Asymmetric synthesis of functionalized chromans via a one-pot organocatalytic domino Michael-hemiacetalization or -lactonization and dehydration sequence

Article abstract of DOI:10.1055/s-0031-1289683

Starting from 2-(nitrovinyl)phenols and various cyclic dicarbonyl nucleophiles, a one-pot thiourea-catalyzed diastereo- and enantioselective synthesis of polyfunctionalized chroman derivatives via a domino Michael-hemiacetalization and dehydration sequence as well as via a domino Michael-lactonization reaction is reported. Cyclopenta[b]chromenes, tricyclic spirochromans, and tetrahydro-1H-xanthenes bearing a variety of functional groups can be synthesized in this way in good to excellent yields (56-91%) and with very good diastereo- (88-99%de) and enantioselectivities (83-99% ee). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289683

PAPER
773
Asymmetric Synthesis of Functionalized Chromans via a One-Pot
Organocatalytic Domino Michael–Hemiacetalization or –Lactonization and
Dehydration Sequence
Asymmetric
O
rga
n
i
ocataly
e
tic Synthe
t
C
e
hromans r Enders,* Gregor Urbanietz, Robert Hahn, Gerhard Raabe
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092127; E-mail: enders@rwth-aachen.de
Received 20 December 2011
of these oxygen-containing heterocycles, (nitrovinyl)phe-
Abstract: Starting from 2-(nitrovinyl)phenols and various cyclic
dicarbonyl nucleophiles, a one-pot thiourea-catalyzed diastereo-
and enantioselective synthesis of polyfunctionalized chroman de-
rivatives via a domino Michael–hemiacetalization and dehydration
nols are important starting materials. During our investi-
gations of new reactive species for developing new
organocatalytic cascade reactions, we decided to expand
sequence as well as via a domino Michael–lactonization reaction is the potential ability of 2-(2-nitrovinyl)phenols 1 to partic-
reported. Cyclopenta[b]chromenes, tricyclic spirochromans, and
tetrahydro-1H-xanthenes bearing a variety of functional groups can
be synthesized in this way in good to excellent yields (56–91%) and
philes like cyclic b-keto esters 2 as well as cyclic 1,3-
with very good diastereo- (88–99% de) and enantioselectivities
(83–99% ee).
ipate in the thiourea amine-catalyzed domino Michael–
hemiacetalization reaction4 with easily enolizable nucleo-
diketones 3,4. Quite recently, we have developed a novel
bifunctional thiourea catalyst, which promotes the asym-
Key words: organocatalysis, domino reaction, thiourea, one-pot re-
metric Michael addition of acyclic b-keto esters to (nitro-
action, chromans
vinyl)phenols as well as nitrostryrenes with great
efficiency. On the basis of this observation we envisaged
that polycyclic chromanols, versatile intermediates to
complex chromenes, spirochromans and tetrahydro-1H-
In recent years, great progress has been made in the asym-
metric organocatalytic synthesis of stereochemically de-
xanthenes, could be generated by Michael addition and
fined complex molecular structures via the concept of
subsequent intramolecular hemiacetalization if 2-(2-nitro-
multi-component domino reactions.1 Owing to the impor-
vinyl)phenol served as substrate. The phenolic hydroxy
tance of the benzopyran framework, its construction has
group participates in this process through carbonyl addi-
attracted considerable attention, and various synthetic
tion and makes this sequence a powerful tool among the
methods have been reported.2 Chiral benzopyrans repre-
existing annulation methodologies. Hemiacetals can be
sent a privileged structural motif that is found in a range
subsequently transformed into many useful chroman core
of natural products and drug candidates with broad bio-
structures. However, different pathways are possible if
prochiral nucleophiles bear more than one carbonyl group
logical implications (Figure 1).3
Thus, it is crucial to develop asymmetric strategies to con-
struct highly enantioenriched scaffolds like dihydrocou-
marins and chromenes. For the stereoselective synthesis
and thus the chemoselectivity of the reaction becomes an
important issue. Cyclization would either afford
chromenes or xanthenes 5, 6, and 9 or spiranes 7 and 8 as
shown in Scheme 1. Herein, we report our findings re-
garding these sequential one-pot reactions.
The studies of the domino Michael–hemiacetalization re-
actions were started by screening the organocatalysts A,
B, and C for the Michael reaction of 2-(2-nitrovi-
nyl)phenol5 (1a) with one equivalent of methyl 2-oxocy-
clopentanecarboxylate (2a). The intermediate chromanol
10a was directly dehydrated to the tetrahydrocyclopen-
ta[b]chromenecarboxylate 5a in a one-pot procedure (see
Table 1). It turned out that 300 mol% P2O5 in dichlo-
romethane at –25 °C for two days is the best reaction con-
dition for the dehydration process, which succeeded in
good yields and no lactonization occurred.
i-Pr
O
O
H
H
O
O
O
i-Pr
O
O
O
O
O
carpanone
rhodomyrthone
HO2C
OH
F
n
O
aldose reductase inhibitors (ARI's)
While the ephedrine derived catalyst A showed excellent
stereoselectivities for acyclic b-keto esters2b in toluene,
low enantioselectivities were obtained when methyl 2-
oxocyclopentanecarboxylate (2a) was used as nucleophile
(Table 1, entry 1). The diastereo- and enantioselectivity
could be improved slightly by using Takemoto’s catalyst
Figure 1 Natural product and bioactive compounds with chroman
and chromene cores
SYNTHESIS 2012, 44, 773–782
x
x
.x
x
.2
0
1
1
Advanced online publication: 30.01.2012
DOI: 10.1055/s-0031-1289683; Art ID: Z116911SS
© Georg Thieme Verlag Stuttgart · New York

774
D. Enders et al.
PAPER
O2N
O
n
R1
R3
R3
O
6
O2N
O
O2N
O
CO2R2
R2
n
R2
R1
R1
R3
R3
OR2
n
O
O
9
O
5
4
O
O
n
O
O
NO2
2
3
O2N
O2N
O
R1
O
OH
n
1
R1
R1
R2
O
O
O
7
8
Scheme 1 Domino Michael–hemiacetalization or –lactonization and dehydration sequences to tricyclic chroman scaffolds
Table 1 Optimization of Conditions for the Domino Michael-Hemiacetalization and Subsequent Dehydration Sequence
(one pot)
O2N
O2N
NO2
+
CO2Me
OH
CO2Me
cat. (10 mol%)
solvent
P2O5 (300 mol%)
–25 °C, 2 d
MeO2C
O
– H2O
O
O
OH
5a
1a
2a
10a
N
CF3
CF3
CF3
S
Ph
S
S
OMe
F3C
N
N
F3C
N
H
N
H
F3C
N
N
H
H
H
H
N
NMe2
N
B
C
A
Entrya
Catalyst
Solvent
PhMe
PhMe
PhMe
PhMe
PhMe
CH2Cl2
THF
Temp (°C)
Time (h)
Yield (%)b
de (%)c
84
ee (%)d
77 (58)
80 (27)e
93 (67)
86 (50)
86 (8)
1
2
3
4
5
6
7
8f
A
B
C
C
C
C
C
C
r.t.
r.t.
r.t.
5
7
7
76
71
81
84
86
74
72
77
86
7
99
16
48
9
92
–25
r.t.
r.t.
r.t.
93
89
92 (79)
91 (87)
76 (56)
9
94
PhMe
48
87
a All reactions were performed on a 1.0 mmol scale.
b Yield of isolated product 5a.
c Determined by HPLC analysis on a chiral stationary phase.
d The enantiomeric excess of the minor diastereomer is given in parentheses.
e The opposite enantiomer ent-5a was obtained.
f The reaction was performed with 5 mol% catalyst loading.
