N. M. Maguire et al. / Tetrahedron: Asymmetry 22 (2011) 2144–2150
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water (80 mL) and extracted with diethyl ether (3 ꢂ 80 mL). The
combined ethereal extracts were washed with water (100 mL),
dried and concentrated in vacuo to afford the enantiopure ester
1.43 (9H, s, 3 ꢂ CH3), 2.18 (3H, s), 6.94 (1H, s), 7.32–7.48 (3H, m),
7.70–7.77 (1H, m); dC (75.5 MHz, CDCl3) 20.54 (CH3), 32.00
(3 ꢂ CH3), 35.31 (C), 60.68 (CH), 117.11 (CN), 126.67, 127.14,
(R)-2 as an oil (1.07 g, 35%); ½a D20
ꢀ
¼ þ11:6 (c 3.0, CHCl3); HPLC Chi-
130.37, 131.11 (4 ꢂ CH, C), 147.98 (C), 169.21 (C@O);
m
max/cmꢁ1
ralcelÒ OD-H, hexane/IPA, 95:5, 1 mL/min, 209 nm, tR(S) = 8.6,
tR(R) = 10.4, ee >99%; dH (300 MHz, CDCl3) 2.21 (3H, s), 6.68 (1H,
s), 7.31–7.39 (1H, m), 7.46 (1H, dt, J 7.6, 1.3), 7.65 (1H, dd, J 7.9,
1.3), 7.74 (1H, dd, J 7.7, 1.7); dC (75.5 MHz, CDCl3) 20.25 (CH3),
62.60 (CH), 115.35 (CN), 123.19 (C), 128.26, 129.66 (CH), 131.13
(film) 3025, 2973, 1756, 1489, 1371, 1215, 1022, 763; HRMS
(ES+) Exact mass calcd for C14H17NO2[MꢁOAc]+ 172.1126, found
172.1132.
4.7. (R)-(+)-Acetoxy-2,5-dimethoxyphenylacetonitrile (R)-5
(C), 131.89, 133.57 (CH), 168.57 (C@O);
m
max/cmꢁ1 (film) 3066,
2939, 1758, 1588, 1473, 1371, 1209, 1027, 757; HRMS (ES+) Exact
Racemic acetoxy-2,5-dimethoxyphenylacetonitrile (1.00 g,
4.25 mmol) was suspended in toluene (12 mL) in a screw-cap con-
ical flask and 0.1 M pH 7 potassium phosphate buffer (17 mL) fol-
lowed by C. antarctica B (381 mg, 38% w/w) were added. The
mixture was shaken at 35 °C at 750 rpm for 118 h. After sonication
it was filtered through CeliteÒ and the pad was washed succes-
sively with diethyl ether (30 mL), water (25 mL) and ether
(30 mL). The filtrate was transferred to a separating funnel and
without shaking the organic phase was removed. The aqueous
phase was extracted with ether (1 ꢂ 30 mL) and the combined or-
ganic extracts were dried and concentrated in vacuo to afford the
crude product mixture as an oil (0.78 g). Column chromatography
(dichloromethane) provided an approximate 3:1 mixture of the
unhydrolysed ester and the aldehyde (0.51 g). This was dissolved
in 95% ethanol (11 mL), Girard’s reagent T (0.71 g, 4.2 mmol) was
added and the reaction mixture was stirred overnight. Thereafter,
it was diluted with water (40 mL) and extracted with diethyl ether
(3 ꢂ 60 mL). The combined organic extracts were washed with
water (120 mL) then brine (120 mL), dried and concentrated in va-
cuo to afford the enantiopure ester (R)-5 as an oil (0.40 g, 40%);
mass calcd for C10H8NO279Br [MꢁOAc]+ 193.9605, found 193.9603.
4.5. (R)-(+)-Acetoxy-2,5-difluorophenylacetonitrile (R)-3
Racemic
acetoxy-2,5-difluorophenylacetonitrile
(3.02 g,
14 mmol) was dissolved in MTBE (15 mL) and 0.1 M pH 7 potas-
sium phosphate buffer (58 mL) was added followed by immobi-
lised C. antarctica B (0.91 g, 30% w/w). The mixture was shaken
and the pH was maintained at 7 via automatic addition of 1 M
NaOH using a pH stat. After 18.5 h the reaction mixture was soni-
cated for 15 min then filtered to remove the enzyme. The enzyme
was washed with ether (50 mL) and the filtrate separated. The
aqueous phase was further extracted with diethyl ether
(2 ꢂ 50 mL) and the combined ethereal extracts were dried and
concentrated in vacuo to afford the crude product mixture
(2.04 g). Column chromatography (dichloromethane) provided an
approximate 2:1 mixture of the unhydrolysed ester and the alde-
hyde (1.42 g) which was dissolved in diethyl ether (200 mL) and
extracted with freshly prepared saturated sodium metabisulfite
(3 ꢂ 200 mL), washed with water (200 mL), dried and concentrated
in vacuo to afford the enantiopure ester (R)-3 as a yellow oil
½
a 2D0
ꢀ
¼ þ17:9 (c 1.7, CHCl3); HPLC ChiralcelÒ AS-H, hexane/IPA,
99:1, 1 mL/min, 209 nm, tR(S) = 30.2, tR(R) = 34.6, ee>99%; dH
(300 MHz, CDCl3) 2.18 (3H, s), 3.81 (3H, s), 3.84 (3H, s), 6.68 (1H,
s), 6.88 (1H, d, J 9.0), 6.95 (1H, dd, J 9.0, 3.0), 7.12 (1H, d, J 3.0);
dC (75.5 MHz, CDCl3) 20.49 (CH3), 55.91, 56.22 (2 ꢂ OCH3), 58.04
(CH), 112.27, 114.35 (Ar CH), 116.21 (CN), 116.51 (Ar CH), 120.62
(1.19 g, 39%); ½a D20
ꢀ
¼ þ17:7 (c 2.8, CHCl3); HPLC ChiralcelÒ OJ-H,
hexane/IPA, 99:1, 1 mL/min, 209 nm, tR(R) = 28.5, tR(S) = 31.8, ee
>99%; dH (300 MHz, CDCl3) 2.20 (3H, s), 6.59 (1H, s), 7.08–7.20
(2H, m), 7.30–7.38 (1H, m); dC (150.9 MHz, CDCl3) 20.23 (CH3),
56.96 (d, J 4.0, CH), 114.97 (CN), 116.12 (dd, J 26.2, 2.2, CH),
117.66 (dd, J 23.6, 8.4, CH), 119.16 (dd, J 23.8, 8.4, CH), 120.84
(dd, J 15.7, 7.9, C), 156.11 (dd, J 247.8, 2.9, CF), 158.71 (dd, J
(Ar C), 150.80, 153.70 (Ar COMe), 168.90 (C@O); m
max/cmꢁ1 (film)
3006, 2941, 1752, 1503, 1371, 1222, 1042; HRMS (ES+) Exact mass
calcd for C12H13NO4 [MꢁOAc]+ 176.0712, found 176.0707.
