Asymmetric Synthesis of 2,2-Disubstituted Chromane Skeletons
0.92 mmol) in EtOH (6.5 mL) at room temp. under Ar and the
mixture was heated at reflux for 1.5 h. After being quenched with
water (80 mL), the aqueous mixture was extracted with AcOEt
(100 mL, 2ϫ50 mL) and the combined organic solutions were
washed with water (3ϫ40 mL) and brine (40 mL), and dried with
MgSO4. After evaporation of the solvent, a crude yellowish oil
(210 mg) was purified by column chromatography (silica gel 60, n-
hexane/AcOEt = 6:1) to give E-12b and Z-12b as a colorless oil,
respectively.
Methyl (2-Methylchroman-2-yl)acetate (5a): Methyl ester 5a was
obtained as a colorless oil from E-12a (25.9 mg, 0.12 mmol) using
TMG (0.003 mL, 0.03 mmol); yield 27.6 mg (quant.). IR (ATR):
ν
max = 1736 cm–1. 1H NMR (400 MHz): δ = 1.45 (s, 3 H, Me), 1.92
˜
(ddd, J = 13.9, 6.4, 6.4 Hz, 1 H, ArCH2CH2), 2.05 (ddd, J = 13.7,
6.6, 6.6 Hz, 1 H, ArCH2CH2), 2.64 (d, J = 14.0 Hz, 1 H,
CH2CO2Me), 2.69 (d, J = 15.0 Hz, 1 H, CH2CO2Me), 2.73–2.86
(m, 2 H, ArCH2CH2), 3.69 (s, 3 H, OMe), 6.78 (d, J = 8.1 Hz, 1
H, ArH), 6.84 (ddd, J = 7.3, 7.3, 1.1 Hz, 1 H, ArH), 7.05–7.11 (m,
2 H, 2ϫArH) ppm. 13C NMR (100 MHz): δ = 22.0, 25.0, 30.7,
43.8, 51.6, 74.6, 117.4, 120.1, 120.8, 127.4, 129.4, 153.2, 170.9 ppm.
MS (FAB): m/z = 220 [M]+. HRMS (FAB): calcd. for C13H16O3
220.1099; found 220.1114. HPLC (CHIRALCEL OD-H; λ =
275 nm; eluent: n-hexane/iPrOH = 95:5; flow rate: 1.0 mL/min): tR
for R isomer: 5.79, tR for S isomer: 7.09 min.
Ethyl (2E)-5-(2-Hydroxyphenyl)-3-methylpent-2-enoate (E-12b):
Yield 157 mg (73%). IR (ATR): νmax = 3422, 1685 cm–1. 1H NMR
˜
(400 MHz): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.21 (d, J =
1.2 Hz, 3 H, Me), 2.42–2.46 (m, 2 H, ArCH2CH2), 2.77–2.81 (m,
2 H, ArCH2CH2), 4.16 (q, J = 7.1 Hz, 2 H, CH2CH3), 5.72 (m, 1
H, CH), 6.00 (br. s, 1 H, OH), 6.76 (d, J = 7.7 Hz, 1 H, ArH),
6.91 (ddd, J = 7.5, 7.3, 1.1 Hz, 1 H, ArH), 7.04–7.09 (m, 2 H,
2ϫArH) ppm. 13C NMR (100 MHz): δ = 14.2, 19.0, 28.4, 40.9,
59.8, 115.2, 115.6, 120.5, 127.3, 127.5, 130.0, 153.8, 160.2,
167.4 ppm. MS (FAB): m/z = 235 [M + H]+. HRMS (FAB): calcd.
for C14H19O3 235.1334; found 235.1313.
Methyl [(2R)-2-Methylchroman-2-yl]acetate [(R)-5a, Table 4, En-
try 5]: Methyl ester (R)-5a was obtained as a colorless oil from Z-
12a (24.9 mg, 0.11 mmol) using chiral guanidine 28 (9.0 mg,
0.023 mmol); yield 18.7 mg (75%, 71% ee). [α]2D4 = +9.52 (c = 0.23,
CHCl3).