Synthesis 2012, 44, 773–782
© Thieme Stuttgart · New York

PAPER
Asymmetric Organocatalytic Synthesis of Chromans
775
B,6 but still did not give satisfactory asymmetric induc- In order to determine the scope of the organocatalytic
tions (Table 1, entry 2). In contrast to catalyst A the oppo- domino dehydration one-pot reaction, the cyclic carbonyl
site enantiomer was obtained with catalyst B. While containing nucleophiles 2–4 were tested. A series of sub-
catalyst A and B showed moderate to good diastereo- and stituted (nitrovinyl)phenols 1a–e were reacted with
enantioselectivity, the quinine thiourea catalyst C7 led to one equivalent of cyclic b-keto esters 2a–d or with one
the best stereoselectivity (Table 1, entry 3). With a suit- equivalent of cyclic 1,3-diketones 4a–d in the presence of
able catalyst in hand, we tried to improve the stereoselec- 10 mol% of catalyst C at ambient temperature in toluene
tivity as well as the yield of the reaction by decreasing the followed by dehydration of the crude products with P2O5
temperature. The domino Michael–hemiacetalization re- in dichloromethane. The tricyclic products 5a–h and 6a–
action proceeds at 5 °C as well as at –25 °C (Table 1, en- d were obtained in good yields and stereoselectivities
tries 4, 5). While decreasing the temperature to –25 °C or (Table 2). Electronic factors had little influence: both,
+5 °C results in a slight decrease in enantioselectivity, the neutral and electron-withdrawing group substituted 2-(2-
diastereoselectivity and yield could be improved, yet nitrovinyl)phenols 1a–e led to the expected products in
longer reaction times were necessary. Therefore, it was good yields (72–86%) and stereoselectivities (83–99%
decided to change the catalyst loading from 10 mol% to 5 ee). While with five-membered nucleophiles 2a,b
mol% at ambient temperature. The selectivity decreased cyclopenta[b]chromenes 5a–f were obtained, the six-
while the loading did not have an effect on the yield membered nucleophiles 2c,d afforded tetrahydro-1H-xan-
(Table 1, entry 8). Next, solvents like dichloromethane thenes 5g,h in moderate yields (61–62%) but with good
and THF were examined in the domino Michael–hemi- enantioselectivities (83–88%). In the case of cyclic 1,3-
acetalization reaction of 1a and 2a, which had no big im- diketones 4a–c as nucleophiles the dehydration occurred
pact on yield, reaction time, and selectivity (Table 1, regioselective to tetrahydro-1H-xanthen-1-ones 6b,c or
entries 6, 7). It turned out that the bulky quinine motif at- 2,3-dihydrocyclopenta[b]chromen-1(9H)-one 6a depend-
tached to the 3,5-bis(trifluoromethyl)phenylthiourea moi- ing on the ring size bearing one stereogenic center. The
ety is the best catalyst for the addition of cyclic b-keto absolute configuration was determined by X-ray crystal
esters to (nitrovinyl)phenols and afforded after dehydra- structure analysis in the case of 5d (Figure 2).
tion tricyclic derivatives of the chroman skeleton with two
adjacent stereocenters, one being an all carbon quarterna-
ry center.
Using cyclic prochiral 1,3-diketones like 3a (R2 = H), 3b
(R2 = Me) as nucleophiles, two possibilities for the in-
tramolecular hemiacetalization exist. Either the acyclic or
the cyclic carbonyl group might react followed by dehy-
Table 2 Scope of the Asymmetric Synthesis of Chroman Derivatives via One-Pot Domino Michael–Hemiacetalization and Dehydrationa
Product
5a
R1
R2
Me
Me
Me
Me
Me
Et
R3
–
n
1
1
1
1
1
1
2
2
0
1
1
1
1
Time (h)
Yield (%)b
de (%)c
99
90
92
91
97
88
99
95
–
ee (%)d,e
93 (67)
96 (73)
90 (67)
89 (2)
99 (99)
96 (48)
83
H
7
5
81
86
83
78
72
88
61
62
64
61
55
76
71
5b
2-OMe
–
5c
3-Me
–
8
5d
4-Br
–
6
5e
4-Br-2-OMe
–
5
5f
H
H
H
H
H
H
H
H
–
7
5gf
5hf
6a
Me
Et
–
24
24
12
16
16
5
–
88 (47)
99
–
H
H
Me
–
6b
–
–
89
6c
–
–
95
8a
H
98
99
93 (43)
91
8b
Me
–
5
a All reactions were performed on a 1.0 mmol scale with catalyst C.
b Yield of isolated product.
c Determined by HPLC analysis.
d Determined by HPLC analysis on a chiral stationary phase.
e The enantiomeric excess of the minor diastereomer is given in parentheses.
f The reaction was performed without any solvent.
© Thieme Stuttgart · New York
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776
D. Enders et al.
PAPER
dration. In fact, the less hindered exocyclic carbonyl showed that the cyclopentane moiety is exclusively cis-
group reacted chemoselectively and after dehydration an annulated. A lactonization could be observed when 10
exocyclic double bond was generated (Table 2, product was treated with 20 mol% PTSA in toluene for two hours
8a). In the case of 3b under thermodynamic control the at 100 °C. Compound 11 was isolated in very good yield
corresponding E-enol ether could be isolated (Table 2, (88%) and with virtually complete diastereo- and enantio-
product 8b). In addition, changing the reaction conditions selectivity (de, ee = 99%).
to protic acids (20 mol% PTSA in toluene) resulted in no
The various transformations performed with the hemiace-
change in chemoselectivity. Only with 2a the reaction
tal 10a underpin the stereochemical outcome of the
conditions had a significant effect on the reaction pathway
Michael reaction. In the case of the addition of 1a to 2a,
we can rationalize the observed configuration through a
favored transition state where 2a approaches 1a from the
Si face. The anti- configuration of the nitro methyl group
between the Michael–hemiacetalization–dehydration se-
quence and the Michael–lactonization cascade. In con-
trast, the six-membered cyclic b-keto esters gave only
xanthenes and no lactonization occurred as observed with
and the methyl ester group can be explained by their steric
the five-membered cyclic b-keto ester 2a by varying the
demand. A potentially favorable electrostatic interaction
between the partially positive nitro group and the partially
negative hydroxy group could not be detected. In all cases
reaction conditions between P2O5 and PTSA (not shown
in Table 2).
Next, the follow-up reactions of the intermediate Michael a cis-configuration of the cyclopentane moiety was ob-
adduct 10 were investigated to emphasize the value of this served. 1,3-Diaxial interactions may explain the favored
approach, for example, towards the synthesis of bioactive diastereoselectivity.
compounds such as pharmaceuticals. It is well known that
In conclusion, we have developed diastereo- and enanti-
the hemiacetal unit can be oxidized, reduced, methylated,
oselective one-pot reactions producing polyfunctional-
or dehydrated to the corresponding chroman derivatives.
ized chromans by employing a thiourea-catalyzed domino
A dynamic equilibrium in CDCl3 (3:2) was observed be-
Michael–hemiacetalization reaction. Subsequent transfor-
mations of the intermediate chromanols gave acetals, lac-
tween the hemiacetal 10a and the hydroxy ketone 10b
(Scheme 2). The relative configuration of 10 was deter-
tones, and hexahydrocyclopenta[b]chromenes bearing up
mined by NOE measurements, showing the cyclopentane
to three contiguous stereocenters. The title compounds are
important heterocycles due to their widespread occur-
moiety exclusively in the cis-configuration. By treatment
with 20 mol% PTSA in methanol for eight hours at room
rence in nature and as privileged scaffolds in medicinal
temperature, 10 was converted into the acetal 13 in mod-
chemistry. They were obtained in good to excellent yields
erate yield (56%), however, with excellent diastereomeric
of 56–88% and enantiomeric excess values of 83–99% ee.
(93%) and enantiomeric excess (92%/70%). The high ste-
In addition, our protocol allows for the introduction of
reoselectivity of our approach is evident from the fact that
several functional groups, such as the nitromethyl, ester,
only two diastereomers are formed while building up
and keto groups as well as double bonds and various sub-
three contiguous stereocenters, two of which are quaterna-
stituents at the aromatic ring.
ry. The intermediate 10 could be reduced to 12 with
three equivalents of HSiEt3 in dichloromethane at –78 °C
Starting materials and reagents were purchased from commercial
in moderate yield (62%) and again with excellent diaste-
suppliers and used without further purification, unless stated other-
wise. All solvents were dried by conventional methods. Preparative
column chromatography: Merck silica gel 60, particle size 0.040–
reo- (88% de) and enantioselectivity (99%/94% ee). The
configuration was determined by NOE measurements and
0.063 mm (230–240 mesh, flash). Analytical TLC: silica gel 60
F254 plates from Merck, Darmstadt. Visualization of the developed
TLC plates was performed by ultraviolet irradiation (254 nm) or by
staining with a solution of KMnO4. Analytical HPLC was carried
out on a Hewlett-Packard 1100 Series instrument using chiral sta-
1
tionary phases. H and 13C NMR spectra were recorded at r.t. on
Varian Mercury 300, Varian Inova 400, or Varian Inova 600 instru-
ment. Mass spectra were acquired on a Finnigan SSQ7000 (EI 70
eV) spectrometer, high-resolution mass spectra on a Finnigan MAT
95, and high-resolution ESI spectra on a Thermo Fisher Scientific
LTQ-Orbitrap XL. IR spectra were recorded on a Perkin-Elmer 100
FT-IR Spectrum instrument. Microanalyses were performed with a
Vario EL element analyzer. Melting points were determined with a
Büchi melting point B-540 apparatus. Optical rotation values were
measured on a Perkin-Elmer 241 polarimeter.
