Asymmetric synthesis of 3-substituted hexahydro-3H-isochromenes via an organocatalytic triple cascade/Yb-catalyzed hetero-Diels-Alder sequence

Article abstract of DOI:10.1055/s-0031-1290374

An efficient two-step asymmetric synthesis of highly substituted 3-alkoxy-hexahydro-3H-isochromenes and 3-sulfenylated hexahydro-3H-isochromenes is described. The procedure involves an organocatalytic triple cascade reaction, followed by an intermolecular [Yb(fod)-catalyzed inverse-electron-demand hetero-Diels-Alder reaction. Using this strategy, a total of six stereogenic centers are obtained with excellent diastereoselectivities and virtually complete enantioselectivities (>95:5 dr,>99%ee). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290374

PAPER
▌2107
paper
Asymmetric Synthesis of 3-Substituted Hexahydro-3H-isochromenes via an
Organocatalytic Triple Cascade/Yb-Catalyzed Hetero-Diels–Alder Sequence
Asymmetric Synthesis of Hexahydro-3H-isochromenes
Nico Erdmann, Iuliana Atodiresei, Dieter Enders*
Institute of Organic Chemisty, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received: 25.04.2012; Accepted: 25.04.2012
52% yield, good diastereoselectivities (dr >95:5) and vir-
Abstract: An efficient two-step asymmetric synthesis of highly
tually complete enantioselectivities (ee >99%).
substituted 3-alkoxy-hexahydro-3H-isochromenes and 3-sulfenyl-
ated hexahydro-3H-isochromenes is described. The procedure in-
volves an organocatalytic triple cascade reaction, followed by an
intermolecular [Yb(fod)3]-catalyzed inverse-electron-demand het-
R3
X
O
∗
R1
R2
ero-Diels–Alder reaction. Using this strategy, a total of six stereo-
genic centers are obtained with excellent diastereoselectivities and
virtually complete enantioselectivities (>95:5 dr, >99% ee).
O
R1
R2
∗
∗
∗
∗
HDA
Ph
∗
Key words: asymmetric synthesis, organocatalysis, Diels–Alder
reaction, domino reaction, isochromenes
NO2
Ph
NO2
2
1
X = O, S
The inverse-electron-demand hetero-Diels–Alder reac-
tion (HDA)1,2 of α,β-unsaturated carbonyl compounds
with electron-rich alkenes is a powerful tool in the synthe-
sis of sugars and their derivatives.3 Furthermore, it is fre-
quently used in the synthesis of other natural products.4
Generally, inverse-electron-demand HDA reactions have
been catalyzed either by Lewis acids5 or by organocata-
lysts.6
O
O
EN
R1
5
3
triple
cascade
Ph
IM
EN
NO2
R2
4
In this communication we would like to report on a two-
step asymmetric approach to the synthesis of the hexa-
hydro-3H-isochromene core. This structural element is
present in several natural products that are known for their
widespread biological activities, such as angiogenesis in-
hibitors,7 herbicides,8 compounds with cytotoxic activity
in selected tumor lines,9 and HeLa cells.10 Other deriva-
tives were tested as therapeutics for postmenopausal
osteoporosis, lipid metabolic disorder, menopausal syn-
drome, and hypogonadism.11
Scheme 1 Retrosynthetic analysis of the asymmetric synthesis of 3-
substituted hexahydro-3H-isochromenes via a triple cascade/hetero-
Diels–Alder (HDA) sequence
With the cyclohexene carbaldehydes in hand, several cat-
alysts and conditions for the HDA reaction were screened
using cyclohexene carbaldehyde 2a and vinylethers 7a
and 7b (Scheme 3).
