R. C. Simon, E. Busto, N. Richter, F. Belaj, W. Kroutil
pTsOH (12.2 mg, 63.9 μmol) were used to provide isochroman (C-5), 100.9 (C-2), 106.2 (C-9), 108.3 (C-4), 114.5 (d, J4Ј,F = 3.9 Hz,
FULL PAPER
(
6
=
5S,7R)-3f as a slightly yellow solid (67.2 mg, 0.215 mmol) in
7.1% yield [dr (syn/anti) = 98:2] after chromatography (PE/EtOAc
4Ј-H), 115.0 (d, J6Ј,F = 8.3 Hz, 6Ј-H), 116.2 (d, J3Ј,F = 24.2 Hz, 3Ј-
F), 127.4 (C-8a), 130.2 (C-4a), 130.3 (d, J1Ј,F = 14.7 Hz, 1Ј-H),
146.2 (arom.-Cipso), 146.4 (arom.-Cipso), 155.2 (d, J2Ј,F = 239.4 Hz,
2Ј-F), 156.0 (d, J5Ј,F = 1.9 Hz, 5Ј-H) ppm. IR (ATR film): ν˜ =
1
80:20). R
f
(PE/EtOAc = 80:20) = 0.54, m.p. 171.3–173 °C. H
3
NMR (300 MHz, CDCl
at C-7), 2.69 (dd,
3
): δ = 1.38 (d, JMe,7 = 6.1 Hz, 1 H, Me
3
2
–1
J
8a,7 = 2.8 Hz,
J8a,8b = 15.9 Hz, 1 H, 8-H
a
),
2968, 2928, 1497, 1477, 1206, 1029, 940, 812, 731 cm . GC–MS
3
2
+
+
20
2
.82 (dd, J8b,3 = 10.9 Hz, J8b,8a = 16.1 Hz, 1 H, 8-H
b
), 3.99 (ddq,
(EI, 70 eV): m/z (%) = 316 [M ] (100), 191 [C11
= –75.8 [c = 0.78, CHCl ; Ͼ99%ee, dr (syn/anti) = 99:1]. HRMS
(TOF-MS, EI+): calcd. for C18 316.1111; found 316.1103.
11 3 D
H O ] (47). [α]
3
7,8a = 2.7 Hz, 3J7,Me = 6.0 Hz, 3J7,8b = 10.8 Hz, 1 H, 7-H), 5.73
J
3
2
2
(s, 1 H, 5-H), 5.85 (d, J2a,2b = 7.6 Hz, 1 H, 2-H
a
), 5.87 (d, J2b,2a
H17FO
4
=
7.6 Hz, 1 H, 2-H ), 6.04 (s, 1 H, 9-H), 6.60 (s, 1 H, 4-H), 7.52
b
3
3
(1R,3S)-6,7-Dimethoxy-3-methyl-1-(3-nitrophenyl)isochroman
[(1R,3S)-3i]: Alcohol (S)-2d (55.1 mg, 0.281 mmol), m-nitrobenz-
aldehyde (44.6 mg, 0.295 mmol), and pTsOH (5.3 mg, 28 μmol)
were used to provide isochroman (1R,3S)-3i as a slightly yellowish
solid (77.8 mg, 0.236 mmol) in 84.0% yield [dr (syn/anti) = 98:2]
(d, J2Ј,3Ј = 8.7 Hz, 2 H, 2Ј-H), 8.21 (d, J3Ј,2Ј = 8.7 Hz, 1 H, 6Ј-H)
13
ppm. C NMR (75 MHz, CDCl
3
): δ = 21.8 (Me at C-7), 36.5 (C-
8
1
1
), 71.6 (C-7), 80.0 (C-5), 101.0 (C-2), 106.2 (C-9), 108.5 (C-4),
24.0 (C-3Ј), 127.4 (C-4a), 129.4 (C-8a), 129.6 (C-2Ј), 146.2 (C-4Ј),
46.7 (arom.-Cipso), 147.8 (arom.-Cipso), 149.7 (C-1Ј) ppm. IR (ATR
after chromatography (PE/EtOAc = 80:20). R
f
(PE/EtOAc = 80:20)
film): ν˜ = 2966, 2916, 2855, 1520, 1500, 1476, 1346, 1347, 1182,
1
–1
+
= 0.25, m.p. 122.3–124 °C. H NMR (300 MHz, CDCl ): δ = 1.38
3
748, 699 cm . GC–MS (EI, 70 eV): m/z (%) = 313 [M ] (100), 191
3
3
+
20
(d,
J
J
Me,3 = 6.2 Hz, 1 H, Me at C-3), 2.69 (dd,
J
4a,3 = 2.7 Hz,
[
(
3
C
11
H
11
O
3
] (78). [α]
syn/anti) = 98:2]. HRMS (TOF-MS, EI+): calcd. for C17
13.0950; found 313.0955.
