chromatographed using EtOAc as an eluent to give (1S,2S)-
N-(2-hydroxycyclohexyl)butyramide [(S,S)-6b] as a white solid
(289 mg, 78%); [a]2D5 −31.8 (c 1.2 in CHCl3); Rf 0.19 (SiO2;
EtOAc); mp 97–98 °C; mmax (neat) cm−1 3294s, 2928s, 2855s,
1632vs (amide), 1563vs (amide), 1454s, 1347s, 1085s, 1071s; dH
(400 MHz, CDCl3) 0.95 (3H, t, J7.5, CH3), 1.13–1.36 (4H, m),
1.65–1.68 (2H, m, CH2Me), 1.68–1.75 (2H, m), 1.90–1.96 (1H,
m), 2.04–2.08 (1H, m), 2.18 (2H, t, J7.5, NCOCH2), 3.26–3.33
(1H, m), 3.55 (1H, d, J5, OH), 3.59–3.67 (1H, m), 5.38 (1H, br
s, NH); dC (100 MHz, CDCl3) 14.05, 19.56, 24.40, 24.99, 31.94,
34.90, 39.04, 56.13, 75.96, 175.42; m/z (EI) 185 (M+, 5%), 114
(65), 98 (60), 88 (100), 71 (55); m/z (APCI) 186 (MH+, 100%);
HRMS found 185.1416, C10H19NO2 (M+) requires 185.1416
(D = 0.01 ppm). Alcohol (S,S)-6b (10.0 mg, 53.9 lmol) was
dissolved in anhydrous CH2Cl2 (1 ml) and Dess–Martin
periodinane (46 mg, 108 lmol) was added. After the mixture
was stirred for 1 h at room temperature under Ar, it was washed
with H2O, dried (MgSO4), filtered, concentrated in vacuo and
rapidly chromatographed using EtOAc as an eluent to give (1S)-
N-(2-oxocyclohexyl)butyramide [(S)-1b] as a white solid (9.8 mg,
99%); mp 50–51 °C; [a]D25 +60.4 (c 2.3 in CHCl3); Rf 0.47 (SiO2;
EtOAc); mmax (neat) cm−1 3300m, 2935m, 2869m, 1719s (ketone),
1643vs (amide), 1535s (amide), 1450m, 1127s; dH (400 MHz,
CDCl3) 0.93 (3H, t, J7.5, CH3), 1.27–1.38 (1H, m), 1.56–1.70
(1H, m), 1.65 (2H, apparent q, J7, CH2Me), 1.73–1.88 (2H, m),
2.10–2.17 (1H, m), 2.18 (2H, t, J7, NCOCH2), 2.34–2.43 (1H,
m), 2.49–2.55 (1H, m), 2.64-2.70 (1H, m), 4.44–4.51 (1H, m,
CHN), 6.39 (1H, br s, NH); dC (100 MHz, CDCl3) 14.05, 19.47,
24.42, 28.48, 36.01, 38.93, 41.55, 58.40, 173.06, 208.35; m/z (EI)
183 (M+, 55%), 88 (100), 71 (65); m/z (APCI) 184 (MH+, 100%);
HRMS found 183.1250, C10H17NO2 (M+) requires 183.1259
(D = 4.9 ppm).
br s, NH); dC (150 MHz, CDCl3) 13.65, 19.02, 23.06, 27.57,
28.97, 32.88, 38.49, 41.53, 58.75, 172.21, 210.38; m/z (APCI)
198 (MH+, 100%); HRMS found 198.1499, C11H20NO2 (MH+)
requires 198.1497 (D = 1.0 ppm).