One-Pot Domino Michael-Hemiacetalization and Dehydration
Reaction; General Procedure
In a glass vial equipped with a magnetic stirring bar, catalyst C
(10 mol%) was added to a mixture of cyclic b-keto ester 2, or 1,3-
diketones 3, 4 (1.0 mmol, 1.0 equiv) and (E)-2-(2-nitrovinyl)phenol
Figure 2 X-ray crystal structure of (9R,9aS)-5d8
Synthesis 2012, 44, 773–782
1 (1.0 mmol, 1 equiv) in toluene (6.0 mL per mmol) at r.t. The reac-
© Thieme Stuttgart · New York

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Asymmetric Organocatalytic Synthesis of Chromans
777
N
CF3
OMe
S
N
N
H
N
H
F3C
N
H
O
O
O
O
OMe
HO
2a
1a
98%
O2N
O
MeO2C
CO2Me
OH
NO2
OH
O
10b
10a
PTSA (0.2 equiv)
MeOH
r.t., 8 h
PTSA (0.2 equiv)
PhMe
100 °C, 2 h
HSiEt3 (3 equiv)
CH2Cl2
–78 °C, 6 h
O2N
O2N
O2N
CO2Me
CO2Me
O
O
O
O
O
OMe
11
88%
de = 99%
ee = 97%
12
62%
de = 88%
ee = 99%
13
56%
de = 93%
ee = 92%
Scheme 2 Various transformations of chromanol 10
tion was monitored by TLC (eluent: n-pentane–Et2O, 1:1). After
complete conversion of the starting material, the solvent was evap-
orated and CH2Cl2 (6 mL per mmol) and P2O5 (3.0 mmol, 3 equiv)
were added and stirred for 2 d at –25 °C. After completion of the re-
action, the crude reaction mixture was filtered through a small plug
of silica gel. Products 5, 6, and 8 were isolated after column chro-
matography as pale yellow to colorless solids (Table 2).
1H NMR (400 MHz, CDCl3): d = 1.97–2.06 (m, 1 H, CH2), 2.20–
2.33 (m, 2 H, CH2), 2.44 (dddd, J = 2.0, 6.7, 9.0, 15.8 Hz, 1 H, CH2),
3.49 (s, 3 H, CH3), 4.18 (dd, J = 8.3, 12.3 Hz, 1 H, CH2), 4.26 (dd,
J = 6.0, 8.3 Hz, 1 H, CH), 4.60 (dd, J = 6.0, 12.3 Hz, 1 H, CH2), 5.32
(dd, J = 2.3, 2.7 Hz, 1 H, CHarom), 6.85–6.90 (m, 2 H, CHarom), 7.00–
7.04 (m, 1 H, CHarom), 7.13–7.18 (m, 1 H, CHarom).
13C NMR (100 MHz, CDCl3): d = 25.8 (CH2), 30.1 (CH2), 40.3
(CH), 52.8 (CH3), 54.5 (C), 77.8 (CH2), 106.0 (CHolef), 116.7
(CHarom), 120.5 (Carom), 122.7 (CHarom), 129.8 (CHarom), 129.9
(CHarom), 148.5 (CaromO), 151.9 (ColefO), 172.9 (CO2Me).
Methyl (9R,9aS)-9-(Nitromethyl)-1,2,9,9a-tetrahydrocyclopen-
ta[b]chromene-9a-carboxylate (5a)
Compound 5a was synthesized according to the general procedure
to yield 234 mg (81%) of a colorless solid; mp 158 °C; Rf = 0.26 (n-
pentane–Et2O, 4:1); [a]D20 –85.0 (c 1.0, CHCl3); ee (major) = 93%,
ee (minor) = 67%; de = 99%. The enantiomeric excess was deter-
mined by chiral stationary phase HPLC using a Chiralcel AD col-
umn [n-heptane–EtOH (98:2), flow rate 0.5 mL/min, l = 254 nm],
tR = 22.79 min (major), tR = 24.95 min (minor), tR = 19.61 min (ma-
jor), tR = 29.22 min (minor).
MS (EI, 70 eV): m/z (%) = 289 ([M+], 26), 242 (10), 184 (24), 183
(100), 169 (26).
Anal. Calcd for C15H15NO5: C, 62.28; H, 5.23; N, 4.84. Found: C,
62.28; H, 5.28; N, 4.90.
Methyl (9R,9aS)-5-Methoxy-9-(nitromethyl)-1,2,9,9a-tetrahy-
drocyclopenta[b]chromene-9a-carboxylate (5b)
Compound 5b was synthesized according to the general procedure
to yield 274 mg (86%) of a colorless solid; mp 183 °C; Rf = 0.40 (n-
pentane–Et2O, 1:1); [a]D20 –71.3 (c 1.0, CHCl3); ee (major) = 96%,
ee (minor) = 73%; de = 90%. The enantiomeric excess was deter-
IR (film): 2964, 2923, 2864, 1723, 1676, 1606, 1550, 1478, 1453,
1377, 1353, 1277, 1227, 1176, 1112, 1032, 984, 905, 863, 803, 764,
662 cm–1.
© Thieme Stuttgart · New York
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D. Enders et al.
PAPER
mined by chiral stationary phase HPLC using a Chiralcel AS col-
umn [n-heptane–i-PrOH (9:1), flow rate 1.0 mL/min, l = 254 nm],
tR = 12.86 min (major), tR = 17.48 min (minor), tR = 11.31 min (ma-
jor), tR = 10.28 min (minor).
1 H, CHolef), 6.82 (d, J = 8.6 Hz, 1 H, CHarom), 7.22–7.26 (m, 1 H,
CHarom), 7.30–7.34 (m, 1 H, CHarom).
13C NMR (100 MHz, CDCl3): d = 25.9 (CH2), 30.1 (CH2), 40.0
(CH), 53.0 (CH3), 54.3 (Cq), 77.4 (CH2), 106.9 (CHolef), 114.9
(Carom), 118.5 (CHarom), 122.7 (Carom), 132.3 (CHarom), 132.9
(CHarom), 148.0 (CaromO), 151.0 (ColefO), 172.6 (CO2CH3).
IR (film): 2965, 2933, 2867, 1716, 1678, 1585, 1549, 1477, 1436,
1376, 1351, 1322, 1214, 1079, 983, 894, 847, 776, 733 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.99–2.11 (m, 1 H, CH2), 2.24–
2.38 (m, 2 H, CH2), 2.45–2.56 (m, 1 H, CH2), 3.55 (s, 3 H, CH3),
3.86 (s, 3 H, OCH3), 4.23 (dd, J = 8.3, 12.3 Hz, 1 H, CH2), 4.32 (dd,
J = 6.0, 8.3 Hz, 1 H, CH), 4.64 (dd, J = 6.0, 12.3 Hz, 1 H, CH2), 5.49
(dd, J = 2.3, 2.3 Hz, 1 H, CHolef), 6.66–6.70 (m, 2 H, CHarom), 6.79–
6.83 (m, 1 H, CHarom), 6.85–6.91 (m, 1 H, CHarom).
13C NMR (100 MHz, CDCl3): d = 25.9 (CH2), 30.2 (CH2), 40.3
(CH), 52.8 (CH3), 54.5 (Cq), 56.0 (CH3), 77.7 (CH2), 106.9 (CHolef),
111.9 (CHarom), 121.2 (CHarom), 121.5 (C), 122.6 (CHarom), 141.3
(Carom), 147.8 (CaromO), 148.2 (ColefO), 172.9 (CO2Me).
MS (EI, 70 eV): m/z (%) = 369 ([M+], 70), 367 (76), 322 (22), 263
(100), 249 (17), 182 (23), 124 (15).
Anal. Calcd for C15H14BrNO5: C, 48.93; H, 3.83; N, 3.80. Found: C,
49.15; H, 3.66; N, 3.74.
Methyl (9R,9aS)-7-Bromo-5-methoxy-9-(nitromethyl)-1,2,9,9a-
tetrahydrocyclopenta[b]chromene-9a-carboxylate (5e)
Compound 5e was synthesized according to the general procedure
to yield 286 mg (72%) of a colorless solid; mp 127 °C; Rf = 0.43 (n-
pentane–Et2O, 1:1); [a]D20 –38.4 (c 1.0, CHCl3); ee (major) = 99%,
ee (minor) = 99%; de = 97%. The enantiomeric excess was deter-
mined by chiral stationary phase HPLC using a Chiralcel OD col-
umn [n-heptane–i-PrOH (95:5), flow rate 0.7 mL/min, l = 254 nm],
tR = 25.23 min (major), tR = 22.66 min (minor), tR = 28.80 min (ma-
jor), tR = 34.79 min (minor).
