10.1002/adsc.201800357
Advanced Synthesis & Catalysis
3-Hydroxy-4,4-dimethoxybutan-2-one (8i)
(ESI/Q-TOF): m/z = 181.1204, calcd for C9H18NaO2
[M+Na]+: 181.1217.
Column chromatography
on florisil gel with
cyclohexane/EtOAc 10:3 afforded 8i as a colorless oil,
(S)-4-Hydroxy-5,5-dimethylhexan-3-one [(S)-13d]
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61% yield. []D +76 (c 1.0, CHCl3); H NMR (300 MHz):
= 4.40 (d, J = 3.2 Hz, 1H, H-4), 4.21 (m, 1H, H-3), 3.64
(bs, 1H, OH), 3.49 (s, 3H, CH3O), 3.46 (s, 3H, CH3O),
2.29 (s, 3H, CH3); 13C NMR (101 MHz): = 207.2, 106.2,
77.7, 57.3, 55.8, 27.3; HRMS (ESI/Q-TOF): m/z =
171.0633, calcd for C6H12NaO4 [M+Na]+: 171.0647.
Column chromatography with cyclohexane/EtOAc 7:3
afforded 13d as a colorless oil, 45% yield. []D +135 (c 0.6,
CHCl3), lit. for (S)-enantiomer +94.5 (c 2.2, CHCl3);[25]
GC (temperature program: 80 to 200 °C, rate 2 °C min–1):
tR (min) = 25.0 (R), 26.0 (S); 99% ee; 1H NMR (300 MHz):
= 3.87 (s, 1H, H-4), 2.66–2.37 (m, 2H, CH2), 1.10 (t, J =
7.2 Hz, 3H, CH3), 0.98 (s, 9H, 3 × CH3); 13C NMR (76
MHz): = 214.2, 84.0, 35.6, 27.1, 26.5, 8.0; HRMS
(ESI/Q-TOF): m/z = 167.1048, calcd for C8H16NaO2
[M+Na]+: 167.1062.
tert-Butyl 4-(1-Hydroxy-2-oxopropyl)piperidine-1-
carboxylate (8j)
Column chromatography with cyclohexane/EtOAc 6:4
afforded 8j as a white waxy solid, 93% yield. []D +91 (c
1.0, CHCl3); 84% ee (determined by chiral-phase HPLC
analysis after conversion into 16j, as described in the
1-Cyclopropyl-1-hydroxybutan-2-one (13e)
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Supporting Information); H NMR (300 MHz): = 4.25–
Column chromatography with cyclohexane/EtOAc 8:2
afforded 13e as a colorless oil, slightly contaminated with
unknown compounds, 70% yield. 1H NMR (300 MHz): =
3.64 (d, J = 7.7 Hz, 1H), 3.55 (bs, 1H, OH), 2.89–2.70 (m,
1H, HaCH2), 2.60–2.40 (m, 1H, HbCH2), 2.06–1.89 (m, 1H,
CHcprop), 1.16 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (76
MHz): = 201.8, 78.8, 37.1; HRMS (ESI/Q-TOF): m/z =
151.0735, calcd for C7H12NaO2 [M+Na]+: 151.0723.
4.10 (m, 2H, CH2), 4.10–4.06 (m, 1H, H-1), 3.39 (bs, 1H,
OH), 2.79–2.50 (m, 2H, CH2), 2.21 (s, 3H, CH3), 2.01–
1.81 (m, 1H, H-4), 1.65 (m, 4H, 2 × CH2), 1.43 (s, 9H,
3 × CH3); 13C NMR (101 MHz): = 209.1, 154.6, 80.0,
79.5, 43.7, 39.4, 28.9, 28.4, 25.7, 24.4; HRMS (ESI/Q-
TOF): m/z = 258.1705, calcd for C13H24NO4 [M+H]+:
258.1721.
Synthesis of 4-Hydroxy-4-methylhexan-3-one (12)
1-Cyclopentyl-1-hydroxybutan-2-one (13f)
To a stirred solution of hexane-3,4-dione (9; 9.4 g, 82.4
mmol) in anhydrous THF (30 mL), a 3.0 M MeMgBr
solution in Et2O (33 mL, 99 mmol) was added dropwise, at
room temperature. The resulting mixture was refluxed for
2 h and then a saturated aqueous solution of NH4Cl (50
mL) was slowly added. The organic layer was separated
and the aqueous phase was extracted with Et2O (2 × 20
mL). The combined organic layers were washed with brine
and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue (6.3 g, 6.6
mL) was purified by vacuum distillation (70 °C/10 mmHg)
to obtain the expected product 12 as a yellow oil, 5.2 g (40
Column chromatography with cyclohexane/EtOAc 7:3
afforded 13f as a colorless oil, 82% yield. []D +60.0 (c 0.5,
CHCl3); 78% ee (determined by chiral-phase HPLC
analysis after conversion into 17f, as described in the
Supporting Information); 1H NMR (300 MHz): = 4.24 (d,
J = 3.2 Hz, 1H, H-1), 3.46 (bs, 1H, OH), 2.63–2.38 (m, 2H,
CH2), 2.37–2.21 (m, 1H, CH), 1.85–1.42 (m, 6H), 1.39–
1.19 (m, 2H), 1.15–1.09 (m, 3H, CH3); 13C NMR (76
MHz): = 212.8, 78.0, 42.4, 31.6, 29.7, 26.2, 26.1, 25.0,
7.9; HRMS (ESI/Q-TOF): m/z = 179.1048, calcd for
C9H16NaO2 [M+Na]+: 179.1039.