Ph
O
From a retrosynthetic perspective, we planned to build up
the second dihydropyran ring of the isochromene title
compounds 1 by an inverse-electron-demand HDA reac-
tion between a chiral cyclohexene carbaldehyde and an
electron-rich double bond present in vinylethers and vin-
ylthioether (Scheme 1). The cyclohexene ring of 2 is con-
structed by an organocatalytic triple cascade reaction12–14
based on a methodology developed in our group.15,16
O
O
Ph
R1
R2
N
R1
H
OTMS
6
5
3a–c
Ph
a)
Ph
NO2
NO2
R2
4a–c
2a–c
Scheme 2 Organocatalytic triple cascade reaction: Reagents and
conditions: (a) 6 (20 mol%), CHCl3, 12 h at 0 °C then 48 h at r.t.
The triple cascade reaction was performed in chloroform
starting from aldehydes 3, nitroalkenes 4, and enals 5 cat-
alyzed by 20 mol% TMS-diphenyl prolinol 6 (Scheme 2,
Table 1) affording cyclohexene carbaldehydes 2 with 41–
OR1
O
O
OR1
Me
Ph
Me
Ph
7
catalyst
Ph
Ph
a: R1 = Et
b: R1 = Bu
NO2
NO2
SYNTHESIS 2012, 44, 2107–2113
Advanced online publication: 04.06.2012
2a
8
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1290374; Art ID: SS-2012-Z0390-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 Hetero-Diels–Alder reaction

2108
N. Erdmann et al.
PAPER
Encouraged by these results, this methodology was then
applied to butyl vinyl ether. To our delight, the reaction
was already finished after five hours (Table 2, entry 10).
Based on this higher reactivity, the catalyst loading could
be lowered to 6 mol% (Table 2, entry 12). Unfortunately,
attempts to reduce the reaction time by increasing the tem-
perature led to a decrease in diastereoselectivity (Table 2,
entry 13). As above, conducting the HDA reaction with
butyl vinyl ether in an oil bath resulted in a lower conver-
sion and extended reaction time.
Table 1 Variations of the Triple Cascade
2
R1
R2
Ph
Yield (%) dra
ee (%)b
a
b
c
Me
Me
41
>95:5 >99
>95:5 >99
>95:5 >99
4-ClC6H4 43
52
4-phenylbut-3-ynyl Ph
a Determined by NMR spectroscopic analysis.
b Determined by chiral stationary phase HPLC.
To determine the scope of the triple cascade/HDA se-
quence, other vinyl ethers were tested (Scheme 4, Table 3;
1c and 1d). Fortunately, even vinyl thioethers could be
employed in the HDA reaction, and 3-sulfenylated hexa-
hydro-3H-isochromenes 1g and 1h were obtained in good
yields and excellent stereoselectivities. To further demon-
strate the scope of the reaction, R2 and R3 were also varied
(Table 3; 1e and 1f). Whereas an intramolecular HDA re-
action of 2c with the triple bond (Table 3, entry f) could
be feasible, the cycloaddition product 1f of the intermo-
lecular HDA reaction was observed exclusively.
For the first part of the screening, ethyl vinyl ether was
used as an electron-rich dienophile. Whereas with 10
mol% catalyst loading of [Yb(fod)3] and two hours micro-
wave irradiation in a sealed flask no conversion could be
detected (Table 2, entries 1 and 2), with 10 mol%
[Yb(fod)3] and an increased time as well as an increased
amount of ethyl vinyl ether (20 equiv) the yield went up
to 60% (Table 2, entries 3 and 4). To confirm the effect of
microwave irradiation for the inverse-electron-demand
HDA cycloaddition, the reaction was performed by heat-
ing in a sealed flask (Table 2, entry 5). Other commonly
used catalysts for inverse-electron-demand HDA reac-
tions on α,β-unsaturated aldehydes with vinylethers
proved to be inferior to those obtained with [Yb(fod)3]
(Table 2, entries 6–8). Increasing the reaction time for the
HDA reaction under microwave irradiation to 15 hours
led to full conversion and 85% yield of the isolated 3-eth-
oxyhexahydro-3H-isocromene 8a (Table 2, entry 9).