MS (EI, 70 eV): m/z (%) = 319.1 ([M+], 61), 272.1 (10), 213.1
(100), 199.1 (26), 153.1 (10), 128.1 (10).
HRMS: m/z calcd for C16H17NO6: 320.1125; found: 320.1129.
Methyl (9R,9aS)-6-Methyl-9-(nitromethyl)-1,2,9,9a-tetrahy-
drocyclopenta[b]chromene-9a-carboxylate (5c)
IR (film): 3097, 2949, 2860, 1725, 1685, 1552, 1478, 1433, 1378,
1348, 1319, 1215, 1174, 1109, 1081, 1033, 980, 899, 846, 798, 672
cm–1.
1H NMR (400 MHz, CDCl3): d = 1.98–2.08 (m, 1 H, CH2), 2.24–
2.39 (m, 2 H, CH2), 2.46–2.46 (m, 1 H, CH2), 3.58 (s, 3 H, CH3),
3.84 (s, 3 H, OCH3), 4.22 (dd, J = 7.6, 12.9 Hz, 1 H, CH2),), 4.29
(dd, J = 7.6, 6.0 Hz, 1 H, CH), 4.61 (dd, J = 6.0, 12.9 Hz, 1 H, CH2),
5.50 (dd, J = 2.3, 2.3 Hz, 1 H, CHolef), 6.84 (d, J = 2.0 Hz, 1 H,
CHarom), 6.90 (d, J = 2.0 Hz, 1 H, CHarom).
Compound 5c was synthesized according to the general procedure
to yield 252 mg (83%) of a colorless solid; mp 131 °C; Rf = 0.42 (n-
pentane–Et2O, 2:1); [a]D20 –64.4 (c 1.0, CHCl3); ee (major) = 90%,
ee (minor) = 67%; de = 92%. The enantiomeric excess was deter-
mined by chiral stationary phase HPLC using a Chiralcel AD col-
umn [n-heptane–i-PrOH (95:5), flow rate 0.5 mL/min, l = 254 nm],
tR = 16.92 min (major), tR = 20.36 min (minor), tR = 18.02 min (ma-
jor), tR = 14.58 min (minor).
IR (film): 2958, 2919, 2861, 1725, 1677, 1619, 1585, 1503, 1430,
1377, 1345, 1306, 1250, 1163, 1123, 1074, 940, 806, 674 cm–1.
13C NMR (100 MHz, CDCl3): d = 25.9 (CH2), 30.2 (CH2), 40.0
(CH), 53.0 (CH3), 54.2 (Cq), 56.3 (CH3), 77.4 (CH2), 107.6 (CHolef),
115.4 (CHarom), 123.0 (Carom), 123.6 (CHarom), 128.3 (Carom), 140.7
(Carom), 147.7 (CaromO), 148.4 (ColefO), 172.6 (CO2Me).
MS (EI, 70 eV): m/z (%) = 397 ([M+], 100), 352 (16), 350 (17), 337
(10), 293 (94), 291 (97), 279 (22), 212 (19), 197 (13), 168 (10), 141
(11).
1H NMR (400 MHz, CDCl3,): d = 1.95–2.05 (m, 1 H, CH2), 2.21 (s,
3 H, CH3), 2.16–2.32 (m, 2 H, CH2), 2.36–2.48 (m, 1 H, CH2), 3.50
(s, 3 H, CH3), 4.16 (dd, J = 8.3, 11.6 Hz, 1 H, CH2), 4.21 (dd,
J = 5.3, 8.3 Hz, 1 H, CH), 4.58 (dd, J = 5.3, 11.6 Hz, 1 H, CH2), 5.49
(dd, J = 2.3, 2.7 Hz, 1 H, CHolef), 6.65–6.70 (m, 2 H, CHarom), 6.85–
6.90 (m, 1 H, CHarom).
13C NMR (100 MHz, CDCl3,): d = 21.0 (CH3), 25.8 (CH2), 30.0
(CH2), 40.0 (CH), 52.8 (CH3), 54.6 (Cq), 77.9 (CH2), 105.8 (CHolef),
117.1 (Carom), 117.4 (CHarom), 123.7 (CHarom), 129.4 (CHarom), 140.2
(Carom), 148.7 (CaromO), 151.7 (ColefO), 173.0 (CO2Me).
HRMS: m/z calcd for C16H16BrNO6: 398.0234; found: 398.0234.
Ethyl (9R,9aS)-9-(Nitromethyl)-1,2,9,9a-tetrahydrocyclopen-
ta[b]chromene-9a-carboxylate (5f)
Compound 5f was synthesized according to the general procedure
to yield 267 mg (88%) of a colorless solid; mp 91 °C; Rf = 0.32 (n-
pentane–Et2O, 4:1); [a]D20 –24.0 (c 0.5, CHCl3); ee (major) = 96%,
ee (minor) = 48%; de = 88%. The enantiomeric excess was deter-
mined by chiral stationary phase HPLC using a Chiralcel OD col-
umn [n-heptane–i-PrOH (97:3), flow rate 0.5 mL/min, l = 254 nm],
tR = 24.43 min (major), tR = 44.37 min (minor), tR = 19.70 min (ma-
jor), tR = 22.07 min (minor).
MS (EI, 70 eV): m/z (%) = 303 ([M+], 39), 256 (20), 213 (100), 197
(100), 183 (25), 115 (14).
HRMS: m/z calcd for C16H17NO5: 304.1180; found: 304.1179.
Methyl (9R,9aS)-7-Bromo-9-(nitromethyl)-1,2,9,9a-tetrahydro-
cyclopenta[b]chromene-9a-carboxylate (5d)
Compound 5d was synthesized according to the general procedure
to yield 387 mg (78%) of a colorless solid; mp 125 °C; Rf = 0.36 (n-
pentane–Et2O, 2:1); [a]D20 –62.4 (c 1.0, CHCl3); ee (major) = 89%,
ee (minor) = 2%; de = 91%. The enantiomeric excess was deter-
mined by chiral stationary phase HPLC using a Chiralcel OD col-
umn [n-heptane–i-PrOH (9:1), flow rate 0.5 mL/min, l = 254 nm],
tR = 18.91 min (major), tR = 21.16 min (minor), tR = 28.08 min (ma-
jor), tR = 32.31 min (minor).
IR (film): 2989, 2942, 2868, 1723, 1678, 1609, 1549, 1484, 1453,
1367, 1297, 1250, 1220, 1175, 1114, 1092, 1050, 1008, 912, 861,
8014, 759, 664 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.95 (t, J = 6.7 Hz, 3 H, CH3),
1.92–2.11 (m, 1 H, CH2), 2.24–2.37 (m, 2 H, CH2), 2.42–2.55 (m, 1
H, CH2), 3.97 (m, 2 H, CH2), 4.22 (dd, J = 8.7, 11.3 Hz, 1 H, CH2),
4.25 (dd, J = 4.3, 8.7 Hz, 1 H, CH), 4.65 (dd, J = 4.3, 11.3 Hz, 1 H,
CH2), 5.35 (dd, J = 2.3, 2.3 Hz, 1 H, CHolef), 6.88–6.95 (m, 2 H,
CHarom), 7.02–7.08 (m, 1 H, CHarom), 7.17–7.23 (m, 1 H, CHarom).
13C NMR (100 MHz, CDCl3): d = 13.8 (CH3), 25.8 (CH2), 30.0
(CH2), 40.5 (CH), 54.6 (Cq), 61.5 (CH2), 77.8 (CH2), 105.6 (CHolef),
116.7 (CHarom), 120.6 (Carom), 122.6 (CHarom), 129.8 (CHarom), 129.9
(CHarom), 148.7 (CaromO), 152.0 (ColefO), 172.3 (CO2Et).
IR (film) 2956, 2921, 2864, 1729, 1678, 1560, 1471, 1435, 1380,
1349, 1274, 1229, 1176, 1121, 1083, 1030, 990, 921, 886, 820, 757,
723, 670 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.98–2.10 (m, 1 H, CH2), 2.24–
2.38 (m, 2 H, CH2), 2.42–2.53 (m, 1 H, CH2), 3.57 (s, 3 H, CH3),
4.23 (dd, J = 8.3, 12.3 Hz, 1 H, CH2), 4.28 (dd, J = 5.6, 8.3 Hz, 1 H,
CH), 4.64 (dd, J = 5.6, 12.3 Hz, 1 H, CH2), 5.39 (dd, J = 2.3, 2.3 Hz,
Synthesis 2012, 44, 773–782
© Thieme Stuttgart · New York

PAPER
Asymmetric Organocatalytic Synthesis of Chromans
779
MS (EI, 70 eV): m/z (%) = 303 ([M+], 66), 256 (39), 183 (100), 169
(45).
