Both Enantiomers of Various Propargylic Alcohols
FULL PAPER
36% yield) of ketone 1h as a red oil, Rf ϭ 0.32 (isohexane/ethyl RecLBADH-Catalysed Reductions of α,β-Acetylenic Ketones (Pre-
1
acetate, 30:1). Ϫ H NMR (CDCl3): δ ϭ 2.45 (s, 3 H, CH3), 7.33 parative Scale). ؊ (R)-4-(4-Methoxyphenyl)-3-butyn-2-ol [(R)-2b]:
(m, 1 H), 7.55 (d, J ϭ 7.8 Hz, 1 H), 7.70 (m, 1 H), 8.62 (d, J ϭ 4.3 Compound 1b (174 mg, 1 mmol) was stirred at room temperature
Hz, 1 H, ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 32.9 (CH3), 86.1, 87.7 with NADPϩ (50 mg, 60 µmol), 2-propanol (1.5 mL), and
(Cq), 124.8, 128.9, 136.6, 140.8, 150.7 (ar-C), 184.5 (CO). Ϫ
recLBADH (50 U) in TEA/NaOH buffer (100 mL, 100 m TEA,
1 m MgCl2; pH 6.5). After 16 h the reaction mixture was ex-
tracted with CH2Cl2 (3 ϫ 40 mL). The combined organic layers
were dried with Na2SO4 and concentrated in vacuo. Flash chroma-
tography afforded alcohol 2b (113 mg, 640 µmol, 64% yield) as a
pale yellow solid, Rf ϭ 0.17 (isohexane/ethyl acetate, 10:1), m.p.
44Ϫ45 °C. Ͼ 99% ee as determined by HPLC on Chiralcel OB
(isohexane/2-propanol, 85:15), Rt ϭ 29.0 min (R). Ϫ 1H NMR
(CDCl3): δ ϭ 1.55 (d, J ϭ 6.5 Hz, 3 H, CH3), 1.90 (s, 1 H, OH),
3.80 (s, 3 H, OCH3), 4.75 (q, J ϭ 6.5 Hz, 1 H), 6.82 (d, J ϭ 7.1 Hz,
2 H), 7.37 (d, J ϭ 7.1 Hz, 2 H, ar-H). Ϫ 13C NMR (CDCl3): δ ϭ
24.7 (CH3), 55.5 (OCH3), 59.1 (CH), 84.1, 89.8 (Cq), 114.1, 114.8,
133.3, 159.8 (ar-C). Ϫ GCMS: Rt ϭ 10.3 min: m/z (%) ϭ 176 (40)
[Mϩ], 161 (100) [Mϩ Ϫ CH3], 145 (5) [Mϩ Ϫ 2 CH3], 133 (26) [Mϩ
Ϫ CH3 Ϫ CO], 118 (14) [Mϩ Ϫ 2 CH3 Ϫ CO]. Ϫ [α]D22 ϭ ϩ39.9
(c ϭ 1.4, Et2O) [ref.[3b]: (S)-2b: [α]D25 ϭ Ϫ35.1 (c ϭ 1.0, Et2O;
ee ϭ 97%)].
GCMS: Rt ϭ 8.4 min: m/z (%) ϭ 145 (23) [Mϩ], 130 (100) [Mϩ
CH3], 102 (3) [Mϩ Ϫ CH3 Ϫ CO], 78 (15).
Ϫ
4-(3-Methyl-2-thienyl)-3-butyn-2-one (1i): Method A was employed
with 2-ethynyl-5-methylthiophene[20] (366 mg, 3.0 mmol), to yield
361 mg (2.2 mmol, 73% yield) of ketone 1i as a yellow oil, Rf ϭ
0.23 (isohexane/ethyl acetate, 30:1). Ϫ 1H NMR (CDCl3): δ ϭ 2.41
(s, 3 H, CH3), 2.51 (s, 3 H, CH3), 6.74 (d, J ϭ 3.8 Hz, 1 H), 7.30
(d, J ϭ 3.8 Hz, 1 H, ar-H). Ϫ 13C NMR (CDCl3): δ ϭ 15.9 (CH3),
32.6 (CH3), 85.6, 93.0 (Cq), 117.3, 126.5, 137.7, 147.7 (ar-C), 184.4
(CO). Ϫ GCMS: Rt ϭ 9.0 min: m/z (%) ϭ 164 (44) [Mϩ], 149 (100)
[Mϩ Ϫ CH3], 121 (24) [Mϩ Ϫ CH3 Ϫ CO].