The relative and absolute configuration of the 3-alkoxy-
or 3-sulfenylated hexahydro-3H-isochromenes was deter-
mined by 1H NMR spectroscopic analysis (coupling con-
stants) and by X-ray crystallography in the case of 1c
(Figure 1).17
In summary, we have developed an organocatalytic triple
cascade/[Yb(fod)3]-catalyzed inverse-electron-demand
Table 2 Optimization of the Hetero-Diels–Alder Reaction
Entry
R1
Catalysta
mol%
7 (equiv)
T (°C)
Time (h)
Conv. (%)b
drb
1
2
Et
Yb(fod)3
Yb(fod)3
Yb(fod)3
Yb(fod)3
Yb(fod)3
Eu(fod)3
Zn(OTf)3
Byp2Cu(OTf)2
Yb(fod)3
Yb(fod)3
Yb(fod)3
Yb(fod)3
Yb(fod)3
Yb(fod)3
5
8
10
10
20
20
20
20
20
20
20
15
10
10
10
15
120
120
120
120
120
120
120
120
120
120
120
120
140
120
2
2
<5
<5
n.d.
Et
n.d.
3
Et
10
10
10
10
10
10
10
10
3
5
56
87:13
88:12
89:11
70:30
n.d.
4
Et
10
24
10
10
10
15
5
64
5c
6
Et
40
Et
54
7
Et
<5
8
Et
<5
n.d.
9
Et
>95 (85)c
>95
69
>95:5d
82:18
85:15
86:14 (>95:5)d
74:26
81:19
10
11
12
13
14e
Bu
Bu
Bu
Bu
Bu
10
5
6
>95 (85)c
>95
87
6
2,5
20
6
a fod: 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate, Byp: 2,2′-bipyridine.
b Determined by GC analysis.
c Yield of isolated hexahydro-3H-isochromene 8 given in parentheses.
d dr of isolated 8.
e Heated in a sealed tube within an oil bath.
Synthesis 2012, 44, 2107–2113
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Hexahydro-3H-isochromenes
2109
Table 3 Scope of the Triple Cascade/HDA Sequence
1
R1
R2
XR3
Yield (%)
dra
1ab
1b
1c
Me
Ph
OEt
85
85
63
61
81
63
78
49
>95:5
>95:5
>95:5
95:5
Me
Ph
OBu
Me
Ph
OCH2CH2Cl
O(i-Bu)
OBu
1d
1e
Me
Ph
Me
4-ClC6H4
>95:5
>95:5
>95:5
>95:5
1f
4-phenylbut-3-ynyl
Ph
Ph
Ph
OBu
1g
1hc
Me
Me
SEt
SPh
a Determined by NMR spectroscopic analysis.
b [Yb(fod)3] (10 mol%), 9 (20 equiv), 15 h.
c After 10 h at 120 °C.
R3
O
X
X
Unless otherwise noted, all commercially available compounds
were used without further purification. CHCl3 was freshly distilled
under argon from CaCl2. The catalyst was prepared according to the
previously described procedure.18 Literature protocols were used to
prepare 2a and 2b.13 All microwave reactions were performed with
a CEM Discover system. For preparative column chromatography,
SIL G-25 UV254 (Macherey-Nagel, particle size 0.040–0.063 mm,
230–240 mesh, flash) was used. Visualization of the developed
TLC plates was performed with ultraviolet irradiation (254 nm).
Optical rotation values were measured with a Perkin–Elmer 241 po-
larimeter. Mass spectra were measured with a Finnigan SSQ7000
(EI 70 eV) spectrometer and a high-resolution mass spectra with a
Thermo Fisher Scientific Orbitrap XL. IR spectra were recorded
with a Perkin–Elmer FT-IR Spectrum 100 using an ATR-Unit. 1H
and 13C NMR spectra were recorded at ambient temperature with
Varian Mercury 300 or Inova 400 spectrometers with tetramethyl-
silane as an internal standard. Analytical HPLC was performed with
a Hewlett–Packard 1100 Series instrument using chiral stationary
phases (Chiralcel OD, Chiralcel OJ, Chiralpak AD, Chiralpak AS,
Chiralcel IA).