HPLC using a Chiralcel AD column [n-heptane–EtOH (7:3), flow
rate 0.7 mL/min, l = 254 nm], tR = 14.45 min (major), tR = 18.68
min (minor).
HRMS: m/z calcd for C16H17NO5 + Na: 326.0999; found: 326.0998.
IR (film): 2929, 2853, 1695, 1649, 1577, 1534, 1487, 1432, 1387,
1248, 1160, 1122, 1022, 981, 839, 766, 682 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.55–2.62 (m, 2 H, CH2), 2.75–
2.85 (m, 2 H, CH2), 4.40 (m, 1 H, CH), 4.72 (dd, J = 3.7, 12.4 Hz,
1 H, CH2), 4.82 (dd, J = 5.5, 12.4 Hz, 1 H, CH2), 7.08–7.30 (m, 4 H,
CHarom).
13C NMR (75 MHz, CDCl3): d = 26.0 (CH2), 31.9 (CH), 33.6 (CH2),
81.1 (CH2), 118.0 (CHarom), 119.1 (Carom), 126.2 (CHarom), 129.0
(CHarom), 129.8 (CHarom), 151.2 (ColefO), 172.5 (ColefO), 181.0
(CaromO), 202.9 (C=O).
Methyl (9R,9aS)-9-(Nitromethyl)-2,3,9,9a-tetrahydro-1H-xan-
thene-9a-carboxylate (5g)
Compound 5g was synthesized according to the general procedure
to yield 184 mg (61%) of a colorless solid; mp 78 °C; Rf = 0.28 (n-
20
pentane–Et2O, 8:1); [a]D –69.4 (c 1.0, CHCl3); ee = 83%; de
>99%. The enantiomeric excess was determined by chiral stationary
phase HPLC using a Chiralcel OD column [n-heptane–i-
PrOH (7:3), flow rate 0.7 mL/min, l = 254 nm], tR = 7.48 min (ma-
jor), tR = 10.17 min (minor).
IR (film): 3009, 2933, 2860, 1727, 1684, 1553, 1485, 1455, 1380,
1279, 1237, 1149, 1119, 1098, 988, 847, 760, 693 cm–1.
MS (EI, 70 eV): m/z (%) = 198 ([M – HNO2]+, 100), 185 (39), 128
(13), 115 (10).
1H NMR (400 MHz, CDCl3): d = 1.46–1.80 (m, 3 H, 1.5 × CH2),
2.18–2.28 (m, 3 H, 1.5 × CH2), 3.50 (s, 3 H, CH3), 4.09 (dd, J = 5.9,
8.7 Hz, 1 H, CH2), 4.27 (dd, J = 8.7, 12.6 Hz, 1 H, CH2), 4.69 (dd,
J = 5.9, 12.6 Hz, 1 H, CH), 5.57 (dd, J = 4.0, 4.2 Hz, 1 H, CHolef),
6.84–6.93 (m, 2 H, CHarom), 6.98–7.03 (m, 1 H, CHarom), 7.17–7.25
(m, 1 H, CHarom).
13C NMR (100 MHz, CDCl3): d = 20.0 (CH2), 23.4 (CH2), 30.3
(CH2), 40.5 (CH), 49.2 (Cq), 52.9 (CH3), 77.5 (CH2), 106.7 (CHolef),
116.4 (CHarom), 120.5 (Carom), 122.1 (CHarom), 128.8 (CHarom), 130.1
(CHarom), 145.8 (CaromO), 151.6 (ColefO), 172.8 (CO2Me).
Anal. Calcd for C13H11NO4: C, 63.67; H, 4.52; N, 5.71. Found: C,
63.43; H, 4.45; N, 5.53.
(R)-9-(Nitromethyl)-2,3,4,9-tetrahydro-1H-xanthen-1-one (6b)
Compound 6b was synthesized according to the general procedure
to yield 158 mg (61%) of a colorless solid; mp 142 °C; Rf = 0.30 (n-
20
pentane–Et2O, 1:1); [a]D –88.4 (c 1.0, CHCl3); ee = 89%. The
enantiomeric excess was determined by chiral stationary phase
HPLC using a Chiralcel AD column [n-heptane–EtOH (9:1), flow
rate 1.0 mL/min, l = 254 nm], tR = 6.32 min (major), tR = 7.14 min
(minor).
MS (EI, 70 eV): m/z (%) = 303 ([M+], 30), 197 (100), 183 (23), 77
(10).
IR (film): 3019, 2953, 1644, 1582, 1584, 1488, 1457, 1427, 1385,
1235, 1183, 1137, 1003, 959, 759 cm–1.
HRMS: m/z calcd for C16H17NO5 + Na: 326.0999; found: 326.0999.
1H NMR (300 MHz, CDCl3): d = 2.03–2.15 (m, 2 H, CH2), 2.36–
2.76 (m, 4 H, 2 × CH2), 4.56–4.71 (m, 3 H, CH, CH2), 7.04–7.32 (m,
4 H, CHarom).
13C NMR (75 MHz, CDCl3): d = 20.4 (CH2), 28.0 (CH2), 31.7 (CH),
36.8 (CH2), 79.6 (CH2), 108.8 (Colef), 117.0 (CHarom), 120.0 (Carom),
125.5 (CHarom), 128.5 (CHarom), 129.0 (CHarom), 150.2 (CaromO),
169.6 (ColefO), 197.3 (C=O).
Ethyl (9R,9aS)-9-(Nitromethyl)-2,3,9,9a-tetrahydro-1H-xan-
thene-9a-carboxylate (5h)
Compound 5h was synthesized according to the general procedure
to yield 197 mg (62%) of a colorless solid; mp 100 °C; Rf = 0.34 (n-
pentane–Et2O, 8:1); [a]D20 –71.0 (c 1.0, CHCl3); ee (major) = 88%,
ee (minor) = 47%; de = 95%. The enantiomeric excess was deter-
mined by chiral stationary phase HPLC using a Chiralcel AD col-
umn [n-heptane–i-PrOH (98:2), flow rate 0.3 mL/min, l = 254 nm],
tR = 30.05 min (major), tR = 32.50 min (minor), tR = 36.39 min (ma-
jor), tR = 39.57 min (minor).
MS (EI, 70 eV): m/z (%) = 212 ([M – HNO2]+, 100), 199 (77), 171
(11), 128 (21), 115 (25).
Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C,
64.80; H, 4.83; N, 5.40.
IR (film): 2965, 2933, 2851, 1720, 1682, 1549, 1487, 1456, 1372,
1277, 1233, 1198, 1145, 1093, 1012, 939, 855, 819, 755, 688 cm–1.
1H NMR (400 MHz, CDCl3): d = 0.89 (t, J = 7.2 Hz, 3 H, CH3),
1.55–1.64 (m, 2 H, CH2), 1.66–1.81 (m, 2 H, CH2), 2.17–2.31 (m, 2
H, CH2), 3.85–4.09 (m, 3 H, CH, CH2), 4.29 (dd, J = 8.8, 12.6 Hz,
1 H, CH2), 4.74 (dd, J = 5.7, 12.6 Hz, 1 H, CH), 5.58 (dd, J = 4.0,
7.9 Hz, 1 H, CHolef), 6.83–6.94 (m, 2 H, CHarom), 6.97–7.04 (m, 1 H,
CHarom), 7.17–7.28 (m, 1 H, CHarom).
13C NMR (100 MHz, CDCl3): d = 13.7 (CH3), 20.6 (CH2), 23.4
(CH2), 30.2 (CH2), 40.6 (CH), 49.1 (Cq), 61.6 (CH2), 77.5 (CH2),
106.4 (CHolef), 116.4 (CHarom), 120.6 (Carom), 122.0 (CHarom), 128.9
(CHarom), 130.1 (CHarom), 146.0 (CaromO), 151.8 (ColefO), 172.2
(CO2Et).
(R)-3,3-Dimethyl-9-(nitromethyl)-2,3,4,9-tetrahydro-1H-xan-
then-1-one (6c)
Compound 6c was synthesized according to the general procedure
to yield 143 mg (55%) of a colorless solid; mp 96 °C; Rf = 0.29 (n-
20
pentane–Et2O, 1:1); [a]D –61.1 (c 1.0, CHCl3); ee = 95%. The
enantiomeric excess was determined by chiral stationary phase
HPLC using a Chiralcel AD column [n-heptane–i-PrOH (8:2), flow
rate 1.5 mL/min, l = 254 nm], tR = 4.40 min (major), tR = 5.24 min
(minor).