245.0, 2.5, CF), 168.59 (C@O);
1502, 1373, 1213, 1027; HRMS (ES+) Exact mass calcd for
10H7NO2F2 [M+H]+ 212.0523, found 212.0524.
m
max/cmꢁ1 (film) 3086, 2954, 1760,
4.8. (R)-(ꢁ)-Hydroxy-2-bromophenylacetonitrile (R)-6
C
(R)-Acetoxy-2-bromophenylacetonitrile (R)-2 (0.10 g, 39 mmol)
was dissolved in dry ethanol (5 mL) and concentrated sulfuric acid
(1 drop) was added. The reaction mixture was heated at 70 °C over-
night then concentrated in vacuo. The residue was crystallised
from ether/hexane to afford the cyanohydrin (R)-6 as lustrous
4.6. (S)-(+)-Acetoxy-2-t-butylphenylacetonitrile (S)-4
Racemic acetoxy-2-t-butylphenylacetonitrile (2.78 g, 12 mmol)
was dissolved in toluene (12 mL) and 0.1 M pH 7 potassium phos-
phate buffer (48 mL) was added followed by C. cylindracea (0.83 g,
30% w/w). The mixture was shaken at 35 °C and the pH was main-
tained at 7 via automatic addition of 1 M NaOH using a pH stat.
After 26 h the reaction mixture was sonicated for 15 min then fil-
tered through CeliteÒ. The filtrate was transferred to a separating
funnel and, without shaking, the organic phase was removed.
The aqueous phase was extracted with diethyl ether (2 ꢂ 80 mL)
and the combined organic phases were dried and concentrated in
vacuo to afford the crude product mixture as an oil (1.68 g). Col-
umn chromatography (dichloromethane) afforded an approximate
3:1 mixture of the unhydrolysed ester and the aldehyde (1.60 g).
This was dissolved in 95% ethanol (30 mL), Girard’s reagent T
(2.01 g, 12 mmol) was added and the reaction mixture was stirred
overnight. Thereafter, it was diluted with water (120 mL) and ex-
tracted with diethyl ether (3 ꢂ 150 mL). The combined organic ex-
tracts were dried and concentrated in vacuo to afford the
white plates (0.05 g, 63%); mp 89–90 °C; ½a D20
¼ ꢁ13:4 (c 1.1,
ꢀ
CHCl3); HPLC ChiralcelÒ OD-H, hexane/IPA, 95:5, 1 mL/min,
209 nm, tR = 15.0, ee >99%; dH (300 MHz, CDCl3) 2.48 (1H, br s),
5.86 (1H, s), 7.27–7.35 (1H, m), 7.44 (1H, dt, J 7.6, 1.2), 7.63 (1H,
dd, J 7.9, 1.1), 7.74 (1H, dd, J 7.7, 1.6); dC (75.5 MHz, CDCl3) 63.27
(CH), 117.88 (CN), 122.41 (C), 128.36, 128.66, 131.41, 133.43
(CH), 134.42 (C); m
max/cmꢁ1 (KBr) 3392, 1476, 1438, 1415, 1327,
1290, 1243, 1193. Crystal data: orthorhombic, P212121, C8H6BrNO,
M = 221.05, a = 4.1010(12) Å, b = 7.4161(19) Å, c = 26.458(8) Å,
U = 804.7(4) Å3, F(000) = 416,
0.051, for 1253 observed reflections with I > 2
l
(Mo-K
a
) = 5.044 mmꢁ1
,
R(Fo) =
r
(I), wR2(F2) =
0.136 for all 1402 unique reflections.
Acknowledgements
enantiopure ester (S)-4 as an oil (1.00 g, 36%); ½a D20
¼ þ8:9 (c 4.4,
ꢀ
This publication has emanated from research conducted with
the financial support of Science Foundation Ireland under Grant
Numbers 08/RFP/MTR1664 (K.E.) and 05/PICA/B802/EC07. We
CHCl3); HPLC ChiralcelÒ OJ-H, hexane/IPA, 99.5:0.5, 1 mL/min,
209 nm, tR(R) = 10.7, tR(S) = 11.7, ee >98%; dH (300 MHz, CDCl3)