9.1 Hz,
1H, Val-NH), 7.12 (d, J ) 8.2 Hz, 2H), 6.73 (d, J ) 8.2 Hz, 2H), 4.35
(m, 1H), 4.15 (m, 1H), 4.06-3.82 (m, 2H), 3.01 (broad d, J ) 13.9
Hz, 1H), 2.75 (broad dd, J ) 13.2, 11.4 Hz, 1H), 2.20-1.77 (m, 4H),
1.75-1.60 (m, 2H), 1.55-1.09 (m, 16H), 0.85 (d, J ) 6.7 Hz, 3H),
0.80 (d, J ) 6.7 Hz, 3H). ISMS: m/z 447 (MH+).
General Method for the Deprotection of Macrocyclic Acids (2-
6) by Hydrogenation. 9S-Isopropyl-7,10-dioxo-2-oxa-8,11-diaza-
bicyclo[12.2.2]octadeca-1(17),14(18),15-triene-12S-carboxylic Acid
(2). A solution of the benzyl ester (9, n ) 5) (3.0 g, 6.6 mmol) in
MeOH (75 mL) was hydrogenated over 10% Pd-C, 2 atm, room
temperature for 3 h. The catalyst was filtered off, and the solvent was
removed in vacuo giving the carboxylic acid as a white powder (2.4 g,
Acknowledgment. The authors thank the Australian Research
Council and the National Health and Medical Research Council
of Australia for partial funding of this work.
9
5682 J. AM. CHEM. SOC. VOL. 124, NO. 20, 2002