IR (film): 2951, 2168, 1982, 1633, 1583, 1490, 1439, 1380, 1335,
1233, 1181, 1038, 959, 923, 852, 760, 659 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.13 (s, 6 H, 2 × CH3), 2.35 (s, 2
H, CH2), 2.50 (s, 2 H, CH2), 4.53 (m, 1 H, CH), 4.60 (dd, J = 3.7,
11.6 Hz, 1 H, CH2), 4.74 (dd, J = 5.5, 11.6 Hz, 1 H, CH2), 7.00–7.07
(m, 1 H, CHarom), 7.11–7.18 (m, 1 H, CHarom), 7.21–7.30 (m, 2 H,
CHarom).
MS (EI, 70 eV): m/z (%) = 317 ([M+], 76), 270 (10), 243 (10), 213
(100), 197 (100), 183 (53), 169 (23), 157 (14).
Anal. Calcd for C17H19NO5: C, 64.34; H, 6.03; N, 4.41. Found: C,
64.63; H, 6.25; N, 4.33.
13C NMR (75 MHz, CDCl3): d = 27.5 (CH3), 29.6 (CH3), 32.0 (CH),
32.3 (Cq), 41.8 (CH2), 50.9 (CH2), 79.6 (CH2), 107.8 (Colef), 117.2
(CHarom), 120.1 (Carom), 125.7 (CHarom), 128.7 (CHarom), 129.3
(CHarom), 150.5 (CaromO), 168.2 (ColefO), 197.5 (C=O).
MS (EI, 70 eV): m/z (%) = 240 ([M – HNO2]+, 100), 227 (48), 184
(14), 171 (33), 128 (9), 115 (12).
(R)-9-(Nitromethyl)-2,3-dihydrocyclopenta[b]chromen-1(9H)-
one (6a)
Compound 6a was synthesized according to the general procedure
to yield 157 mg (64%) of a pale yellow solid; mp 130 °C; Rf = 0.26
(n-pentane–Et2O, 4:1); [a]D20 –18.6 (c 0.9, CHCl3); ee = 99%. The
enantiomeric excess was determined by chiral stationary phase
© Thieme Stuttgart · New York
Synthesis 2012, 44, 773–782

780
D. Enders et al.
PAPER
Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C,
66.74; H, 6.03; N, 4.95.
of the reaction, the solvent was evaporated and compound 10 was
isolated as a mixture of hydroxy ketone 10b and hemiacetal 10a by
column chromatography (silica gel, n-pentane–Et2O, 1:1) as a col-
orless solid (301 mg, 98%); mp 150 °C; Rf = 0.31 (n-pentane–
Et2O, 1:1); [a]D20 –92.4 (c 1.0, CHCl3). Ratio 10a/10b = 3:2.
(1¢S,4R)-2-Methylene-4-(nitromethyl)spiro[chroman-3,1¢-cy-
clopentan]-2¢-one (8a)
Compound 8a was synthesized according to the general procedure
to yield 208 mg (76%) of a colorless solid; mp 109 °C; Rf = 0.26 (n-
pentane–Et2O, 4:1); [a]D –7.1 (c 1.0, CHCl3); ee (major) = 93%,
ee (minor) = 43%; de = 98%. The enantiomeric excess was deter-
mined by chiral stationary phase HPLC using a Chiralcel AD col-
umn [n-heptane–i-PrOH (95:5), flow rate 1.0 mL/min, l = 254 nm],
tR = 7.55 min (major), tR = 9.44 min (minor), tR = 3.24 min (major),
tR = 4.25 min (minor).
IR (film): 3368, 2967, 2891, 1727, 1598, 1548, 1458, 1431, 1339,
1233, 1152, 1108, 994, 840, 765, 665 cm–1.
20
1H NMR (600 MHz, CDCl3): d = 1.17–1.87 (m, 4 H, CH2, 10b),
1.49–1.57 (m, 2 H, CH2, 10b), 2.00–2.14 (m, 2 H, CH2, 10a, 10b),
2.21–2.33 (m, 2 H, CH2, 10a), 2.34–2.45 (m, 2 H, CH2, 10a), 3.74
(s, 3 H, CH3, 10a), 3.77 (s, 3 H, CH3, 10b), 3.95 (dd, J = 4.5, 8.4 Hz,
1 H, CH, 10b), 4.34 (br s, 1 H, OH, 10a), 4.71 (dd, J = 4.5, 13.4 Hz,
1 H, CH, 10a, 10b), 4.78 (dd, J = 8.4, 13.4 Hz, 1 H, CH, 10a), 4.88
(dd, J = 3.5, 13.4 Hz, 1 H, CH, 10b), 5.28 (dd, J = 10.9, 13.4 Hz, 1
IR (film): 2980, 2916, 2869, 1726, 1651, 1544, 1486, 1455, 1381,
1334, 1289, 1234, 1187, 1166, 1113, 1036, 843, 760, 691 cm–1.
H, CH, 10a), 5.87 (br s, 1 H, OH, 10a), 6.75–6.79 (m, 1 H, CHarom
10a), 6.84–6.88 (m, 1 H, CHarom, 10a), 6.90–6.93 (m, 1 H, CHarom
10b), 6.94–6.98 (m, 1 H, CHarom, 10b), 7.06–7.10 (m, 1 H, CHarom
,
,
,
1H NMR (600 MHz, CDCl3): d = 1.68–1.78 (m, 1 H, CH2), 1.90–
2.07 (m, 3 H, CH2), 2.43–2.57 (m, 2 H, CH2), 3.61 (dd, J = 5.3, 9.3
Hz, 1 H, CH2), 3.99 (d, J = 2.3 Hz, 1 H, CH2), 4.27 (dd, J = 9.3, 13.6
Hz, 1 H, CH), 4.82 (d, J = 2.3 Hz, 1 H, CH2), 5.43 (dd, J = 5.3, 13.6
Hz, 1 H, CH2), 6.84–6.94 (m, 2 H, CHarom), 7.01–7.07 (m, 1 H,
CHarom), 7.18–7.27 (m, 1 H, CHarom).
13C NMR (150 MHz, CDCl3): d = 18.2 (CH2), 36.4 (CH2),
39.7(CH2), 41.1 (CH), 51.9 (Cq), 77.0 (CH2), 93.2 (CH2), 116.3
(CHarom), 120.6 (Carom), 122.3 (CHarom), 129.1 (CHarom), 129.9
(CHarom), 151.4 (CaromO), 152.4 (ColefO), 217.0 (C=O).
10a, 10b), 7.11–7.15 (m, 1 H, CHarom, 10a), 7.21–7.25 (m, 1 H,
CHarom, 10b).
13C NMR (150 MHz, CDCl3): d = 19.3 (CH2, 10b), 19.8 (CH2, 10a),
33.3 (CH2, 10b), 33.4 (CH2, 10a), 38.4 (10b), 39.1 (CH2, 10a), 39.3
(CH2, 10b), 40.4 (CH3, 10b), 52.9 (CH3, 10a), 53.1 (CH, 10b), 53.2
(CH, 10a), 56.1 (Cq, 10a), 62.1 (Cq, 10b), 76.3 (CH2, 10a), 77.5
(CH2, 10b), 107.5 (Cacetal, 10a), 116.4 (CHarom, 10a), 117.6 (CHarom
10b), 120.5 (CHarom, 10a), 121.3 (CHarom, 10b), 122.2 (CHarom
,
,
10b), 122.3 (Carom, 10a), 127.8 (CHarom, 10a), 129.4 (CHarom, 10a),
129.5 (CHarom, 10b), 151.0 (CaromOH, 10b), 154.4 (CaromO, 10a),
172.0 (CO2CH3, 10a), 174.3 (CO2CH3, 10b), 216.3 (C=O, 10b).
MS (EI, 70 eV): m/z (%) = 307 ([M+], 53), 216 (25), 183 (22), 159
MS (EI, 70 eV): m/z (%) = 273 ([M+], 15), 226 (66), 213 (100), 185
(83), 169 (15), 158 (12), 128 (30), 115 (23), 77 (31).
HRMS: m/z calcd for C15H15NO4: 273.0996; found: 273.0998.
(30), 142 (100), 119 (38), 91 (64), 77 (33), 55 (69).
(1¢R,4R,E)-2-Ethylidene-4-(nitromethyl)spiro[chroman-3,1¢-
cyclopentan]-2¢-one (8b)
Anal. Calcd for C15H17NO6: C, 58.63; H, 5.58; N, 4.56. Found: C,
58.76; H, 5.59; N, 4.45.
