Organic & Biomolecular Chemistry
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9%); δH (500 MHz, DMSO-d6) 8.98 (s, 1H, 2-NH), 8.77 (t, 1H, J =
5.9 Hz, 3-NH), 8.14 (d, 1H, J = 8.4 Hz, 2-H5), 7.53 (d, 1H, J =
1.7 Hz, 2-H2), 7.50 (dd, 1H, J = 8.4, 1.7 Hz, 2-H6), 7.36 (dd, 1H,
J = 8.1, 1.9 Hz, 1-H6), 7.34 (d, 1H, J = 1.9 Hz, 1-H2), 6.68 (d, 1H,
J = 8.1 Hz, 1-H5), 4.14 (t, 2H, J = 6.2 Hz, 2-Hα), 4.04 (t, 2H, J =
6.2 Hz, 1-Hα), 3.92 (d, 2H, J = 5.8 Hz, 3-Hα), 2.44–2.47 (m, 4H,
1-Hγ and 2-Hγ), 2.05 (quint., 2H, J = 6.7 Hz, 2-Hβ), 1.99 (quint,
2H, J = 6.7 Hz, 1-Hβ); δC (125 MHz, DMSO-d6) 174.9, 174.7,
171.9, 166.4, 165.1, 148.9, 145.0, 142.6, 131.3, 129.6, 122.0,
121.3, 121.1, 120.4, 112.7, 111.0, 110.7, 68.2, 67.5, 41.6, 30.9,
30.8, 24.8, 24.7; HRMS: Calcd [M + H]+ (C24H28N3O10) m/z =
518.1769, found [M + H]+ m/z = 518.1775.
Fig. 5 Example of numbering for an O-alkylated dimer 1.
(4-(4-Amino-3-(sec-butoxy)benzamido)-3-(sec-butoxy)benzoyl)
glycine 3
Using the general SPPS procedure with 44-((((9H-fluoren-9-yl)
methoxy)carbonyl)amino)-3-(sec-butoxy)benzoic acid (86 mg,
0.2 mmol) for each cycle of coupling. The residue was purified
using semi-preparative HPLC (eluent: acetonitrile/water/formic
acid: 0.5/9.5/0.1 to 9.5/0.5/0.1) and the product isolated as a
dark yellow solid (10 mg, 22%); δH (500 MHz, DMSO-d6) 8.89
(s, 1H, 2-NH), 8.74 (t, 1H, 3-NH) 8.24 (d, 1H, J = 8.4 Hz, 2-H5),
7.56 (d, 1H, J = 1.7 Hz, 2-H2), 7.52 (dd, 1H, J = 8.4 Hz, 1.7 Hz,
2-H6), 7.34–7.31 (m, 1H, 1-H2), 7.30 (d, 1H, J = 1.9 Hz, 1-H6),
6.72 (d, 1H, J = 8.1 Hz, 1-H5), 5.41 (s, 2H, 1-NH2), 4.56 (sxt.,
1H, J = 5.9 Hz, 2-Hα), 4.40 (sxt., 1H, J = 5.9 Hz, 1-Hα), 3.92 (d,
2H, J = 5.9 Hz, 3-Hα), 1.79–1.61 (m, 4H, 1-Hβ, 2-Hβ), 1.32 (dd,
3H, J = 6.1 Hz, 1.3 Hz, 2-CHα(CH3)), 1.28 (dd, 3H, J = 6.1 Hz,
2.3 Hz, 1-CHα(CH3)), 0.99–0.94 (m, 6H, 1-Hγ, 2-Hγ);
δC (125 MHz, DMSO-d6) 171.4, 165.8, 164.4, 147.0, 143.5,
143.2, 131.7, 128.9, 121.1, 120.9, 119.9, 112.8, 112.2, 76.0, 75.3,
41.3, 40.4, 28.6, 28.5, 19.1, 19.0 18.9, 9.6, 9.4; HRMS: Calcd
[M + H]+ (C24H32N3O6) m/z = 458.2286, found [M + H]+ m/z =
458.2299.
trimers are considered separately, numbered 1 to 2 or 3 start-
ing from the N-terminus, and the glycine is numbered 3 or 4.
All the monomers are numbered following the same standard
system: the carbon bearing the carboxylic acid is C1 and the
one bearing the amine is C4. The carbon attached to the nitro-
gen is Cα, and the numbering of the aliphatic part of the
chain continues with Cβ, etc. Numbering of protons corres-
ponds to numbering of the carbons (Fig. 5). For clarity, the
monomer number is added as a prefix to the proton number.