N-Butyryl–L-homoserine lactone (BHL)
(S)-(−)-a-Amino-c-butyrolactone hydrobromide (401 mg,
2.2 mmol), and Na2CO3 (466 mg, 4.4 mmol) were partitioned
between CH2Cl2 (5 ml) and H2O (5 ml). Butyryl chloride (0.21 ml,
2.0 mmol) was added and the mixture was stirred vigorously at
room temperature for 1 h. The two-phase mixture was separated
and the aqueous layer extracted twice with CH2Cl2. The organic
layers were combined, washed (brine), dried (MgSO4), filtered,
concentrated in vacuo and rapidly chromatographed using
EtOAc as an eluent to give N-butyryl-L-homoserine lactone
(BHL) as a white solid (298 mg, 87%); [a]2D5 +8.85 (c 2.3 in
CHCl3); Rf 0.34 (SiO2; EtOAc); mp 127–129 °C (lit.24 83 °C);
mmax (neat) cm−1 3308m, 2959m, 2872m, 1774s (lactone), 1644s
(amide), 1547s (amide), 1361m, 1227m, 1171s, 1014s, 998m,
948m, 658m; dH (500 MHz, CDCl3) 0.89 (3H, t, J7, CH3),
1.57–1.65 (2H, m, CH2Me), 2.06–2.14 (1H, m, OCH2CHH),
2.17 (2H, t, J7, COCH2), 2.68–2.76 (1H, m, OCH2CHH),
4.19–4.25 (1H, m, OCHH), 4.39 (1H, apparent t, J9, OCHH),
4.51–4.57 (1H, m, CHN), 6.34 (1H, br s, NH); dC (125 MHz,
CDCl3) 13.63 (CH3), 18.86, 30.27, 37.96, 49.05 (CHN), 66.07
(OCH2), 173.64 (CO), 175.74 (CO); m/z (ESI) 194 (MNa+,
100%); HRMS found 194.0785, C8H13NO3Na (MNa+) requires
194.0793 (D = 4.1 ppm).
2,2-Difluoro-3-hydroxydodecanoic acid (11)13
Ethylbromodifluoroacetate (3.20 ml, 25.0 mmol) was slowly
added to a stirred mixture of decanal (1.88 ml, 10.0 mmol)
and activated zinc dust (2.46 g, 37.5 mmol) in anhydrous THF
(50 ml) and room temperature under Ar. [Caution: exotherm]
The reaction mixture was stirred vigourously for 3 h (TLC) and
then a saturated aqueous solution of NH4Cl was added (30 ml).
The mixture was filtered through Celite and the precipitate
washed with EtOAc. The two phase solution was separated
and the aqueous layer was extracted with EtOAc. The organic
layers were combined, washed (brine), dried (MgSO4), filtered,
concentrated in vacuo and chromatographed (hexane:EtOAc;
17:3) to give 2,2-difluoro-3-hydroxydodecanoic acid ethyl ester
as a colourless oil (2.79 g, 99%); Rf 0.30 (SiO2; hexane:EtOAc;
17:3; KMnO4); mmax (neat) cm−1 3478w, 2926s, 2856s, 1760vs
(ester), 1466m, 1374m, 1314s, 1092vs, 855m, 783m, 722m; dH
(400 MHz, CDCl3) 0.88 (3H, t, J7, CH2CH2CH3), 1.25–1.40
(14H, m, CH2), 1.36 (3H, t, J8, OCH2CH3), 1.49–1.72 (2H,
m, CHOHCH2), 2.13 (1H, d, J7, OH), 3.97–4.08 (1H, m,
CHOH), 4.37 (2H, q, J8, OCH2CH3); dC (100 MHz, CDCl3)
14.12, 14.30, 23.04, 25.59, 29.65, 29.67, 29.80, 32.25, 63.37
(OCH2CH3), 72.18 (t, J25, CHOH), 115.05 (t, J255, CF2),
164.11 (t, J28, CO); m/z (ESI) 303 (MNa+, 100%); HRMS
found 303.1751, C14H26F2O3Na (MNa+) requires 303.1748
(D = 1.0 ppm). The ester (3.52 g, 12.6 mmol) was stirred in
a solution of NaOH (552 mg, 13.8 mmol) in H2O (5 ml) for
8 h (TLC) at room temperature, extracted with Et2O, and then
acidified by the addition of 3 M aqueous HCl (until pH = 1).
