8
P. A. Procopiou et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
m), 0.72–0.66 (2H, m). [
a
]
22 –43 (c 1.8 in CHCl3); Anal. Chiral HPLC
obtained, presumed inorganic material and was discarded. The fil-
trate was checked by LCMS (System A) which showed the presence
of lactone 5e and acid 15 together with addition product 11 and
hydrolysis product 12. The solution was applied to an aminopropyl
cartridge (20 g) eluting with MeOH. The solvent from the fractions
was evaporated in vacuo to give an orange coloured oil (510 mg):
LCMS (System A) indicated the presence of three products:
RT = 1.05 min (1%), RT = 1.15 min (3%), and 1.35 min (9%). Elution
of the cartridge with 2 M ammonia in MeOH gave a yellow solid
(132 mg), which contained only BINAP oxides, and was discarded.
The orange coloured oil was first purified by chromatography on a
silica cartridge (25 g) eluting with a gradient of 0–100% EtOAc–cy-
clohexane and the fractions were further purified by MDAP
(Method A): the fractions with RT = 8.7 min were combined and
evaporated under reduced pressure to give tert-butyl 4-acetoxy-
3-(4-chlorophenyl)butanoate 11e (15.6 mg, 4%) as a colourless
oil: LCMS (System A) RT = 1.35 min, ES+ve m/z 313, 315 (M+H)+;
1H NMR (CDCl3, 600 MHz) 7.29 (2H, d, J = 8.4 Hz), 7.17 (2H, d,
J = 8.4 Hz), 4.22 (1H, dd, J = 11.1, 6.5 Hz), 4.14 (1H, dd, J = 11.0,
7.0 Hz), 3.44 (1H, dq, J = 8.8, 6.7 Hz), 2.69 (1H, dd, J = 15.5,
6.5 Hz), 2.54 (1H, dd, J = 15.5, 8.9 Hz), 2.02 (3H, s), 1.33 (9H, s);
13C NMR (CDCl3, 151 MHz) 170.7 (s, 1C), 170.6 (s, 1C), 139.0 (s,
1C), 132.9 (s, 1C), 129.1 (s, 2C), 128.6 (s, 2C), 80.9 (s, 1C), 67.3 (s,
1C), 40.8 (s, 1C), 38.5 (s, 1C), 27.9 (s, 3C), 20.8 (s, 1C).
The fractions with RT = 8.3 min, were combined and evaporated
under reduced pressure to give tert-butyl 3-(4-chlorophenyl)-4-
hydroxybutanoate 12e (26 mg, 8%) as a colourless oil: LCMS (Sys-
tem A) RT = 1.15 min, 100%; 1H NMR (CDCl3, 600 MHz) 7.28 (2H,
d, J = 8.4 Hz), 7.16 (2H, d, J = 8.3 Hz), 3.73 (2H, qd, J = 10.8,
6.4 Hz), 3.26 (1H, quin, J = 7.0 Hz), 2.69 (1H, dd, J = 15.4, 7.2 Hz),
2.51 (1H, dd, J = 15.4, 7.9 Hz), 1.33 (9H, s); 13C NMR (CDCl3,
151 MHz): 171.5 (s, 1C), 139.7 (s, 1C), 132.7 (s, 1C), 129.2 (s, 2C),
128.7 (s, 2C), 80.8 (s, 1C), 66.8 (s, 1C), 44.1 (s, 1C), 38.5 (s, 1C),
27.9 (s, 3C).
D
RT = 16.1 min, 2.1% and RT = 18.4 min, 97.9% on a Chiralpak AD-H
column (4.6 mm ꢂ 250 mm), eluting with 5% EtOH in heptane,
flow rate = 1 mL/min), detecting at 215 nm.
4.5. ( )-4-(4-Chlorophenyl)dihydrofuran-2(3H)-one ( )-5e
A
mixture of tert-butyl (E)-4-acetoxybut-2-enoate4 10b
(110 mg, 0.55 mmol), 6e (172 mg, 1.1 mmol), [RhCl(cod)]2
(14 mg, 0.03 mmol) and 3.8 M KOH (0.3 mL, 1.1 mmol) in 1,4-diox-
ane (2.5 mL) was deoxygenated by evacuating and re-filling with
nitrogen gas three times, before the mixture was heated to 90 °C
for 1 h. LCMS (System A) RT = 1.28 min, 313 (M+H)+ (for addition
product). Next, 3.8 M KOH aq solution (1.1 mL, 4.2 mmol) was
added, followed by MeOH (3 mL) and the mixture was heated to
90 °C for 1.5 h. LCMS (System A) RT = 0.72 min, ES+ve m/z 293 (M
+Na)+ for hydroxy ester product. The mixture was cooled to room
temperature and then concentrated under reduced pressure. The
residue was diluted with chloroform (4 mL) and treated with conc.
sulfuric acid (1 mL, 18 mmol) and the mixture was stirred for 2 h.