4-(2-Amino-5-((2-(3-aminopropoxy)-4-((carboxymethyl)
carbamoyl)phenyl)carbamoyl)-phenoxy)butanoic acid 1
Using the general SPPS procedure with 4-((((9H-fluoren-9-yl)
methoxy)carbonyl)amino)-3-(3-((tert-butoxycarbonyl)amino)pro-
poxy)benzoic acid (107 mg, 0.2 mmol); 4-((((9H-fluoren-9-yl)
methoxy)carbonyl)amino)-3-(4-(tert-butoxy)-4-oxobutoxy)benzoic
acid (104 mg, 0.2 mmol). The residue was purified using semi-
preparative HPLC (eluent: acetonitrile/water/formic acid:
0.5/9.5/0.1 to 9.5/0.5/0.1) and the product was collected as a
pale cream powder (9.3 mg, 19%): δH (500 MHz, DMSO-d6)
9.01 (s, 1H, 2-NH), 8.48 (s, 1H, 3-NH), 8.11 (d, 1H, J = 8.3 Hz,
2-H5), 7.55 (s, 1H, 2-H2), 7.50 (d, 1H, J = 8.3 Hz, 2-H6), 7.38 (s,
1H, 1–H6), 7.36 (s, 1H, 1-H2), 6.71 (d, 1H, J = 8.1 Hz, 1-H5),
5.43 (s broad, 2H, NH2), 4.18 (t, 2H, J = 5.5 Hz, 2-Hα), 4.05 (t,
2H, J = 6.5 Hz, 1-Hα), 3.79 (d, 2H, J = 4.9 Hz, 3-Hα), 2.99 (t, 2H,
J = 6.6 Hz, 2-Hγ), 2.29 (t, 2H, J = 6.6 Hz, 1-Hγ), 2.08–2.15 (m,
2H, 2-Hβ), 1.96–2.01 (m, 2H, 1-Hβ); δC (125 MHz, DMSO-d6)
175.7, 171.8, 166.2, 165.2, 149.1, 145.0, 142.5, 131.1, 130.1,
130.0, 122.4, 121.6, 121.3, 120.2, 112.9, 111.2, 110.3, 68.0,
Trimer 4
Trimer 4 was prepared directly from cross-linked dimer using
procedure (b) followed by coupling with using dichlorotriphe-
nyl phosphorene in chloroform as previously described. Yield:
26%; mp: 237 °C; 1H (CDCl3, 500 MHz) δ: 8.66–8.63 (m, 3H,
1-NH, 2-H5, 3-H5), 8.49 (s, 1H, 2-NH), 7.95–7.93 (d, J = 8.3 Hz,
1H, 1-H5), 7.78 (s, 1H, 1-H2), 7.75–7.72 (m, 2H, 2-H6, 3-H6),
7.56 (s, 1H, 3-H2), 7.50–7.48 (m, 2H, Ph-H1), 7.43–7.40 (m, 3H,
1-H6, Ph-H2), 7.37–7.34 (m, 1H, Ph-H3), 7.17 (s, 1H, 2-H2),
5.34 (s, 2H, OCH2Ph), 4.33–4.30 (m, 2H, OCH2), 4.17–4.15 (m,
2H, OCH2), 3.91 (s, 3H, OCH3), 1.89–1.83 (m, 4H, CH2),
1.61–1.50 (m, 8H, CH2); 13C (CDCl3, 125 MHz) δ: 166.8, 165.3,
163.1, 152.2, 146.9, 146.6, 142.1, 139.8, 135.0, 132.0, 131.2,
131.0, 128.8, 128.5, 127.2, 125.9, 125.2, 123.3, 122.7, 120.4,
118.7, 117.9, 115.0, 111.1, 107.4, 71.5, 69.3, 68.6, 52.1, 29.3,
66.0, 42.2, 36.7, 27.7, 25.4. HRMS: Calcd [M
+
H]+
(C23H29N4O8) m/z = 489.1980, found [M + H]+ m/z = 489.1978.
4-(2-(4-Amino-3-(3-carboxypropoxy)benzamido)-5-
((carboxymethyl)carbamoyl)phenoxy)-butanoic acid 2
Using the general SPPS procedure with 4-((((9H-fluoren-9-yl) 26.8, 26.6, 26.4, 24.7, 22.1; IR (neat) ν (cm−1): 3424, 2934, 2864,
methoxy)carbonyl)amino)-3-(4-(tert-butoxy)-4-oxobutoxy)benzoic 1722, 1689, 1667, 1594, 1515, 1345, 1262, 1204, 1124, 1108,
acid (104 mg, 0.2 mmol) for each cycle of coupling. The 1006; HRMS: Calcd [M − H]− (C37H36N3O9) m/z = 666.2452.
residue was purified using semi-preparative HPLC (eluent: Found [M − H]− m/z = 666.2485. Elemental analysis calculated
acetonitrile/water/formic acid: 0.5/9.5/0.1 to 9.5/0.5/0.1) and for C37H37N3O9: C, 66.56; H, 5.59; N, 6.29; Found: C, 65.85; N,
the product was collected as a pale cream powder (4.6 mg, 5.50; N, 6.00.
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