3 (10 equiv)
R
9
O
Yb(fod)3 (6 mol%)
5 h, 120 °C, MW
R1
R2
R1
R2
Ph
Ph
NO2
NO2
X = O, S
2
1
Scheme 4 Scope of the hetero-Diels–Alder reaction
General Procedure 1 (GP 1)
TMS-prolinol 6 (0.2 equiv) and nitroalkene 4 (1 equiv) were dis-
solved in CHCl3 (2 mL per 1 mmol of 4) at 0 °C. Aldehyde 3
(1.4 equiv) was slowly added, followed by slow addition of the α,β-
unsaturated aldehyde 5 (1.4 equiv). The reaction was kept at 0 °C
for 12 h and then allowed to warm to r.t. Stirring was continued for
48 h. The product was purified by flash chromatography.
General Procedure 2 (GP 2)
Cyclohexene carbaldehyde (0.31 mmol), [Yb(fod)3] (6 mol%) and
vinyl ether (10 equiv) were mixed in a 5 mL microwave flask. The
reaction mixture was heated for 5 h to 120 °C (300 W with ‘cooling
off’ setting). The crude product was directly loaded onto a flash col-
umn and purified.
6-(4-Phenylbut-3-yn-1-yl)cyclohexene-carbaldehyde 2c
The synthesis followed GP 1 to give the main diastereomer.
Figure 1 Determination of the absolute configuration of 1c by X-ray
analysis
Yield: 455 mg (52%); colorless crystals; mp 74 °C; ee >99%;
Rf = 0.27 (pentane–Et2O, 2:1); [α]D24 –7.59 (c 1, CHCl3).
IR (CDCl3): 1686, 1491, 1366, 1160, 757, 695 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.77 (m, 1 H), 1.98 (m, 1 H), 2.60
(t, J = 6.6 Hz, 2 H), 3.13 (dd, J = 2.3, 10.4 Hz, 1 H), 3.66 (m, 1 H),
4.48 (s, 1 H), 4.90 (s, 1 H), 7.05 (m, 2 H), 7.34 (m, 14 H), 9.59 (s,
1 H).
hetero-Diels–Alder sequence to afford highly functional-
ized 3-substituted hexahydro-3H-isochromenes bearing
six stereogenic centers in virtually enantiopure form with
excellent diastereomeric ratios and in moderate to good
yields.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2107–2113

2110
N. Erdmann et al.
PAPER
13C NMR (75 MHz, CDCl3): δ = 16.8, 31.2, 36.2, 43.1, 82.5, 88.6,
92.6, 123.3, 127.0 (2C), 128.0 (3C), 128.1 (2C), 128.2, 128.4 (2C),
129.2 (2C), 129.4 (2C), 131.5 (2C), 136.9, 137.5, 138.8, 153.7,
192.0.
6.32 (d, J = 1.3 Hz, 1 H), 7.08 (d, J = 7.3 Hz, 2 H), 7.28 (m, 4 H),
7.44 (m, 4 H).
13C NMR (150 MHz, CDCl3): δ = 17.7, 32.8, 34.5, 36.0, 42.9, 47.0,
48.3, 68.8, 93.1, 99.5, 110.5, 127.1 (2C), 127.3, 127.5, 128.3 (2C),
128.8 (2C), 129.1 (2C), 138.7, 139.1, 140.0.
MS (EI): m/z = 388 [M – HNO2]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H25NO3: 436.1907; found:
MS (EI): m/z = 427 [M]+.
436.1899.
HRMS (EI): m/z [M + Na]+ calcd for C24H26NO4Cl: 450.1443;
Anal. Calcd for C29H25NO3: C, 79.98; H, 5.79; N, 3.22. Found: C,
79.48; H, 5.57; N, 2.99.
found: 450.1442.
