The Journal of Organic Chemistry
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and brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue was chromatographed on SiO2 (n-hexane/EtOAc = 4:1 to
2:1 then CHCl3/MeOH = 80:1) to yield 18 (1.44 g, 2.35 mmol,
92.0%) as a colorless oil: [α]20D +3.0 (c 0.13, MeOH); IR (neat) 2978,
(25:75)) as a colorless amorphous solid: [α]20D −3.3 (c 0.45, MeOH);
IR (neat) 3299 (br), 3065, 3033, 2930, 2876, 1675, 1579, 1518, 1455,
1429, 1365, 1289, 1202, 1081 cm−1; 1H NMR (acetone-d6, 500
MHz)16 δ 8.62−8.35 (m, 1H), 8.19 (br s, 1H), 7.97 (br s, 1H), 7.74
(d, J = 8.6 Hz, 1H), 7.55−7.24 (m, 32H), 7.15 (d, J = 8.4 Hz, 1H),
5.40−5.10 (m, 6H), 5.06 (s, 2H), 5.02 (s, 2H), 4.89 (s, 2H), 4.84−
4.68 (m, 1H), 4.64−4.54 (m, 1H), 3.70−3.40 (m, 2H), 3.36−3.12 (m,
2H), 1.98−1.80 (m, 2H), 1.8−1.68 (m, 3H), 1.68−1.50 (m, 3H); 13C
NMR (acetone-d6, 125 MHz)16 δ 172.4, 164.6, 163.5, 162.4, 152.7,
149.9, 149.5, 138.9, 138.1, 137.5, 137.0, 136.9, 132.9, 130.6−128.5,
128.1, 127.4, 126.2, 125.2, 78.0, 77.4, 76.6, 76.1, 75.9, 67.3, 53.5, 53.1,
43.9, 41.2, 31.3, 29.4 (judged from the HMQC spectrum), 25.8, 24.2;
HRMS (ESI) m/z 1213.4253 [M + H]+ calcd for C68H66Cl2N6O11,
1213.4239.
1
1740, 1712, 1548, 1499, 1456, 1177 cm−1; H NMR (acetone-d6, 500
MHz) δ 8.14−8.10 (m, 1H), 7.97−7.91 (m, 1H), 7.85−7.79 (m, 2H),
7.50−7.45 (m, 2H), 7.43−7.28 (m, 8H), 6.32 (d, J = 8.5 Hz, 1H), 5.19
(d, J = 12.3 Hz, 1H), 5.14 (d, J = 12.3 Hz, 1H), 5.14−5.05 (m, 2H),
4.29−4.20 (m, 1H), 3.16 (br s, 2H), 2.02−1.88 (m, 1H), 1.86−1.65
(m, 3H), 1.41 (s, 9H); 13C NMR (acetone-d6, 125 MHz) δ 172.9,
156.3, 150.5, 136.9, 136.5, 135.7, 133.1, 132.1, 130.6 (2C), 129.6,
129.3 (2C), 129.2 (2C), 128.8, 128.6 (2C), 125.9, 124.6, 80.8, 79.3,
67.0, 54.3, 53.7, 29.6, 28.5 (3C), 23.9; HRMS (ESI) m/z 652.1742 [M
+ K]+ calcd for C30H35N3KO9S, 652.1726.
(R)-Benzyl 11,11-Dimethyl-9-oxo-1-phenyl-2,10-dioxa-3,8-diaza-
dodecane-7-carboxylate (19). To a stirred mixture of compound 18
(1.37 g, 2.24 mmol) and K2CO3 (333 mg, 2.41 mmol) in dry DMF
(11 mL) under nitrogen atmosphere was added PhSH (280 μL, 2.74
mmol). After being stirred for 50 min, the reaction was quenched with
sat. aq NH4Cl (20 mL) and extracted with EtOAc (3 × 15 mL).