The aqueous solution was extracted three times with EtOAc
and the organic extracts were combined, washed (brine), dried
(MgSO4), filtered and concentrated in vacuo to give 2,2-difluoro-
3-hydroxydodecanoic acid (11) as a white solid (3.06 g, 96%);
mp 59–60 °C [hexane]; mmax (neat) cm−1 3349w, 3245w, 2952m,
2921s, 2855s, 1759m (monomer acid), 1727s (dimer acid), 1472s,
1391m, 1198s, 1149s, 1126vs, 1102vs, 1047s, 765s, 721m, 693s;
dH (400 MHz, CDCl3) 0.88 (3H, t, J7, CH3), 1.22–1.42 (14H,
m, CH2), 1.54–1.78 (2H, m, CHOHCH2), 4.04–4.12 (1H, m,
CHOH), 7.07 (2H, br s, OH); dC (100 MHz, CDCl3) 14.45, 23.04,
25.49, 29.65, 29.79, 29.88, 32.25, 72.34 (t, J29, CHOH), 114.83
(t, J253, CF2), 166.86 (t, J30, CO); m/z (ESI) 275 (MNa+,
(1R)-N-(2-Oxocyclohexyl)butyramide [(R)-1b]
Synthesis identical to the synthesis of [(S)-1b]. [(R,R)-6b]:
[a]2D5 +36.9 (c 0.44 in CHCl3). [(R)-1b]: [a]2D5 −58.8 (c 0.40 in
CHCl3).
(1S)-N-(2-Oxocycloheptyl)butyramide [(S)-1c]
(1S,2S)-2-Hydroxycycloheptylamine [(S,S)-5c], 10.0 mg,
60.4 lmol) and Na2CO3 (19.2 mg, 181 lmol) were partitioned
between CH2Cl2 (1 ml) and H2O (1 ml). Butyryl chloride (6.2 ll,
60.4 lmol) was added and the mixture was stirred vigorously at
room temperature for 1 h. The two-phase mixture was separated
and the aqueous layer extracted twice with CH2Cl2. The
organic layers were combined, washed (brine), dried (MgSO4),
filtered, concentrated in vacuo and chromatographed using
EtOAc as an eluent to give (1S,2S)-N-(2-hydroxycycloheptyl)-
butyramide [(S,S)-6c] as a colourless oil (10.7 mg, 89%); Rf 0.32
(SiO2; EtOAc); mmax (neat) cm−1 3300m, 2926s, 1637s (amide),
1542s (amide), 1461m; dH (400 MHz, CDCl3) 0.95 (3H, t, J7,
CH3), 1.19–1.28 (2H, m), 1.45–1.78 (10H, m), 2.18 (2H, t, J7.5,
NCOCH2), 3.56–3.62(1H, m, CHOH), 3.76–3.83(1H, m, CHN),
4.04 (1H, d, J3, OH), 5.55 (1H, br s, NH); dC (125 MHz, CDCl3)
13.68, 19.16, 22.91, 24.91, 29.70, 31.46, 34.05, 38.64, 59.26, 78.97,
174.62; m/z (APCI) 200 (MH+, 100%). Alcohol (S,S)-6c (3.5 mg,
17.6 lmol) was dissolved in anhydrous CH2Cl2 (1 ml) and Dess–
Martin periodinane (11.2 mg, 26.3 lmol) was added. After the
reaction mixture was left to stir for 1 h at room temperature it
was washed with H2O, dried (MgSO4), filtered, concentrated in
vacuo and rapidly chromatographed (hexane:EtOAc; 1:1) to
give (1S)-N-(2-oxocycloheptyl)butyramide [(S)-1c] as a white
paste (3.3 mg, 95%); [a]D25 +32.1 (c 0.39 in CHCl3); Rf 0.25 (SiO2;
hexane:EtOAc; 1:1); mmax (neat) cm−1 2929s, 1713s (ketone),
1647vs (amide), 1535s (amide); dH (600 MHz, CDCl3) 0.94 (3H,
t, J8, CH3), 1.22–1.28 (2H, m), 1.41–1.47 (1H, m), 1.67 (2H,
apparent q, J8, CH2Me), 1.73–1.88 (3H, m), 1.92–1.98 (1H,
m), 2.08–2.14 (1H, m), 2.19 (2H, t, J7.5, NCOCH2), 2.42–2.49
(1H, m), 2.63–2.70 (1H, m), 4.47–4.71 (1H, m, CHN), 6.58 (1H,
3 3 3 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 3 2 9 – 3 3 3 6