Anal. Calcd for C24H26NO4Cl: C, 67.36; H, 6.12; N, 3.27. Found: C,
67.40; H, 5.93; N, 3.20.
3-Ethoxy-hexahydro-3H-isochromene (1a)
The synthesis followed GP 2 to give the main diastereomer.
3-Isobutoxy-hexahydro-3H-isochromene (1d)
The synthesis followed GP 2 to give the main diastereomer.
Yield: 105 mg (85%); colorless solid; mp 55 °C; ee >99%; Rf = 0.18
(pentane–Et2O, 20:1); [α]D24 –60.5 (c 1, CHCl3).
Yield: 80 mg (61%); colorless solid; mp 30 °C; Rf = 0.26 (pentane–
Et2O, 40:1); [α]D24 –19.0 (c 2, CHCl3).
IR (CDCl3): 2969, 2926, 2868, 1661, 1548, 1493, 1451, 1367, 1240,
1125, 1061, 1000, 948, 874, 761, 701 cm–1.
IR (CDCl3): 2963, 2927, 2870, 1661, 1550, 1453, 1366, 1129, 1055,
759, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.77 (d, J = 6.0 Hz, 3 H), 1.31 (t,
J = 7.1 Hz, 3 H), 1.90 (ddd, J = 8.6, 12.9, 17.3 Hz, 1 H), 2.28 (m,
1 H), 2.37 (ddd, J = 2.0, 6.9, 12.9 Hz, 1 H), 2.70 (dd, J = 3.3,
12.0 Hz, 1 H), 2.77 (m, 1 H), 3.65 (m, 1 H), 3.94 (s, 1 H), 4.00 (m,
1 H), 5.07 (dd, J = 1.9, 8.5 Hz, 1 H), 5.32 (dd, J = 1.9, 3.3 Hz, 1 H),
6.32 (d, J = 1.6 Hz, 1 H), 7.06 (m, 2 H), 7.27 (m, 4 H), 7.44 (m,
4 H).
13C NMR (100 MHz, CDCl3): δ = 15.5, 18.1, 34.3, 35.0, 36.8, 47.2,
48.3, 64.7, 93.4, 99.8, 110.0, 127.5 (2C), 127.6, 127.8, 128.5 (2C),
129.1 (2C), 129.4 (2C), 139.0, 139.6, 141.0.
1H NMR (600 MHz, CDCl3): δ = 0.78 (d, J = 6.4 Hz, 3 H), 0.98 (m,
6 H), 1.94 (m, 2 H), 2.26 (m, 1 H), 2.36 (ddd, J = 1.8, 6.8, 13.2 Hz,
1 H), 2.70 (dd, J = 3.2, 12.0 Hz, 1 H), 2.79 (m, 1 H), 3.32 (dd,
J = 6.9, 9.2 Hz, 1 H), 3.74 (dd, J = 6.6, 9.1 Hz, 1 H), 3.94 (s, 1 H),
5.05 (dd, J = 1.8, 8.1 Hz, 1 H), 5.32 (dd, J = 1.6, 3.2 Hz, 1 H), 6.33
(s, 1 H), 7.07 (d, J = 7.4 Hz, 2 H), 7.28 (m, 5 H), 7.43 (m, 3 H).
13C NMR (150 MHz, CDCl3): δ = 17.8, 19.3, 19.4, 28.6, 33.6, 34.7,
36.5, 47.0, 48.3, 75.9, 93.1, 99.9, 109.8, 127.2 (2C), 127.2, 127.5,
128.3 (2C), 128.8 (2C), 129.1 (2C), 138.8, 139.4, 140.7.
MS (EI): m/z = 393 [M]+.
HRMS (EI): m/z [M + Na]+ calcd for C24H27NO4: 416.1832; found:
MS (EI): m/z = 421 [M]+.
HRMS (EI): m/z [M + Na]+ calcd for C26H31NO4: 444.2145; found:
416.1832.