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mmol, 48% yield). H NMR (400 MHz): = 3.89 (bs, 1H,
(S)-1-Cyclohexyl-1-hydroxybutan-2-one [(S)-13g]
OH), 2.60–2.41 (m, 2H, CH2), 1.79–1.66 (m, 2H, CH2),
1.34 (s, 3H, CH3), 1.10 (t, J = 7.3 Hz, 3H, CH3), 0.78 (t, J
= 7.4 Hz, 3H, CH3); 13C NMR (101 MHz): = 215.1, 78.9,
32.5, 28.9, 25.3, 7.8, 7.7; HRMS (ESI/Q-TOF): m/z =
153.0891, calcd for C7H14NaO2 [M+Na]+: 153.0905.
Column chromatography with cyclohexane/EtOAc 7:3
afforded 13g as a colorless oil, 78% yield. []D +73.6 (c
1.0, CHCl3), lit. for (R)-enantiomer –112.5 (c 1.0,
CHCl3);[21] 59% ee;[21] 1H NMR (300 MHz): = 4.24 (d, J
= 1.7 Hz, 1H, H-1), 2.56–2.39 (m, 2H, CH2), 1.89–1.56 (m,
10H), 1.55–1.41 (m, 1H), 1.11 (t, J = 7.2 Hz, 3H, CH3);
13C NMR (101 MHz): = 212.8, 80.5, 41.4, 31.4, 30.1,
29.7, 26.6, 26.0, 25.8, 25.1, 7.6; HRMS (ESI/Q-TOF): m/z
= 193.1204, calcd for C10H18NaO2 [M+Na]+: 193.1219.
General Procedure for the Synthesis of Products 13c–j
on an Analytical Scale
The reactions were performed and analyzed as described
for the synthesis of products 8a–j on an analytical scale,
using 4-hydroxy-4-methylhexan-3-one (12; 6.2 L, 45
mol) instead of methylacetoin.
1-(Benzyloxy)-2-hydroxypentan-3-one (13h)
Column chromatography with cyclohexane/EtOAc 8:2
afforded 13h as a colorless oil, 68% yield. []D +48.1 (c
1.0, CHCl3); chiral-phase HPLC (Phenomenex Amylose-2
Lux column, n-hexane/propan-2-ol 9:1, flow 1.0 mL min–
1): tR (min) = 14.9 (major), 34.0 (minor); 92% ee; 1H NMR
(300 MHz): = 7.38–7.23 (m, 5H), 4.60 (d, J = 12.1 Hz,
1H, HaBn), 4.49 (d, J = 12.1 Hz, 1H, HbBn), 4.30–4.22 (m,
1H, H-2), 3.81 (dd, J = 10.4, 3.7 Hz, 1H, OCHa), 3.71 (dd,
J = 10.4, 3.7 Hz, 1H, OCHb), 2.69–2.34 (m, 2H, CH2),
1.10 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (76 MHz): =
210.8, 137.7, 128.7, 128.1, 128.0, 76.5, 73.9, 71.3, 71.2,
31.8, 7.6; HRMS (ESI/Q-TOF): m/z = 231.0997, calcd for
C12H16NaO3 [M+Na]+: 231.0985.
General Procedure for the Synthesis of Products 13c–j
on a Semipreparative Scale
The reactions were performed and worked up as described
for the synthesis products 8c–j on a semipreparative scale,
using 4-hydroxy-4-methylhexan-3-one (12; 103 L, 0.75
mmol) instead of methylacetoin.
5-Ethyl-4-hydroxyheptan-3-one (13c)
Column chromatography with cyclohexane/EtOAc 7:3
afforded 13c as a colorless oil, 52% yield. []D +60.8 (c
0.5, CHCl3); 90% ee (determined by chiral-phase HPLC
analysis after conversion into 17c, as described in the
2-Hydroxy-1,1-dimethoxypentan-3-one (13i)
1
Supporting Information); H NMR (300 MHz): = 4.28–
4.22 (m, 1H, H-4), 3.41 (d, J = 4.5 Hz, 1H, OH), 2.60–2.33
(m, 2H, CH2), 1.67–1.37 (m, 4H), 1.29–1.15 (m, 1H), 1.12
(t, J = 7.3 Hz, 3H, CH3), 1.01 (t, J = 7.2 Hz, 3H, CH3),
0.83 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (76 MHz): =
213.9, 77.8, 45.3, 31.4, 23.6, 21.6, 12.4, 12.3, 8.0; HRMS
Column chromatography
on florisil gel with
cyclohexane/EtOAc 12:3 afforded 13i as a colorless oil,
62% yield. []D +72.7 (c 0.8, CHCl3); 1H NMR (300
MHz): = 4.37 (d, J = 3.2 Hz, 1H, H-1), 4.19 (dd, J = 5.3,
3.2 Hz, 1H, H-2), 3.62 (d, J = 5.3 Hz, 1H, OH), 3.45 (s, 3H,
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