Compound 8b was synthesized according to the general procedure
to yield 204 mg (71%) of a colorless oil; Rf = 0.38 (n-pentane–
20
Et2O, 4:1); [a]D –11.3 (c 1.0, CHCl3); ee = 91%; de = 99%. The
One-Pot Domino Michael–Lactonization Reaction; (1¢R,4R)-4-
(Nitromethyl)spiro[chroman-3,1¢-cyclopentane]-2,2¢-dione (11)
In a glass vial equipped with a magnetic stirring bar, catalyst C
(10 mol%) was added to a mixture of cyclic b-keto ester 2a (135 mL,
1.0 mmol) and (E)-2-(2-nitrovinyl)phenol (1a; 165 mg, 1.0 mmol)
in toluene (6.0 mL) at r.t. The reaction was monitored by TLC (elu-
ent: n-pentane–Et2O, 1:1). After completion of the reaction, PTSA
monohydrate (20 mol%, 38 mg) was added and the reaction mixture
was heated to 100 °C for 2 h. Product 11 was obtained after column
chromatography (silica gel, n-pentane–EtOAc, 4:1) as a colorless
solid (242 mg, 88%); mp 159 °C; Rf = 0.36 (n-pentane–
enantiomeric excess was determined by chiral stationary phase
HPLC using a Chiralcel AD column [n-heptane–i-PrOH (95:5),
flow rate 1.0 mL/min, l = 254 nm], tR = 6.08 min (major), tR = 7.10
min (minor).
IR (film): 3442, 2969, 1732, 1601, 1550, 1491, 1451, 1376, 1259,
1212, 1173, 756, 706 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.64–1.74 (m, 1 H, CH2), 1.77 (d,
J = 6.7 Hz, 3 H, CH3), 1.87–1.96 (m, 2 H, CH2), 1.99–2.07 (m, 1 H,
CH2), 2.36–2.54 (m, 2 H, CH2), 3.59 (dd, J = 5.1, 9.2 Hz, 1 H, CH),
4.25 (dd, J = 9.2, 13.4 Hz, 1 H, CH2), 4.47 (q, J = 6.7 Hz, 1 H, CH),
5.46 (dd, J = 5.1, 13.4 Hz, 1 H, CH2), 6.89–6.94 (m, 1 H, CHarom),
6.97–7.05 (m, 2 H, CHarom), 7.24–7.29 (m, 1 H, CHarom).
13C NMR (150 MHz, CDCl3): d = 10.0 (CH3), 18.2 (CH2), 36.4
(CH2), 39.8 (CH2), 41.6 (CH), 52.2 (Cq), 77.5 (CH2), 103.9 (CH),
116.3 (CHarom), 120.8 (Carom), 122.0 (CHarom), 129.2 (CHarom), 129.8
(CHarom), 145.0 (CaromO), 151.7 (ColefO), 217.7 (C=O).
20
EtOAc, 4:1); [a]D –42.4 (c 1.0, CHCl3); ee (major) = 99%;
de = 99%. The enantiomeric excess was determined by chiral sta-
tionary phase HPLC using a Chiralpak IA column [n-heptane–
EtOH (9:1), flow rate 1.2 mL/min, l = 254 nm], tR = 24.06 min
(major), tR = 21.80 min (minor).
IR (film): 3017, 2968, 2890, 1738, 1549, 1487, 1458, 1380, 1345,
1219, 1158, 1131, 1028, 1001, 943, 823, 763, 686 cm–1.
MS (EI, 70 eV): m/z (%) = 287 ([M+], 25), 240 (82), 227 (100), 199
(46), 183 (25), 128 (12), 116 (14), 91 (21), 77 (25).
1H NMR (600 MHz, CDCl3): d = 1.94–2.08 (m, 3 H, CH2), 2.16–
2.22 (m, 1 H, CH2), 2.43–2.50 (m, 1 H, CH2), 2.64–2.72 (m, 1 H,
CH2), 3.77 (dd, J = 5.0, 9.9 Hz, 1 H, CH2), 4.40 (dd, J = 9.9, 13.9
Hz, 1 H, CH), 5.54 (dd, J = 5.0, 13.9 Hz, 1 H, CH2), 7.00–7.20 (m,
3 H, CHarom), 7.35–7.40 (m, 1 H, CHarom).
HRMS: m/z calcd for C16H17NO4 + Na: 310.1049; found: 310.1044.
Methyl (3aR,9R,9aS)-3a-Hydroxy-9-(nitromethyl)-
13C NMR (150 MHz CDCl3): d = 18.7 (CH2), 35.7 (CH2), 39.1
(CH2), 41.6 (CH), 54.9 (Cq), 75.5 (CH2), 117.2 (CHarom), 120.6
(Carom), 125.6 (CHarom), 168.8 (CHarom), 130.4 (CHarom), 150.3
(CaromO), 166.5 (CO2), 212.5 (C=O).
MS (EI, 70 eV): m/z (%) = 275 ([M+], 13), 215 (78), 200 (94), 187
(82), 159 (100), 115 (71), 91 (58), 77 (43).
1,2,3,3a,9,9a-hexahydrocyclopenta[b]chromene-9a-carboxy-
late (10a) and Methyl (S)-1-[(R)-1-(2-Hydroxyphenyl)-2-nitro-
ethyl]-2-oxocyclopentanecarboxylate (10b)
In a glass vial equipped with a magnetic stirring bar, catalyst C
(10 mol%) was added to a mixture of methyl 2-oxocyclopentane-
carboxylate (2a; 135 mL, 1.0 mmol) and (E)-2-(2-nitrovinyl)phenol
(1a; 165 mg, 1.0 mmol) in toluene (6.0 mL) at r.t. The reaction was
monitored by TLC (eluent: n-pentane–Et2O, 1:1). After completion
Synthesis 2012, 44, 773–782
© Thieme Stuttgart · New York

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Asymmetric Organocatalytic Synthesis of Chromans
781
Anal. Calcd for C14H13NO5: C, 61.09; H, 4.76; N, 5.09. Found: C,
61.06; H, 4.73; N, 4.98.
IR (film): 2954, 2847, 1730, 1556, 1492, 1452, 1379, 1322, 1246,
1133, 1083, 1029, 973, 912, 840, 803, 756, 663 cm–1.
1H NMR (400 MHz, CDCl3,): d = 1.48–1.59 (m, 1 H, CH2), 1.72–
1.88 (m, 1 H, CH2), 2.02–2.15 (m, 3 H, CH2), 2.18–2.26 (m, 1 H,
CH2), 3.34 (s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 4.47 (dd, J = 4.7, 13.3
Hz, 1 H, CH2), 4.60 (dd, J = 4.7, 6.3 Hz, 1 H, CH), 4.68 (dd, J = 6.3,
13.3 Hz, 1 H, CH2), 6.86–6.90 (m, 1 H, CHarom), 6.94–7.00 (m, 1 H,
CHarom), 7.04–7.13 (m, 1 H, CHarom), 7.16–7.22 (m, 1 H, CHarom).
13C NMR (100 MHz, CDCl3,): d = 19.5 (CH2), 27.8 (CH2), 32.0
(CH2), 35.3 (CH), 52.0 (OCH3), 52.7 (CH3), 56.2 (Cq), 78.1 (CH2),
108.9 (CHolef), 117.6 (CHarom), 120.4 (Carom), 122.2 (CHarom), 126.8
(CHarom), 128.6 (CHarom), 150.2 (ColefO), 173.0 (CO2CH3).
One-Pot Domino Michael–Hemiacetalization and Reduction
Reaction; Methyl (3aR,9R,9aS)-9-(Nitromethyl)-1,2,3,3a,9,9a-
hexahydrocyclopenta[b]chromene-9a-carboxylate (12)
In a glass vial equipped with a magnetic stirring bar, catalyst C
(10 mol%) was added to a mixture of cyclic b-keto ester 2a (135 mL,
1.0 mmol) and (E)-2-(2-nitrovinyl)phenol (1a; 165 mg, 1.0 mmol)
in toluene (6.0 mL) at r.t. The reaction mixture was monitored by
TLC. After completion of the reaction, the solvent was evaporated,
and CH2Cl2 (6 mL), HSiEt3 (240 mL, 1.5 mmol), and BF3·OEt2 (130
mL, 1.0 mmol) were added at –78 °C. After stirring for 6 h, the re-
action mixture was warmed up to r.t. The crude mixture was
quenched with sat. aq NaHCO3 (5 mL), the organic phase was sep-
arated, and the aqueous phase was extracted with EtOAc (3 × 5
mL). The organic extracts were combined and dried (Na2SO4), and
concentrated under reduced pressure. The residue was purified after
chromatography (silica gel, n-pentane–EtOAc, 6:1) to afford 12 as
a colorless solid (181 mg, 62%); mp 161 °C; Rf = 0.45 (n-pentane–
MS (EI, 70 eV): m/z (%) = 321 ([M+], 13), 274 (56), 243 (65), 215
(44), 183 (42), 156 (100), 141 (41), 124 (20), 109 (26).
HRMS: m/z calcd for C16H19NO6 + Na: 344.1105; found: 344.1104.