Ethyl (2Z)-5-(2-Hydroxyphenyl)-3-methylpent-2-enoate (Z-12b):
Determination of Absolute Configuration of Chromane Methyl Ester
(+)-5a
Yield 21.8 mg (10%). IR (ATR): νmax = 3422, 1686 cm–1. 1H NMR
˜
(400 MHz): δ = 1.29 (t, J = 7.1 Hz, 3 H, CH2CH3), 2.02 (d, J =
1.5 Hz, 3 H, Me), 2.63–2.76 (m, 4 H, CH2CH2), 4.22 (q, J = 7.1 Hz,
2 H, CH2CH3), 5.77 (q, J = 1.5 Hz, 1 H, CH), 6.82 (ddd, J = 7.5,
7.3, 1.3 Hz, 1 H, ArH), 6.93 (dd, J = 8.1, 1.3 Hz, 1 H, ArH), 7.08
(dd, J = 7.5, 1.6 Hz, 1 H, ArH), 7.15 (ddd, J = 7.9, 7.5, 1.6 Hz, 1
H, ArH), 7.76 (br. s, 1 H, OH) ppm. 13C NMR (100 MHz): δ =
14.2, 26.1, 30.8, 35.4, 60.4, 115.8, 116.5, 119.9, 126.0, 128.1, 129.8,
155.2, 161.6, 167.4 ppm. MS (FAB): m/z = 234 [M]+. HRMS
(FAB): calcd. for C14H18O3 234.1256; found 234.1272.
(+)-2-(2-Methylchroman-2-yl)ethanol [(+)-36]: A solution of (+)-
chromane methyl ester (+)-5a (53.9 mg, 0.25 mmol, 71% ee) in
THF (1.4 mL) was added dropwise to a solution of LiAlH4
(20.8 mg, 0.50 mmol) in THF (0.2 mL) under ice-cooling and Ar.
The whole mixture was stirred at 0 °C for 20 min, quenched with
methanol (1.0 mL) and then aq. 30% Rochelle salt, and the mixture
was extracted with diethyl ether (3ϫ5 mL). The combined organic
solutions were washed with brine (3 mL), dried with MgSO4, and
the solvents evaporated in vacuo. The resulting crude oil (42.7 mg)
was purified by column chromatography (silica gel 60, n-hexane/
AcOEt = 4:1) to afford a colorless oil; yield 40.4 mg (86%, 71%
Typical Procedure for the Intramolecular Oxa-Michael Addition
Ethyl (2-Methylchroman-2-yl)acetate (5b, Table 1, Entry 3): TMG
(0.090 mL, 0.72 mmol) was added to a solution of ester E-12b
(56.2 mg, 0.24 mmol) in chloroform (0.28 mL) at room temp. under
Ar. After stirring at room temp. for 2 d, the mixture was diluted
with chloroform (5 mL) and quenched with 10% HCl (2 mL). The
organic layer was washed with water (2ϫ2 mL) and brine, and
dried with MgSO4. The organic layer was concentrated in vacuo to
afford a yellowish oil (57.4 mg). The resulting crude oil was purified
by column chromatography (silica gel 60, n-hexane/AcOEt = 7:1)
ee). [α]2D4 = +6.04 (c = 0.58, CHCl ). IR (ATR): ν
= 3364 cm–1.
˜
3
max
1H NMR (400 MHz): δ = 1.34 (s, 3 H, Me), 1.75–2.03 (m, 4 H,
CH2CH2OH), 2.23 (br. s, H, OH), 2.74–2.88 (m, H,
1
2
ArCH2CH2), 3.82–3.98 (m, 2 H, ArCH2CH2), 6.77 (d, J = 8.1 Hz,
1 H, ArH), 6.85 (dd, J = 7.3, 1.1 Hz, 1 H, ArH), 7.06–7.11 (m, 2
H, 2ϫArH) ppm. HPLC (CHIRALCEL OD-H; λ = 275 nm; n-
hexane/iPrOH = 95:5; flow rate: 1.0 mL/min): tR for major isomer:
9.62, tR for minor isomer: 18.68 min.