Combined organic layers were washed with sat. aq NH4Cl and brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The residue
was chromatographed on SiO2 (n-hexane/EtOAc = 10:3 to 4:3) to
yield 19 (900 mg, 2.10 mmol, 93.8%) as a colorless oil: [α]20D +25.1 (c
1.3, MeOH); IR (neat) 3354 (br), 3032, 2976, 2931, 2868, 1713,
1498, 1455, 1365, 1249, 1161 cm−1; 1H NMR (acetone-d6, 500 MHz)
δ 7.42−7.22 (m, 10H), 6.29 (br d, J = 8.3 Hz, 1H), 6.10 (s, 1H), 5.19
(d, J = 12.4 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 4.64 (s, 2H), 4.25−
4.16 (m, 1H), 2.89 (br t, J = 8.6 Hz, 2H), 1.94−1.85 (m, 1H), 1.81−
1.70 (m, 1H), 1.68−1.55 (m, 2H), 1.40 (s, 9H); 13C NMR (acetone-
d6, 125 MHz) δ 173.3, 156.5, 139.7, 137.3, 129.3 (2C), 129.1 (2C),
128.9 (2C), 128.9, 128.8 (2C), 128.2, 79.2, 76.6, 66.9, 54.7, 52.1, 29.5,
28.6 (3C), 24.5; HRMS (ESI) m/z 451.2204 [M + Na]+ calcd for
C24H32N2NaO5, 451.2203.
Pentabenzyl-chlorocatechelin A (22). A mixture material described
above (127.2 mg) was dissolved in THF (2.5 mL) and hydrolyzed
with 1.2 mL of 1 M LiOH for 20 min. After being quenched with 1.25
mL of 1 N aq HCl and brine, the mixture was extracted with EtOAc (2
× 15 mL). The combined organic layers were washed with H2O and
brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was chromatographed on SiO2 (CHCl3/acetone/MeOH =
20:10:1, 4:0:1) followed by purification on RP-HPLC (Cosmosil
5C18-AR-II, 250 × 20 mm, H2O/MeCN containing 0.1% TFA
(30:70)) to yield 22 (86.9 mg, 0.0773 mmol, 65.4% in two steps
(based on compound 4)) as a colorless amorphous solid: [α]20D −2.8
(c 1.7, MeOH); IR (neat) 3299 (br), 3064, 3033, 2946, 1670, 1580,
1
1456, 1429, 1366, 1290, 1202, 1135 cm−1; H NMR (CD3OD, 500
MHz) δ 8.07 and 7.96 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.55−7.49
(m, 2H), 7.47 (d, J = 8.6 Hz, 1H), 7.45−7.22 (m, 24H), 7.17 (d, J =
7.3 Hz, 2H), 5.23 (d, J = 10.8 Hz, 1H), 5.20 (s, 2H), 5.14 (s, 2H), 5.13
(d, J = 10.9 Hz, 1H), 4.99 (s, 2H), 4.84 (overlapped with HDO),
4.71−4.60 (m, 1H), 4.55−4.45 (m, 1H), 3.70−3.38 (m, 2H), 3.33−
3.20 (m, 2H), 2.02−1.84 (m, 2H), 1.82−1.63 (m, 6H); 13C NMR
(CD3OD, 125 MHz) δ 174.9, 173.3, 167.2, 166.5, 164.8, 160.4, 154.5,
152.9, 152.5, 150.3, 149.9, 137.7, 137.7, 137.2, 136.3, 136.2, 133.9,
131.0−129.3, 128.2, 127.4, 127.4, 127.0, 127.0, 126.7, 78.8, 78.4, 77.8,
77.1, 76.8, 76.6, 54.2, 53.3, 44.3, 42.2, 30.9, 29.7, 29.5, 25.1, 24.5;
HRMS (ESI) m/z 1123.3786 [M + H]+ calcd for C61H61Cl2N6O11,
1123.3770.