D 3
= –17.4 [c = 1.25, CHCl ; Ͼ99%ee, dr
2
3
2
4a,4b = 15.9 Hz, 1 H, 4-H
a
), 2.86 (dd, J4b,3 = 11.0 Hz, J4b,4a =
H15NO
5
1
5.9 Hz, 1 H, 4-H ), 3.60 (s, 3 H, OMe at C-7), 3.85 (s, 3 H, OMe
b
3
3
3
at C-6), 4.00 (ddq, J3,4a = 2.6 Hz, J3,Me = 6.1 Hz, J3,4b = 10.9 Hz,
H, 3-H), 5.78 (s, 1 H, 1-H), 6.06 (s, 1 H, 5-H), 6.63 (s, 1 H, 8-
(
[
5R,7R)-5-(2-Chlorphenyl)-7-methyl-7,8-dihydro-5H-[1,3]dioxolo-
4,5-g]isochromene [(5R,7R)-3g]: Alcohol (R)-2c (51.0 mg,
1
3
4
3
H), 7.52 (t, J = 7.9 Hz, 1 H, 5Ј-H), 7.68 (dt, J = 1.5 Hz, J =
7
8
0
.283 mmol), 2-chlorobenzaldehyde (41.8 mg, 0.297 mmol), and
pTsOH (10.8 mg, 56.6 μmol) were used to provide isochroman
5R,7R)-3g as a colorless solid (72.8 mg, 0.240 mmol) in 85.0 %
4
3
.8 Hz, 1 H, 6Ј-H), 6.16 (dq, J = 1.2 Hz, J = 8.1 Hz, 1 H, 4Ј-H),
4
13
3
.22 (t, J = 2.0 Hz, 1 H, 2Ј-H) ppm. C NMR (75 MHz, CDCl ):
(
δ = 21.8 (Me at C-3), 35.9 (C-4), 55.9 (OMe), 56.0 (OMe), 71.6 (C-
yield [dr (syn/anti) = 92:8] after flash chromatography (silica, PE/
EtOAc = 98:2). The pure syn diastereomer was obtained by an
additional chromatographic separation (elutes first). R
=
=
3
1
1
), 79.7 (C-1), 109.1 (C-5), 111.3 (C-8), 123.2 (C-4Ј), 123.8 (C-2Ј),
26.5 (C-4a), 128.1 (C-8a), 129.5 (C-5Ј), 135.0 (C-6Ј), 144.7 (C-1Ј),
f
(PE/EtOAc
): δ
47.5 (arom.-Cipso), 148.2 (arom.-Cipso), 148.4 (C-3Ј) ppm. IR (ATR
1
80:20) = 0.66, m.p. 92.3–93 °C. H NMR (300 MHz, CDCl
3
–1
film): ν˜ = 2911, 2857, 1515, 1340, 1065, 810, 736 cm . GC–MS
3
3
1.38 (d,
J
Me,7 = 6.2 Hz, 1 H, Me at C-7), 2.67 (dd,
J
8a,7
=
+
+
(
EI, 70 eV): m/z (%) = 329 [M ] (100), 207 [C12
H
15
O
3
] (100).