to afford a colorless oil; yield 38.2 mg (76%). IR (ATR): ν
=
˜
max
(+)-2-Methyl-2-{2-[(2-nitrophenyl)seleno]ethyl}chromane [(+)-37]:
Tributylphosphane (0.08 mL, 0.32 mmol) was added to a solution
of (+)-36 (31.9 mg, 0.17 mmol, 71% ee) and 2-nitrophenyl seleno-
cyanate (78.8 mg, 0.35 mmol) in THF (0.4 mL) at room temp. un-
der Ar. The whole was stirred at room temp. for 10 min, quenched
with ethanol (10 mL), and the solvents evaporated in vacuo. The
resulting crude oil (206 mg) was purified by column chromatog-
raphy (silica gel 60, n-hexane/AcOEt = 20:1) to afford a colorless
oil; yield 58.7 mg (94%). [α]2D3 = +27.6 (c = 0.49, CHCl3). IR
1735 cm–1. 1H NMR (400 MHz): δ = 1.26 (t, J = 7.1 Hz, 3 H,
CH2CH3), 1.46 (s, 3 H, Me), 1.88–2.08 (m, 2 H, ArCH2CH2), 2.62
(d, J = 14.0 Hz, 1 H, CH2CO2Et), 2.65 (dd, J = 14.0 Hz, 1 H,
CH2CO2Et), 2.74–2.82 (m, 2 H, ArCH2CH2), 4.15 (q, J = 7.1 Hz,
2 H, CH2CH3), 6.78 (dd, J = 8.2, 1.2 Hz, 1 H, ArH), 6.83 (ddd, J
= 7.5, 7.3, 1.1 Hz, 1 H, ArH), 7.05–7.10 (m, 2 H, 2ϫArH) ppm.
13C NMR (100 MHz): δ = 14.2, 21.9, 25.0, 30.7, 43.9, 60.4, 74.6,
117.3, 120.1, 120.8, 127.3, 129.4, 153.2, 170.4 ppm. MS (FAB): m/z
= 234 [M]+. HRMS (FAB): calcd. for C14H18O3 234.1256; found
234.1267. HPLC: (1) (CHIRALCEL OD-H; λ = 275 nm; eluent:
n-hexane; flow rate: 1.0 mL/min): tR for R isomer: 24.19, tR for S
isomer: 32.25 min; (2) (CHIRALCEL OD-H; λ = 275 nm; eluent:
n-hexane/iPrOH = 95:5; flow rate: 1.0 mL/min): tR for R isomer:
4.83, tR for S isomer: 5.27 min.
(ATR): ν
= 1508, 1330 cm–1. 1H NMR (400 MHz): δ = 1.39
˜
max
(s, 3 H, Me), 1.77–2.19 (m, 4 H, CH2CH2Se), 2.75–2.84 (m, 2 H,
ArCH2CH2), 2.95–3.17 (m, 2 H, ArCH2CH2), 6.85–6.89 (m, 2 H,
2ϫArH), 7.06–7.08 (m, 1 H, ArH), 7.13–7.17 (m, 1 H, ArH), 7.26
(ddd, J = 7.7, 7.7, 1.3 Hz, 1 H, ArH), 7.34 (ddd, J = 8.1, 7.1,
1.6 Hz, 1 H, ArH), 7.43 (dd, J = 8.2, 1.4 Hz, 1 H, ArH), 8.28 (dd,
J = 8.2, 1.6 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz): δ = 19.8,
21.8, 24.0, 31.3, 38.2, 75.8, 117.2, 120.1, 120.9, 125.2, 126.4, 127.4,
128.7, 129.6, 133.3, 133.6, 146.7, 153.5 ppm. MS (EI): m/z = 377
[M]+. HRMS (EI): calcd. for C18H19NO3Se 377.0530; found
377.0545.
Ethyl [(2S)-2-Methylchroman-2-yl]acetate [(S)-5b, Table 4, Entry 3]:
Ethyl ester (S)-5b was obtained as a colorless oil from E-12b
(44.3 mg, 0.19 mmol) by using chiral guanidine 28 (15.3 mg,
0.038 mmol, 0.20 equiv.); yield 22.6 mg (51%, 28% ee); [α]2D4
–2.41 (c = 1.29, CHCl3).
=
Eur. J. Org. Chem. 2008, 2759–2766
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2765