Arch. Pharm. Chem. Life Sci. 2009, 342, 150–164
Efflux Pump Inhibitors of Candida albicans
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CH3(CH2)3), 1.69–.77 (m, 2H, CH2[CHCHOCHCOO]lactone), 1.93–
2.19 (m, 4H, CH3(CH2)3CH2CHCHCH2), 3.75 (dd, J = 2.52 Hz, J =
0.76 Hz, 1H, CH2[CHCHOCHCOO]lactone), 3.96 (d, J = 2.52 Hz, 1H,
CH2[CHCHOCHCOO]lactone), 4.58 (t, J = 6.56 Hz, 1H, CH2[CHCHOCH-
COO]lactone), 5.24–5.58 (m, 2H, 26CHCHdb); dC NMR (100 MHz,
CDCl3): 14.00 (CH3), 22.45, 27.22, 29.02, 31.33, 31.86, 32.42
(CH3(CH2)4CHCHCH2CH2), 49.78 (CH2[CHCHOCHCOO]lactone), 57.97
(CH2[CHCHOCHCOO]lactone), 79.19 (CH2[CHCHOCHCOO]lactone),
127.33, 132.87 (26CHdb), 170.26 (CO).
(2Z,7E)-Methyl 4-hydroxytrideca-2,7-dienoate 9
The intermediate (E)-methyl-4-hydroxytridec-7-en-2-ynoate was
prepared as reported by Jakubowski et al. [11] by coupling trans-
4-decenal to methyl propiolate as in route B to 5 (colourless oil
(b.p.: 110–1148C (10– 3 mbar), yield: 54%)). Purification by col-
umn chromatography (silica gel, EtOAc / petroleum ether
(15 : 85)). Colourless oil (yield: 75%); mmax/cm– 1: 937, 1095, 1246,
1442, 1662, 1752, 2232, 2916, 3320; dH NMR (400 MHz, CDCl3):
0.87 (t, J = 6.94 Hz, 3H, CH3), 1.20–1.33 (m, 6H, CH3(CH2)3), 1.78–
1.84 (m, 2H, CH2CHOHCCCOOMe), 1.92–1.99 (m, 2H,
CH3(CH2)3CH2CHCH), 2.12–2.18 (m, 2H, CH2CH2CHOHCC-
COOMe), 2.50 (br s, 1H, OH), 3.76 (s, 3H, OCH3), 4.48 (dd, J =
12.62 Hz, J = 6.58 Hz, 1H, CHOH), 5.36–5.46 (m, 2H, 26CHdb); dC
NMR (100 MHz, CDCl3): 13.98 (CH3), 22.45, 27.93, 29.08, 31.32,
32.45, 36.51 (CH3(CH2)4CHCHCH2CH2CHOH), 52.74 (OCH3), 61.46
(CHOHCCCOOMe), 76.27, 88.25 (CCCO), 128.05, 132.23 (26CHdb),
153.83 (CO).
cis-2,3-Epoxy-4-hydroxyalkenamides (analogous to
7a–e)
Synthesized from (7E)-cis-2,3-epoxytridec-7-enoic acid c-lactone.