444.2137.
3-Butoxy-hexahydro-3H-isochromene (1b)
The synthesis followed GP 2 to give the main diastereomer.
Anal. Calcd for C26H31NO4: C, 74.08; H, 7.41; N, 3.32. Found: C,
73.89; H, 7.61; N, 3.18.
Yield: 110 mg (85%); colorless solid; mp 78 °C; Rf = 0.33 (pen-
tane–Et2O, 20:1); [α]D24 –15.4 (c 6.1, CHCl3).
3-Butoxy-6-(4-chlorophenyl)hexahydro-3H-isochromene (1e)
The synthesis followed GP 2 to give the main diastereomer.
IR (CHCl3): 1649, 1544, 1372, 1235, 1133, 1071, 987, 946, 762,
703 cm–1.
Yield: 115 mg (81%); colorless solid; mp 29 °C; ee >99%; Rf = 0.27
(pentane–Et2O, 20:1); [α]D24 –56.3 (c 0.4, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 0.76 (d, J = 6.0 Hz, 3 H), 0.95 (t,
J = 7.4 Hz, 3 H), 1.43 (m, 2 H), 1.65 (m, 2 H), 1.88 (ddd, J = 8.5,
12.9, 17.0 Hz, 1 H), 2.26 (m, 1 H), 2.35 (ddd, J = 2.0, 6.9, 12.9 Hz,
1 H), 2.73 (m, 2 H), 3.56 (td, J = 6.7, 9.4 Hz, 1 H), 3.93 (m, 2 H),
5.04 (dd, J = 2.0, 8.5 Hz, 1 H), 5.30 (dd, J = 1.9, 3.3 Hz, 1 H), 6.31
(d, J = 1.6 Hz, 1 H), 7.05 (m, 2 H), 7.28 (m, 4 H), 7.42 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 13.9, 17.8, 19.3, 31.8, 33.9, 34.8,
36.6, 47.0, 48.2, 68.9, 93.1, 99.8, 109.8, 127.2 (2C), 127.3, 127.5,
128.3 (2C), 128.8 (2C), 129.1 (2C), 138.8, 139.5, 140.7.
IR (CDCl3): 2961, 2932, 2871, 1662, 1550, 1492, 1457, 1366, 1239,
1130, 1094, 911, 730 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.76 (d, J = 5.9 Hz, 3 H), 0.97 (t,
J = 7.4 Hz, 3 H), 1.45 (m, 2 H), 1.67 (m, 2 H), 1.89 (ddd, J = 8.3,
12.9, 16.8 Hz, 1 H), 2.26 (m, 1 H), 2.35 (ddd, J = 2.0, 6.9, 12.9 Hz,
1 H), 2.72 (m, 2 H), 3.57 (td, J = 6.7, 9.5 Hz, 1 H), 3.94 (m, 2 H),
5.05 (dd, J = 2.0, 8.3 Hz, 1 H), 5.27 (dd, J = 1.9, 3.1 Hz, 1 H), 6.32
(d, J = 1.6 Hz, 1 H), 7.01 (m, 2 H), 7.25 (m, 2 H), 7.33 (m, 1 H),
7.42 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 13.9, 17.7, 19.3, 31.8, 33.7, 34.7,
36.4, 47.0, 47.6, 68.8, 92.8, 99.7, 109.4, 127.1 (2C), 127.3, 129.0
(2C), 129.1 (2C), 129.7 (2C), 133.3, 137.3, 139.2, 140.8.
MS (EI): m/z = 421 [M]+.
HRMS (ESI): m/z [M + Na]+ calcd for C26H31NO4: 444.2145;
found: 444.21456.
Anal. Calcd for C26H31NO4: C, 74.08; H, 7.41; N, 3.32. Found: C,
74.11; H, 7.42; N, 3.24.
MS (EI): m/z = 455 [M]+.
HRMS (EI): m/z [M + Na]+ calcd for C26H30NO4Cl: 478.1757;
found: 478.0867.