LCMS (System A) RT = 0.83 min and 0.91 min, ES+ve m/z 197 (M
+H)+ for both. The mixture was stood at room temperature over-
night and then passed through a phase separator cartridge and
washed with chloroform. The organic solution was concentrated
to a small volume under reduced pressure and then applied to a sil-
ica cartridge (5 g). The cartridge was eluted with cyclohexane,
ether, 50% EtOAc–cyclohexane and finally EtOAc (1CV each). The
fractions were combined and evaporated under reduced pressure
and the residue was further purified by MDAP (Method A) collect-
ing fractions with RT = 8 min. The fractions were concentrated
under reduced pressure to give ( )-5e (80 mg, 74%) as a yellow
oil, which solidified on standing: LCMS (System A) RT = 0.93 min,
ES+ve m/z 197 (M+H)+ and 214 (M+NH4)+; IR mmax (neat) 1775,
1495, 1064, 1092, 1013, 826 cmꢀ1 1H NMR (CDCl3, 400 MHz)
;
7.35 (2H, d, J = 8 Hz), 7.18 (2H, d, J = 8 Hz), 4.66 (1H, dd, J = 9,
8 Hz), 4.24 (1H, dd, J = 9, 8 Hz), 3.77 (1H, quint, J = 8 Hz), 2.94
(1H, dd, J = 17.5, 9 Hz), 2.64 (1H, dd, J = 17.5, 9 Hz). Anal. Chiral
HPLC RT = 28.3 min, 50%; and RT = 30.3 min, 50% on a Chiralpak
IA column (4.6 mm ꢂ 250 mm) eluting with 5% EtOH-heptane,
flow-rate = 1 mL/min at room temperature, detecting at 215 nm.
The fractions with RT = 7.97 min, ES+ve m/z 197, 199 (M+H)+
and ESꢀve m/z 195, 197 (MꢀH)ꢀ were combined and evaporated
under reduced pressure to give 15, more characterisation was
obtained in the reaction with 13: 1H NMR (CDCl3, 400 MHz) 7.43
(2H, d, J = 8.5 Hz), 7.36 (2H, d, J = 8.5 Hz), 6.14 (1H, br s), 2.56
(3H, s).
The hydroxy ester 12e (26 mg) was then treated with DCM
(0.3 mL) and TFA (0.3 mL) and the solution was stood at RT for
3 h. The mixture was then evaporated in a blow-down unit using
nitrogen gas at 40 °C to give 5e (19 mg, 8%): LCMS (System A)
RT = 0.97 min. Anal. Chiral HPLC RT = 29.1 min, 72.2% and
RT = 31.2 min, 27.8% on Chiralpak IA (250 mm ꢂ 4.6 mm) eluting
with 5% EtOH-heptane containing 0.1% isopropylamine, flow-
rate = 1 mL/min and detecting at 235 nm.
4.5.1. Resolution of ( )-5e
A racemic mixture of 5e (75 mg) was resolved by preparative
chiral HPLC, on a Chiralpak IA (250 ꢂ 30 mm) column, eluting with
7.5% EtOH-heptane, run-time 30 min, collecting the first com-
pound to come off the column (eluting between 23 and
24.5 min), flow-rate = 35 mL/min, detecting at 280 nm to give after
evaporation of the solvent (S)-5e (34 mg, 35%): [a]
20 = +51 (c 0.71,
D
CHCl3), lit.21 for (R)-5e [
RT = 17.5 min, 99.5% on a Chiralpak IA (250 ꢂ 4.6 mm) column,
eluting with 7.5% EtOH-heptane, flow-rate = 1 mL/min, detecting
at 280 nm. Other spectral data as reported above.
a]
25 = ꢀ51 (c 0.5, CHCl3). Anal. Chiral HPLC
D
4.5.3. (R)-5e from 7 and 6e using [Rh(nbd)2]BF4
A
solution of [Rh(nbd)2]BF4 (18.7 mg, 0.05 mmol) and 6e
(391 mg, 2.5 mmol) in 1,4-dioxane (5 mL) was treated with 7
(0.071 mL, 1.0 mmol), 3.8 M KOH (0.5 mL, 1.9 mmol), and (R)-
BINAP (62.3 mg, 0.1 mmol) and the mixture was evacuated and
purged with nitrogen twice. The reaction mixture was heated to
100 °C for 1 h. The reaction mixture was concentrated under
reduced pressure, the residue was dissolved in DCM and applied
to a silica cartridge (20 g). The cartridge was eluted with a gradient
of 0–100% TBME-cyclohexane and the major peak was isolated and
purified twice by MDAP (Method A) collecting the fraction with
RT = 11.49 min. The fraction was evaporated under reduced pres-
sure to give (R)-5e (33 mg, 17%): Anal. Chiral HPLC RT = 33.1 min,
4.5.2. Preparation of 4-(4-chlorophenyl)dihydrofuran-2(3H)-
one (5e) from 6e and 10b using [RhCl(cod)]2 and (R)-BINAP
A mixture of (E)-tert-butyl 4-acetoxybut-2-enoate 10b (241 mg,
1.2 mmol), [RhCl(cod)]2 (29.7 mg, 0.06 mmol, 0.05 equiv.), (4-
chlorophenyl)boronic acid 6e (471 mg, 3.0 mmol, 2.5 equiv.), (R)-
BINAP (75 mg, 0.12 mmol, 0.1 equiv.) and 3.8 M KOH (0.633 mL,
2.4 mmol, 2.0 equiv.) in 1,4-dioxane (6 mL) was deoxygenated for
a few minutes by passing nitrogen gas through the solution and
then the mixture was heated to 65 °C for 75 min, allowed to cool
to 20 °C overnight. The crude reaction mixture was concentrated
under reduced pressure and MeOH was added, whereupon a solid
precipitated out. The solid, which was soluble in water, was
removed by filtration and checked by LCMS; no mass-ions were
5.2% and RT = 36.2 min, 94.8% using
a Chiralpak IA column
(4.6 mm ꢂ 250 mm) eluting with 5% EtOH-heptane, flow-
rate = 1 mL/min, detecting at 215 nm. Major isomer having the
(R) configuration.