4-(Triethylsilyl)-3-butyn-2-one (3c): Method A was employed with
(triethylsilyl)acetylene (420 mg, 3.0 mmol), to yield 377 mg
(2.1 mmol, 69% yield) of ketone 3c as a colourless oil, Rf ϭ 0.34
1
(isohexane/ethyl acetate, 30:1). Ϫ H NMR (CDCl3): δ ϭ 0.69 (q,
J ϭ 7.8 Hz, 6 H, CH2), 1.20 (t, J ϭ 7.8 Hz, 9 H, CH3), 2.37 (s, 3
H, CH3). Ϫ 13C NMR (CDCl3): δ ϭ 3.9 (CH2), 7.5 (CH3), 32.9
(CH3), 95.9, 103.9 (Cq), 184.6 (CO). Ϫ GCMS: Rt ϭ 7.3 min: m/z
(S)-1-Pentyn-3-ol [(S)-6a]: Compound 5a (82 mg, 1 mmol) was
stirred at room temperature with NADPϩ (50 mg, 60 µmol), 2-
propanol (1.5 mL), and recLBADH (50 U) in TEA/NaOH buffer
(100 mL, 100 m TEA, 1 m MgCl2; pH 6.5). After 16 h the reac-
tion mixture was extracted with CH2Cl2 (3 ϫ 40 mL). The com-
bined organic layers were dried with Na2SO4 and concentrated in
vacuo. Alcohol 6a was obtained in 90% conversion as crude prod-
uct; 34% ee as determined by GC on Lipodex E column (T ϭ 35
(%) ϭ 182 (1) [Mϩ], 167 (3) [Mϩ Ϫ CH3], 153 (100) [Mϩ
CH2CH3], 125 (52) [Mϩ Ϫ CH2CH3 Ϫ CO].
Ϫ
4-(tert-Butyldimethylsilyl)-3-butyn-2-one (3d): Method A was em-
ployed with (tert-butyldimethylsilyl)acetylene (420 mg, 3.0 mmol),
to yield 355 mg (2.0 mmol, 65% yield) of ketone 3d as a colourless
oil, Rf ϭ 0.32 (isohexane/ethyl acetate, 30:1). Ϫ 1H NMR (CDCl3):
δ ϭ 0.17 (s, 6 H, CH3), 0.95 (s, 9 H, tBu), 2.33 (s, 3 H, CH3). Ϫ
13C NMR (CDCl3): δ ϭ Ϫ4.9 (CH3), 16.7 (Cq), 26.1 (CH3), 32.8
(CH3), 96.4, 103.3 (Cq), 184.5 (CO). Ϫ GCMS: Rt ϭ 6.5 min: m/z
(%) ϭ 182 (5) [Mϩ], 167 (17) [Mϩ Ϫ CH3], 125 (100) [Mϩ Ϫ 2 CH3
Ϫ CO].
˜
°C), Rt ϭ 30.5 min (S) ϩ 32.0 min (R). Ϫ IR (neat): ν ϭ 3292
1
(CϵCH), 2973, 2938, 2881 cmϪ1. Ϫ H NMR (CDCl3): δ ϭ 1.01
(t, J ϭ 7.4 Hz, 3 H, C5), 1.72 (m, 2 H, C4), 2.45 (s, 1 H, C1), 4.32
(t, J ϭ 6.4 Hz, 1 H, C3). Ϫ 13C NMR (CDCl3): δ ϭ 9.4 (C5), 30.9
(C4), 63.6 (C3), 72.9 (C1), 84.9 (C2). Ϫ [α]2D1 ϭ Ϫ8.4 (c ϭ 0.5,
Et2O) [ref.[22] (R)-6a: [α]D22 ϭ ϩ34.0 (c ϭ 2.2, Et2O; ee Ͼ 97%)].
(S)-1-Hexyn-3-ol [(S)-6b]: Compound 5b (1.50 g, 15.6 mmol) was
stirred at room temperature with NADPϩ (115 mg, 138 µmol), 2-
propanol (30 mL), and recLBADH (750 U) in phosphate buffer
(1000 mL, 50 m phosphate, 1 m MgCl2; pH 7). After 16 h the
reaction mixture was extracted with Et2O (3 ϫ 200 mL). The com-
bined organic layers were dried with Na2SO4 and concentrated in
vacuo. Distillation afforded 6b (1.06 g, 10.8 mmol, 69% yield) as a
colourless liquid (92 °C/100 mm). Ͼ 99% ee as determined by GC
4-Dimethylphenylsilyl-3-butyn-2-one (3e): Method A was employed
with (dimethylphenylsilyl)acetylene[21] (480 mg, 3.0 mmol), to yield
345 mg (1.7 mmol, 57% yield) of ketone 3e as a colourless oil, Rf ϭ
0.24 (isohexane/ethyl acetate, 30:1). Ϫ 1H NMR (CDCl3): δ ϭ 0.49
(s, 6 H, CH3), 2.37 (s, 3 H, CH3), 7.32Ϫ7.70 (m, 5 H, ar-H). Ϫ 13C
NMR (CDCl3): δ ϭ Ϫ1.7 (CH3), 32.6 (CH3), 96.8, 102.7 (Cq),
128.1, 130.0, 133.7, 134.2 (ar-C), 184.5 (CO). Ϫ GCMS: Rt
ϭ
8.8 min: m/z (%) ϭ 201 (23) [Mϩ Ϫ H], 187 (100) [Mϩ Ϫ CH3],
159 (86) [Mϩ Ϫ CH3 Ϫ CO], 145 (58) [Mϩ Ϫ 2 CH3 Ϫ CO].