(R)-Benzyl 3-Formyl-11,11-dimethyl-9-oxo-1-phenyl-2,10-dioxa-
3,8-diazadodecane-7-carboxylate (20). A mixture of acetic anhy-
dride (400 μL, 4.26 mmol) and formic acid (320 μL, 8.48 mmol) was
stirred for 1 h, and this mixture was poured into a solution of
compound 19 (886 mg, 2.07 mmol) in dry DCM (10 mL). After being
stirred for 1.5 h, the solution was washed with sat. aq NaHCO3 (20
mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give
20 (939 mg, 2.06 mmol, 99.5%) as a colorless oil: [α]20D +14.9 (c 1.2,
MeOH); IR (neat) 3336 (br), 2974, 2938, 2876, 1744, 1710, 1679,
Chlorocatechelin A (1). To a solution of compound 22 (44.2 mg,
0.0393 mmol) in THF (2 mL) was added 10% Pd/C (22.8 mg), and
the mixture was stirred under hydrogen. After being stirred for 2 h, the
catalyst was removed with Celite. The filtrate was concentrated in
vacuo and purified on RP-HPLC (Senshu Pak PEGASIL ODS SP100,
250 × 20 mm, H2O/MeCN (80:20 to 0:100)) to give 1 (13.5 mg,
1
1508, 1456, 1365, 1251, 1212, 1162 cm−1; H NMR (acetone-d6, 500
MHz) δ 8.22 (br s, 1H), 7.49−7.44 (m, 2H), 7.42−7.29 (m, 8H), 6.33
(br d, J = 8.2 Hz, 1H), 5.18 (d, J = 12.3 Hz, 1H), 5.13 (d, J = 12.3 Hz,
1H), 4.94 (s, 2H), 4.27−4.21 (m, 1H), 3.72−3.48 (m, 2H), 1.91−1.81
(m, 1H), 1.80−1.68 (m, 3H), 1.39 (s, 9H); 13C NMR (acetone-d6, 125
MHz) δ 173.0, 163.4, 156.4, 137.1, 130.4 (2C), 129.5, 129.3, 129.2,
128.8, 128.7 (9C from 129.5 to 128.7), 79.3, 77.9, 66.9, 54.3, 43.9,
29.5, 28.5 (3C), 24.1; HRMS (ESI) m/z 479.2166 [M + Na]+ calcd for
C25H32N2NaO6, 479.2153.
Synthesis of Chlorocatechelin A (1). Hexabenzyl-chlorocate-
chelin A (21). To a solution of compound 20 (89.6 mg, 0.196 mmol)
in dry DCM (400 μL) was added TFA (400 μL). After being stirred
for 1 h, the solution was concentrated in vacuo. This material was
mixed with compound 4 (125.4 mg, 0.143 mmol) in dry DMF (200
μL), to which DIEA (100 μL, 0.588 mmol), HATU (60.6 mg, 0.159
mmol), and HOAt (20.6 mg, 0.151 mmol) were added at 0 °C under
nitrogen atmosphere. After being stirred for 30 min at the same
temperature, the mixture was allowed to warm slowly to rt, stirred for
2.5 h, and quenched with sat. aq NH4Cl. The aqueous solution was
extracted with EtOAc twice, and combined organic layers were washed
with sat. aq NH4Cl and brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was chromatographed on SiO2
(CHCl3/acetone/MeOH = 50:10:1 to 20/10/1) to yield a mixture of
21 and an unseparable compound (153.9 mg). This mixture was used
in the next reaction without further purification. Analytical samples
were obtained after purification on reversed-phase HPLC (Cosmosil
5C18-AR-II, 250 × 20 mm, H2O/MeCN containing 0.1% TFA
0.0200 mmol, 51.0%) as a brown amorphous solid: [α]20 +3.9 (c
D
0.24, MeOH) ; 1H NMR (DMSO-d6, 500 MHz) δ 9.30 (br, 1H), 9.02
(br, 1H), 8.37 (br d, J = 5.2 Hz, 1H) 8.25 and 7.90 (s, 1H
(combined)), 7.48 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.87
(d, J = 8.4 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 4.60−4.50 (m, 1H),
4.26−4.15 (m, 1H), 3.51−3.35 (m, 2H), 3.35−3.18 (m, 2H), 1.94−
1.50 (m, 8H); 13C NMR (DMSO-d6, 125 MHz) δ 173.4, 173.0, 171.2,
169.0, 161.8 (157.1), 158.4, 153.6, 151.1, 142.9, 142.6, 123.6, 121.8,
119.5, 118.4, 118.3, 116.8, 116.1, 113.6, 52.7, 51.8 (51.7), 48.7 (45.4),
40.4, 29.0, 28.1 (27.7), 25.0, 23.4 (22.9); HRMS (ESI) m/z 673.1444
[M + H]+ calcd for C26H31Cl2N6O11, 673.1422.
Antimicrobial Assay. Antimicrobial activities of 1, 2, VCM, and
DFB were tested with an agar dilution streak method (2-fold dilution).
Microbes listed in Table 1 were incubated in culture medium 1 (1/3
brain-heart infusion broth and 2% NaCl) with test compounds at 27
°C for 18 h. Microbes in Table 2 were incubated in culture medium 2
(5% polypeptone) with test compounds at 37 °C for 18 h.
ASSOCIATED CONTENT
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* Supporting Information
1H and 13C NMR spectra for synthesized products. The
Supporting Information is available free of charge on the ACS
F
J. Org. Chem. XXXX, XXX, XXX−XXX