3-(2-Chloroethoxy)hexahydro-3H-isochromene (1c)
The synthesis followed GP 2 to give the main diastereomer.
3-Butoxy-5-(4-phenylbut-3-yn-1-yl)hexahydro-3H-iso-
chromene (1f)
The synthesis followed GP 2 to give the main diastereomer.
Yield: 85 mg (63%); colorless crystals; mp 193 °C; Rf = 0.24 (pen-
tane–Et2O, 15:1); [α]D24 –15.7 (c 1.2, CHCl3).
Yield: 105 mg (63%); colorless crystals; mp 53 °C; Rf = 0.40 (pen-
tane–Et2O, 20:1); [α]D24 –10.0 (c 2.5, CHCl3).
IR (CDCl3): 1654, 1542, 1450, 1366, 138, 1122, 1065, 945, 881,
767, 704, 659 cm–1.
1H NMR (600 MHz, CDCl3): δ = 0.77 (d, J = 6.4 Hz, 3 H), 1.98
(ddd, J = 7.7, 13.5, 15.4 Hz, 1 H), 2.26 (m, 1 H), 2.37 (ddd, J = 1.9,
6.9, 13.5 Hz, 1 H), 2.71 (dd, J = 3.3, 12.0 Hz, 1 H), 2.85 (m, 1 H),
3.75 (m, 2 H), 3.86 (s, 1 H), 3.95 (s, 1 H), 4.16 (td, J = 5.3, 10.7 Hz,
1 H), 5.14 (dd, J = 1.9, 7.7 Hz, 1 H), 5.34 (dd, J = 1.6, 3.3 Hz, 1 H),
IR (CDCl3): 2925, 2866, 1548, 1491, 1452, 1366, 1126, 1079, 971,
872, 756, 698 cm–1.
1H NMR (600 MHz, CDCl3): δ = 0.96 (t, J = 7.4 Hz, 3 H), 1.44 (m,
2 H), 1.65 (m, 4 H), 1.99 (ddd, J = 8.4, 13.2, 16.7 Hz, 1 H), 2.13 (m,
2 H), 2.44 (ddd, J = 1.4, 6.5, 13.2 Hz, 1 H), 2.71 (m, 1 H), 2.96 (m,
Synthesis 2012, 44, 2107–2113
© Georg Thieme Verlag Stuttgart · New York

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Asymmetric Synthesis of Hexahydro-3H-isochromenes
2111
1 H), 3.05 (dd, J = 3.3, 12.0 Hz, 1 H), 3.55 (td, J = 6.7, 9.3 Hz,
1 H), 3.94 (m, 2 H), 5.05 (dd, J = 1.4, 8.4 Hz, 1 H), 5.31 (dd,
J = 2.1, 3.3 Hz, 1 H), 6.34 (s, 1 H), 7.10 (m, 2 H), 7.28 (m, 9 H),
7.40 (m, 4 H).
13C NMR (150 MHz, CDCl3): δ = 13.9, 15.3, 19.3, 28.8, 31.8, 33.1,
33.6, 38.3, 45.5, 46.8, 68.9, 80.9, 89.6, 93.3, 99.5, 109.9, 123.6,
127.2 (2C), 127.3, 127.6, 127.8, 128.2 (2C), 128.4 (2C), 129.0 (2C),
129.1 (2C), 131.4 (2xC), 138.3, 139.5, 140.9.
References
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MS (EI): m/z = 488 [M – HNO2]+.
HRMS (EI): m/z [M + H]+ calcd for C35H37NO4: 536.2795; found:
536.2799.
3-(Ethylthio)hexahydro-3H-isochromene (1g)
The synthesis followed GP 2 to give the main diastereomer.
Yield: 100 mg (78%); colorless crystals; mp 144 °C; ee >99%;
Rf = 0.28 (pentane–Et2O, 20:1); [α]D24 –21.4 (c 0.8, CHCl3).