2
3
2
J
.8 Hz, J8a,8b = 15.9 Hz, 1 H, 8-H
a
), 2.82 (dd, J8b,3 = 11.0 Hz,
20
[α]
D
= –42.8 [c = 1.03, CHCl
3
; Ͼ99%ee, dr (syn/anti) = 98:2].
329.1263; found
2
), 4.01 (ddq, 3J7,8a = 3.0 Hz, 3J7,Me
8b,8a = 15.9 Hz, 1 H, 8-H
b
=
HRMS (TOF-MS, EI+): calcd. for C18
29.1262.
H19NO
5
3
2
6
2
.1 Hz, J7,8b = 10.8 Hz, 1 H, 7-H), 5.83 (d, J2a,2b = 5.8 Hz, 1 H,
3
a b
-H ), 6.17 (s, 1 H, 5-H), 6.18
), 5.84 (d, 2J2b,2a = 5.8 Hz, 1 H, 2-H
(
1S,3S)-1-(2-Chloro-5-nitrophenyl)-6,7-dimethoxy-3-methyliso-
(s, 1 H, 9-H), 6.57 (s, 1 H, 4-H), 7.16–7.26 (m, 2 H, arom.-H),
, 1 H, arom-H) ppm. 1 C NMR
3
chroman [(1S,3S)-3j]: Alcohol (S)-2d (55.1 mg, 0.281 mmol), 2-
chloro-5-nitrobenzaldehyde (54.8 mg, 0.295 mmol), and pTsOH
7
.32 (m
c
, 1 H, arom.-H), 7.39 (m
): δ = 21.9 (Me at C-7), 36.5 (C-8), 71.6 (C-7),
6.7 (C-5), 100.9 (C-2), 106.3 (C-9), 108.3 (C-4), 127.4 (C-4a),
27.5, 129.2, 129.6 (arom.-CH), 130.3 (C-8a), 130.6 (arom.-CH),
33.6 (C-2Ј), 140.4 (C-1Ј), 146.1 (arom.-Cipso), 146.4 (arom.-Cipso
c
(75 MHz, CDCl
3
(
5.3 mg, 28 μmol) were used to provide isochroman (1S,3S)-3j as a
slightly orange solid (80.8 mg, 0.222 mmol) in 79.1 % yield [dr
syn/anti) = 99:1] after chromatography (PE/EtOAc = 90:10). R
7
1
1
(
f
)
1
–
1
(PE/EtOAc = 80:20) = 0.31, m.p. 139–141 °C. H NMR (300 MHz,
ppm. IR (ATR film): ν˜ = 2969, 2923, 1482, 1238, 1028, 800 cm .
GC–MS (EI, 70 eV): m/z (%) = 302 [M ] (63), 223 [C16
3
+
+
CDCl ): δ = 1.42 (d, J
Me,3
= 6.1 Hz, 1 H, Me at C-3), 2.72 (dd,
J4a,3 = 2.7 Hz, J4a,4b = 16.0 Hz, 1 H, 4-H ), 2.91 (dd, J4b,3 =
a
H
15O ]
3
3
2
3
+
20
(
100), 191 [C11
Ͼ99%ee, dr (syn/anti) = 99:1]. HRMS (TOF-MS, EI+): calcd. for
15ClO 302.0710; found 302.0709.