(7E)-N,N-Diethyl-cis-2,3-epoxy-4-hydroxytridec-7-
enamide
Compound 9 was hydrogenated starting from the intermedi-
ate (E)-methyl-4-hydroxytridec-7-en-2-ynoate and following the
same procedure as for substance 5 route A. Colourless oil, (yield:
87%); mmax/cm– 1: 942, 1090, 1242, 1455, 1608,1665, 1729, 2920,
3323; dH NMR (400 MHz, CDCl3): 0.87 (t, J = 6.94 Hz, 3H, CH3),
1.23–1.33 (m, 6H, CH3(CH2)3), 1.65-1.71 (m, 2H, CH2CHOHCHCH-
COOMe), 1.94–1.97 (m, 2H, CH3(CH2)3CH2CHCH), 2.08-2.14 (m,
2H, CH2CH2CHOHCHCHCOOMe), 3.45 (br s, 1H, OH), 3.73 (OCH3),
4.86–4.90 (m, 1H, CHOHCHCHCOOMe), 5.39-5.44 (m, 2H,
CH3(CH2)4CHCH), 5.83 (d, J = 11.86 Hz, 1H, CHCOOMe), 6.28 (dd, J
= 11.86 Hz, J = 7.06 Hz, 1H, CHCHCOOMe); dC NMR (100 MHz,
CDCl3): 14.01 (CH3), 22.50, 28.41, 29.19, 31.35, 32.51, 36.31
(CH3(CH2)4CHCHCH2CH2CHOH), 51.62 (OCH3), 67.78 (CHOH),
119.70, 152.66 (CHCHCOOMe), 129.16, 131.32 (CH3(CH2)4CHCH),
167.12 (COOMe).
Purification by column chromatography (silica gel, CH2Cl2). Yel-
low oil (yield: 34%); mmax/cm– 1: 967, 1072, 1271, 1363, 1380, 1436,
1489, 1621, 1787, 2855, 2923, 3395; dH NMR (400 MHz, CDCl3):
0.86 (t, J = 6.94 Hz, 3H, CH3(CH2)4, 1.18–1.32 (m, 12H, CH3(CH2)3,
26NCH2CH3), 1.70–1.76 (m, 2H, CH2CHOHCHOCHCON), 1.91–
2.18 (m, 4H, CH3(CH2)3CH2CHCHCH2), 3.06 (dd, J = 8.08 Hz, J =
4.32 Hz, 1H, CHOHCHOCHCON), 3.16–3.22 (m, 1H, CHOH-
CHOCHCON), 3.33–3.58 (m, 5H, CHCHOCHCON, 26NCH2CH3),
3.95 (br s, 1H, OH), 5.39–5.43 (m, 2H, 26CHdb); dC NMR (100 MHz,
CDCl3): 12.55, 14.24 (26NCH2CH3), 14.01 (CH3(CH2)3), 22.48,
27.98, 29.20, 31.34, 32.49, 34.57 (66CH2), 40.05, 41.90 (26NCH2),
53.83 (CHOHCHOCHCON), 59.39 (CHOHCHOCHCON), 71.05
(CHOHCHOCHCON), 129.13, 131.19 (26CHdb), 166.64 (CONH).
(7E)-N-Benzyl-cis-2,3-epoxy-4-hydroxytridec-7-enamide
Purification by column chromatography (silica gel, CH2Cl2
EtOAc (80 : 20)). White solid (m.p.: 82–838C, yield: 56%); mmax
/
/
(2Z,7E)-Trideca-2,7-dienoic acid c-lactone 9a
The ester 9 (7.38 g, 35.44 mmol) was dissolved in Et2O (100 mL), a
catalytic amount of p-toluene sulfonic acid (200 mg) was added
and the mixture was stirred at RT overnight. The suspension was
filtered, dried over Na2SO4, and evaporated. Purification by col-
umn chromatography (silica gel, CH2Cl2). Colourless oil (yield:
72%); mmax /cm– 1: 818, 918, 1101, 1162, 1738, 2859, 2929, 2955,
3457; dH NMR (400 MHz, CDCl3): 0.87 (t, J = 6.94 Hz, 3H, CH3),
1.24–1.33 (m, 6H, CH3(CH2)3), 1.62-1.81 (m, 2H, CH2[CHCH-
CHCOO]lactone), 1.92–2.19 (m, 4H, CH3(CH2)3CH2CHCHCH2), 5.04
(td, J = 6.44 Hz, J = 2.04 Hz, 1H, CH2[CHCHCHCOO]lactone), 5.32–
5.51 (m, 2H, CH3(CH2)4CHCH), 6.08, 7.44 (2 x (d, J = 5.80 Hz, 1H,
CH2[CHCHCHCOO]lactone)); dC NMR (100 MHz, CDCl3): 14.00 (CH3),
22.45, 28.06, 29.07, 31.33, 32.45, 33.09 (CH3(CH2)4CHCHCH2CH2),
82.71 (CH2[CHCHCHCOO]lactone), 121.45, 156.25 (CH2[CHCHCH-
COO]lactone), 127.74, 132.65 (CH3(CH2)4CHCH), 173.03 (CO).