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IR (CDCl3): 3020, 2970, 2906, 2873, 1660, 1548, 1450, 1369, 1221,
1128, 758, 707, 544 cm–1.
1H NMR (600 MHz, CDCl3): δ = 0.72 (d, J = 6.3 Hz, 3 H), 1.29 (t,
J = 7.4 Hz, 3 H), 1.91 (m, 1 H), 2.31 (m, 1 H), 2.47 (ddd, J = 1.7,
6.7, 13.3 Hz, 1 H), 2.56 (m, 1 H), 2.65 (dd, J = 3.5, 12.1 Hz, 1 H),
2.75 (m, 2 H), 3.87 (s, 1 H), 5.09 (dd, J = 1.7, 11.2 Hz, 1 H), 5.21
(dd, J = 1.8, 3.5 Hz, 1 H), 6.36 (d, J = 1.5 Hz, 1 H), 6.97 (m, 2 H),
7.18 (m, 3 H), 7.26 (m, 1 H), 7.37 (m, 4 H).
13C NMR (150 MHz, CDCl3): δ = 15.2, 18.0, 24.4, 34.9, 35.2, 37.9,
46.8, 47.8, 80.6, 93.0, 109.6, 127.2 (2C), 127.3, 127.6, 128.1 (2C),
128.9 (2C), 129.1 (2C), 138.5, 139.5, 143.1.
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MS (EI): m/z = 409 [M]+.
HRMS (EI): m/z [M + Na]+ calcd for C24H27NO3S: 432.1604;
found: 432.1600.
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3-(Phenylthio)hexahydro-3H-isochromene (1h)
The synthesis followed GP 2 to give the main diastereomer.
Yield: 70 mg (49%); colorless solid; mp 69 °C; ee >99%; Rf = 0.22
(pentane–Et2O, 20:1); [α]D24 –10.4 (c 2.2, CHCl3).
IR (CDCl3): 3555, 3363, 2923, 2861, 1660, 1552, 1461, 1125, 735,
487 cm–1.
1H NMR (600 MHz, CDCl3): δ = 0.72 (d, J = 6.3 Hz, 3 H), 1.93
(ddd, J = 11.2, 13.3, 21.2 Hz, 1 H), 2.33 (m, 1 H), 2.56 (m, 2 H),
2.64 (dd, J = 3.4z, 12.1 Hz, 1 H), 3.87 (s, 1 H), 5.20 (dd, J = 1.7,
3.4 Hz, 1 H), 5.29 (dd, J = 1.8, 11.2 Hz, 1 H), 6.36 (d, J = 1.5 Hz,
1 H), 6.97 (m, 2 H), 7.22 (m, 8 H), 7.34 (m, 3 H), 7.53 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 18.0, 34.9, 35.0, 37.8, 46.8, 47.8,
83.3, 93.0, 109.7, 127.2 (2C), 127.3, 127.6, 127.9, 128.1 (2C), 128.9
(2C), 129.0 (2C), 129.1 (2C), 132.4 (2C), 133.1, 138.5, 139.3,
142.9.
MS (EI): m/z = 410 [M – HNO2]+.
HRMS (EI): m/z [M + Na]+ calcd for C28H27NO3S: 480.1604;
found: 480.1603.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
(Priority Program Organocatalysis) and the Fonds der Chemischen
Industrie (Kekulé stipend to N.E.). We thank the former Degussa
AG and BASF SE for the donation of chemicals, as well as Peter
Becker for his experimental help.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2107–2113

2112
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Synthesis 2012, 44, 2107–2113
© Georg Thieme Verlag Stuttgart · New York

PAPER
Asymmetric Synthesis of Hexahydro-3H-isochromenes
2113
(17) Crystallographic data for 1c reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication no. CCDC 876519. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk].
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Angew. Chem. Int. Ed. 2005, 44, 794; Angew. Chem. 2005,
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www.ccdc.cam.ac.uk/data_request/cif or on application to
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2107–2113