H
11
O
3
] (88). [α]
D
= +50.7 [c = 1.15, CHCl
3
;
1
3
6
0.9 Hz, 2J4b,4a = 15.9 Hz, 1 H, 4-H
.87 (s, 3 H, OMe at C-6), 4.05 (ddq,
b
), 3.65 (s, 3 H, OMe at C-7),
3
3
J
3,4a = 3.0 Hz,
3,Me
J =
C
17
H
3
3
.1 Hz, J3,4b = 10.9 Hz, 1 H, 3-H), 6.17 (s, 1 H, 5-H), 6.26 (s, 1
(
[
(
5R,7R)-5-(2-Fluoro-5-methoxyphenyl)-7-methyl-7,8-dihydro-5H-
1,3]dioxolo[4,5-g]isochromene [(5R,7R)-3h]: Alcohol (R)-2c
47.9 mg, 0.266 mmol), 2-fluoro-5-methoxybenzaldehyde (43.0 mg,
3
H, 1-H), 6.64 (s, 1 H, 8-H), 7.60 (d, J3Ј,4Ј = 8.8 Hz, 1 H, 3Ј-H),
8
=
.10 (dd, J4Ј6Ј = 2.8 Hz, J4Ј,3Ј = 8.8 Hz, 1 H, 4Ј-H), 8.22 (d, 4J6Ј,4Ј
2.8 Hz, 1 H, 6Ј-H) ppm. C NMR (75 MHz, CDCl ): δ = 21.8
3
4
3
13
0
.279 mmol), and pTsOH (10.1 mg, 53.2 μmol) were used to pro-
vide isochroman (5R,7R)-3h as a colorless solid (60.7 mg,
.192 mmol) in 72.2 %yield [dr (syn/anti) = 90:10] after flash
(
(
Me at C-3), 35.9 (C-4), 56.0 (OMe), 56.1 (OMe), 71.9 (C-3), 75.8
C-1), 108.6 (C-5), 111.6 (C-8), 123.9 (C-6Ј), 126.0 (C-4Ј), 126.5 (C-
0
4a), 127.5 (C-8a), 130.5 (C-3Ј), 140.1 (C-2Ј), 142.8 (C-1Ј), 147.3 (C-
chromatography (silica, PE/EtOAc = 95:5). The pure syn dia-
stereomer was obtained by an additional chromatographic separa-
5
=
Ј), 147.8 (arom.-Cipso), 148.4 (arom.-Cipso) ppm. IR (ATR film): ν˜
–1
3083, 2962, 2923, 1525, 1345, 1216, 1077, 741 cm . GC–MS (EI,
tion (elutes first). R
f
(PE/EtOAc = 80:20) = 0.37, m.p. 125.8–
+
+
20
7
–
0 eV): m/z (%) = 363 [M ] (100), 207 [C12
58.1 [c = 1.22, CHCl ; Ͼ99%ee, dr (syn/anti) = 99:1]. HRMS
18ClNO 363.0873; found
15 3 D
H O ] (97). [α] =
26.0 °C. 1H NMR (300 MHz, CDCl
.2 Hz, 1 H, Me at C-7), 2.66 (dd, J8a,7 = 3.1 Hz, J8a,8b = 15.9 Hz,
): δ = 1.39 (d, J =
3
1
6
1
3 Me,7
3
3
2
(
TOF-MS, EI+): calcd. for C18
H
5
3
2
H, 8-H
), 3.73 (s, 3 H, OMe), 3.99 (ddq, J7,8a = 3.1 Hz, 3J7,Me = 6.1 Hz,
b
a
), 2.82 (dd, J8b,3 = 11.0 Hz, J8b,8a = 16.0 Hz, 1 H, 8-
363.0899.
3
H
3
2
J
7,8b = 10.8 Hz, 1 H, 7-H), 5.86 (d, J2a,2b = 5.7 Hz, 1 H, 2-H
a
), 2-Chloro-3-[(1S,3S)-6,7-dimethoxy-3-methylisochroman-1-yl]-
), 6.00 (s, 1 H, 5-H), 6.22 (s, 1 phenol [(1S,3S)-3k]: Alcohol (S)-2d (50.0 mg, 0.255 mmol), 2-
H, 9-H), 6.57 (s, 1 H, 4-H), 6.76–6.83 (m, 2 H, arom.-H), 7.01 (m chloro-3-hydroxybenzaldehyde (41.9 mg, 0.267 mmol), and pTsOH
H, arom.-H) ppm. 13C NMR (75 MHz, CDCl
): δ = 21.9 (Me at (9.7 mg, 56 μmol) were used to provide isochroman (1S,3S)-3k as
C-7), 36.5 (C-8), 55.9 (d, JMe,F = 2.5 Hz, OMe), 71.6 (C-7), 73.7 a colorless solid (77.4 mg, 0.231 mmol) in 90.6% yield [dr (syn/anti)
5
.87 (d, 2J2b,2a = 5.7 Hz, 1 H, 2-H
b
c
,
1
3
118
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 111–121