cm– 1: 698, 737, 968, 1027, 1060, 1261, 1441, 1541, 1631, 1682,
2853, 2922, 3239, 3535; dH NMR (400 MHz, CDCl3): 0.81 (t, J = 7.08
Hz, 3H, CH3), 1.17–1.25 (m, 6H, CH3(CH2)3), 1.60–1.64 (m, 2H,
CH2CHOHCHOCHCON), 1.83–2.10 (m, 4H, CH3(CH2)3CH2CH-
CHCH2), 2.62 (br s, 1H, OH), 3.04 (dd, J = 8.10 Hz, J = 4.52 Hz, 1H,
CHOHCHOCHCON), 3.24–3.30 (m, 1H, CHOHCHOCHCON), 3.51
(d, J = 4.52 Hz, 1H, CHOHCHOCHCON), 4.39 (d, J = 5.80 Hz, 2H,
NHCH2), 5.28–5.37 (m, 2H, 26CHdb), 6.45 (br s, 1H, NH), 7.18–
7.28 (5H, 56CHarom); dC NMR (100 MHz, CDCl3): 14.03 (CH3),
22.50, 27.97, 29.22, 31.37, 32.50, 34.59 (66CH2), 43.16 (NHCH2),
54.65 (CHOHCHOCHCON), 60.18 (CHOHCHOCHCON), 68.61
(CHOHCHOCHCON), 127.85 (2 signals overlapping), 128.83,
128.93, 131.47 (Carom.), 137.29 (Carom. q), 167.21 (CONH).
(7E)-N-Morpholino-cis-2,3-epoxy-4-hydroxytridec-7-
enamide
Dihydrocerulenin analogues 10a–c
Purification by column chromatography (silica, EtOAc). White
solid (m.p.: 63–648C, yield: 72%); mmax /cm– 1: 853, 966, 1012,
1102, 1114, 1240, 1445, 1477, 1635, 2852, 2922, 2956, 3471; dH
NMR (400 MHz, CDCl3): 0.88 (t, J = 6.96 Hz, 3H, CH3), 1.24–1.33
(m, 6H, CH3(CH2)3), 1.72–1.78 (m, 2H, CH2CHOHCHOCHCON),
1.96–2.22 (m, 2H, CH3(CH2)3CH2CHCHCH2), 3.10 (dd, J = 8.08 Hz,
J = 4.28 Hz, 1H, CHOHCHOCHCON), 3.19–3.22 (m, 1H, CHOH-
CHOCHCON), 3.55–3.77 (m, 10H, CHOHCHOCHCON,
26NCH2CH2O, OH), 5.39–5.47 (m, 2H, 26CHdb); dC NMR
(100 MHz, CDCl3): 14.03 (CH3), 22.50, 28.02, 29.23, 31.35, 32.51,
34.57 (66CH2), 42.25, 45.88 (26NCH2CH2O), 53.49 (CHOH-
Compounds 10a–c were synthesized starting from 9 following
the same procedures as for substances 8a–e from 5 including
the following intermediate compounds:
(7E)-cis-2,3-Epoxytridec-7-enoic acid c-lactone
(analogous to 6)
Synthesized from 9. Purification by column chromatography
(silica, CH2Cl2). Colourless oil (yield: 35%); mmax /cm– 1: 817, 916,
970, 1103, 1160, 1335, 1457, 1747, 2858, 2926, 2954; dH NMR
(400 MHz, CDCl3): 0.87 (t, J = 6.94 Hz, 3H, CH3), 1.25–1.32 (m, 6H,
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