on FS-Cyclodex-β-I/P column (T ϭ 60 °C), Rt ϭ 26.3 min (S). Ϫ
1
IR (neat): ν ϭ 3311 (CϵCH), 2965, 2935, 2874 cmϪ1. Ϫ H NMR
˜
3-Hexyn-2-one (5b): Method B was employed with ethynyltrime-
thylsilane (12.0 g, 122.4 mmol) and butyryl chloride (12.2 g,
114.2 mmol), to yield 4.5 g (46.8 mmol, 41% yield) of ketone 5b as
(CDCl3): δ ϭ 0.94 (t, J ϭ 7.3 Hz, 3 H, C6), 1.50 (m, 2 H, C5), 1.72
(m, 2 H, C4), 2.48 (s, 1 H, C1), 4.39 (t, J ϭ 6.4 Hz, 1 H, C3). Ϫ
13C NMR (CDCl3): δ ϭ 13.8 (C6), 18.4 (C5), 39.8 (C4), 62.2 (C3),
72.9 (C1), 85.3 (C2). Ϫ GCMS (T0 min ϭ 40 °C): Rt ϭ 5.7 min:
1
a colourless oil after distillation (b.p. 63 °C/30 mm). Ϫ H NMR
m/z (%) ϭ 97 (5) [Mϩ Ϫ H], 83 (33) [Mϩ Ϫ CH3], 70 (17) [Mϩ
Ϫ
(CDCl3): δ ϭ 0.94 (t, J ϭ 7.4 Hz, 3 H, CH3), 1.72 (‘‘hex’’, J ϭ
7.4 Hz, 2 H, CH2), 2.58 (t, J ϭ 7.4 Hz, 2 H, CH2), 3.21 (s, 1 H).
H2O], 55 (100) [Mϩ Ϫ CH3 Ϫ CO]. Ϫ [α]2D1 ϭ Ϫ33.8 (c ϭ 1.2,
Et2O) [ref.:[23] [α]D22 ϭ Ϫ24.0 (c ϭ 2.4, Et2O; ee ϭ 68%)].
Ϫ
13C NMR (CDCl3): δ ϭ 13.6 (CH3), 17.5 (CH2), 47.4 (CH2),
78.5, 81.6 (Cq), 187.7 (CO). Ϫ GCMS (T0 min. ϭ 40 °C): Rt ϭ
4.4 min: m/z (%) ϭ 95 (42) [Mϩ Ϫ H], 81 (36) [Mϩ Ϫ CH3], 68
(97) [Mϩ Ϫ C2H4], 53 (100) [Mϩ Ϫ C3H7].
(R)-4-Phenyl-3-butyn-2-ol [(R)-2a]: 4-Phenyl-3-butyn-2-one (1a)
(2.08 g, 14.4 mmol) in 2-propanol (50 mL) was steadily added by
syringe pump over 20 h to a stirred solution of NADPϩ (6.0 mg,
Enzyme Assays: recLBADH[6] and CPCR[7] assays were performed 7.2 µmol, 0.05 mol %, total turnover number 2000), 2-propanol
by combining the following solutions and monitoring at 340 nm
(εNAD(P)H 6.22 L·molϪ1·cmϪ1) and 20 °C: 970 µL solution of ke-
tone in TEA/NaOH buffer (5 m ketone [2 m for aromatically
(50 mL), and recLBADH (250 U) in deionized water (250 mL,
1 m MgCl2, ph 6.6, HCl) at 22 °C. After this had stirred for an
additional 4 h, the conversion was determined by GCMS and
substituted alkynones], 100 m TEA, 1 m MgCl2) pH 6.5, 20 µL NMR as 98%. After a total reaction time of 30 h the conversion
NAD(P)H solution (12.5 m), and 10 µL enzyme solution. Initial
rate data were recorded relative to ethyl 5-oxohexanoate.
was determined as Ͼ 99%. Extraction with ethyl acetate afforded
(R)-2a (1.98 g, 13.5 mmol, 94% yield) as a light yellow oil, free of
Eur. J. Org. Chem. 2001, 4181Ϫ4187
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