References
20
EtOAc, 6:1); [a]D –13.4 (c 1.0, CHCl3); ee (major) = 94%, ee
(1) For reviews on organocatalytic domino reactions, see:
(a) Grossmann, A.; Enders, D. Angew. Chem. Int. Ed. 2012,
51, 314. (b) Pellissier, H. Adv. Synth. Catal. 2012, 354, in
press. (c) Enders, D.; Jeanty, M.; Grondal, C. Nat. Chem.
2010, 2, 167. (d) Alba, A.-N.; Companyo, X.; Viciano, M.;
Rios, R. Curr. Org. Chem. 2009, 13, 1432. (e) Yu, X.;
Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (f) Enders,
D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed.
2007, 46, 1570.
(2) For recent examples of organocatalytic asymmetric
syntheses of chromans, see: (a) Enders, D.; Yang, X.;
Wang, C.; Raabe, G.; Runsink, J. Chem. Asian J. 2011, 6,
2255. (b) Enders, D.; Urbanietz, G.; Raabe, G. Synthesis
2011, 1905. (c) Hong, B. C.; Kotame, P.; Liao, J.-H. Org.
Biomol. Chem. 2011, 9, 382. (d) Ren, Q.; Siau, W.-Y.; Du,
Z.; Zhang, K.; Wang, J. Chem. Eur. J. 2011, 17, 778.
(e) Hong, B. C.; Kotame, P.; Lee, G.-H. Org. Lett. 2011, 13,
5758. (f) Lee, Y.; Seo, S. W.; Kim, S.-G. Adv. Synth. Catal.
2011, 353, 2671. (g) Zhang, X.; Zhang, S.; Wang, W.
Angew. Chem. Int. Ed. 2010, 49, 1481. (h) Alemán, J.;
Nuńez, A.; Marzo, L.; Marcos, V.; Alvarado, C.; Ruano, J.
L. G. Eur. J. Org. Chem. 2010, 16, 9453. (i) Lu, D.; Li, Y.;
Gong, Y. J. Org. Chem. 2010, 75, 6900. (j) Ramachary, D.
B.; Sakthidevi, R. Org. Biomol. Chem. 2010, 8, 4259.
(k) Manzano, R.; Andrés, J. M.; Muruzábal, M. D.; Pedrosa,
R. Adv. Synth. Catal. 2010, 352, 3364. (l) Enders, D.;
Wang, C.; Yang, X.; Raabe, G. Adv. Synth. Catal. 2010, 352,
2869.
(minor) = 99%; de = 88%. The enantiomeric excess was deter-
mined by chiral stationary phase HPLC using a Chiralcel OD col-
umn [n-heptane–i-PrOH (95:5), flow rate 0.7 mL/min, l = 254 nm],
tR = 13.36 min (major), tR = 27.32 min (minor), tR = 21.13 min (ma-
jor), tR = 44.50 min (minor).
IR (film): 2982, 2951, 2875, 1723, 1543, 1482, 1447, 1373, 1326,
1223, 1151, 1105, 1035, 996, 804, 757, 660 cm–1.
1H NMR (600 MHz, CDCl3): d = 1.51–1.61 (m, 1 H, CH2), 1.81–
1.90 (m, 1 H, CH2), 1.99–2.22 (m, 2 H, CH2), 2.34–2.40 (m, 1 H,
CH2), 2.64–2.72 (m, 1 H, CH2), 3.93 (dd, J = 6.0, 6.4 Hz, 1 H, CH),
4.14 (dd, J = 7.4, 11.4 Hz, 1 H, OCH), 4.68 (dd, J = 6.0, 13.4 Hz, 1
H, CH2), 5.00 (dd, J = 6.4, 13.4 Hz, 1 H, CH2), 6.87 (d, J = 7.0 Hz,
1 H, CHarom), 6.96 (t, J = 7.4 Hz, 1 H, CHarom), 7.05 (d, J = 8.0 Hz,
1 H, CHarom), 7.16 (t, J = 8.0 Hz, 1 H, CHarom).
13C NMR (150 MHz, CDCl3): d = 19.2 (CH2), 26.4 (CH2), 31.1
(CH2), 46.2 (CH), 52.1 (CH3), 52.2 (Cq), 77.9 (CH2), 83.8 (OCH),
117.3 (CHarom), 121.8 (CHarom), 122.9 (Carom), 126.0 (CHarom), 128.2
(CHarom), 155.5 (CaromO), 171.9 (CO2CH3).
MS (EI, 70 eV): m/z (%) = 291 ([M+], 52), 244 (80), 200 (94), 185
(100), 157 (11), 115 (71), 91 (42), 77 (20).
Anal. Calcd for C15H17NO5: C, 61.85; H, 5.88; N, 4.81. Found: C,
61.50; H, 5.87; N, 4.74.
One-Pot Domino Michael–Hemiacetalization and Acetalization
Reaction; Methyl (3aR,9R,9aS)-3a-Methoxy-9-(nitromethyl)-
1,2,3,3a,9,9a-hexahydrocyclopenta[b]chromene-9a-carboxy-
late (13)
(3) (a) Shen, H. C. Tetrahedron 2009, 65, 3931. (b) Ferreira, S.
B.; da Silva, F. de C.; Pinto, A. C.; Gonzaga, D. T. G.;
Ferreira, V. F. J. Heterocycl. Chem. 2009, 46, 1080.
(c) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
(d) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao,
G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000,
122, 9939. (e) Keay, B. A. In Comprehensive Heterocyclic
Chemistry II, Vol. 2; Pergamon: Oxford, 1996.
In a glass vial equipped with a magnetic stirring bar, catalyst C
(10 mol%) was added to a mixture of cyclic b-keto ester (2a; 135
mL, 1.0 mmol) and (E)-2-(2-nitrovinyl)phenol (1a; 165 mg, 1.0
mmol) in toluene (6.0 mL) at r.t. The reaction was monitored by
TLC. After completion of the reaction, the solvent was evaporated
and MeOH (6 mL) and PTSA monohydrate (20 mol%, 38 mg) were
added and the mixture was stirred for 8 h at r.t. After completion,
the crude reaction mixture was filtered through a small plug of silica
gel. Product 13 was isolated after column chromatography (silica
gel, n-pentane–Et2O, 6:1) as a colorless oil (180 mg, 56%); Rf =
(f) Schweizer, E. E.; Meeder-Nycz, O. In Chromenes,
Chromans, Chromones; Ellis, G. P., Ed.; Wiley-
Interscience: New York, 1977.
(4) For examples of organocatalytic asymmetric Michael–
hemiacetalization reactions, see: (a) Wang, Y.; Zhu, S.; Ma,
D. Org. Lett. 2011, 13, 1602. (b) Ishikawa, H.; Sawano, S.;
Yasui, Y.; Shibata, Y.; Hayashi, Y. Angew. Chem. Int. Ed.
2011, 50, 3774. (c) Belot, S.; Quintard, A.; Alexakis, A.;
Krause, N. Adv. Synth. Catal. 2010, 352, 667. (d) Maltsev,
O. V.; Kucherenko, A. S.; Zlotin, S. G.; Chimishkyan, A. L.
Tetrahedron: Asymmetry 2010, 21, 2659. (e) Yao, W.; Wu,
20
0.45 (n-pentane–Et2O, 6:1); [a]D –23.5 (c 1.0, CHCl3); ee
(major) = 92%, ee (minor) = 70%; de = 93%. The enantiomeric ex-
cess was determined by chiral stationary phase HPLC using a
Chiralcel OD column [n-heptane–EtOH (9:1), flow rate 1.0 mL/
min, l = 254 nm], tR = 6.02 min (major), tR = 9.90 min (minor),
tR = 5.46 min (major), tR = 7.13 min (minor).
© Thieme Stuttgart · New York
Synthesis 2012, 44, 773–782

782
D. Enders et al.
PAPER
procedure: Zhang, B.-L.; Wang, F.-D.; Yue, J.-M. Synlett
Y.; Wang, G.; Zhang, Y.; Cheng, M. Angew. Chem. Int. Ed.
2009, 48, 9713. (f) Chandrasekhar, S.; Mallikarjun, K.;
Pavankumarreddy, G.; Rao, K. V.; Jagadeesh, B. Chem.
Commun. 2009, 4985. (g) Wang, J.; Yu, F.; Zhang, X.; Ma,
D. Org. Lett. 2008, 10, 2561. (h) Xie, J. W.; Uang, X.; Fan,
L. P.; Xu, D. C.; Li, X. S.; Su, H.; Wen, Y. H. Adv. Synth.
Catal. 2008, 350, 1474.
2006, 567.
(6) Okino, T.; Yasutaka Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672.
(7) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett.
2005, 7, 1967.
(8) CCDC 859260 contains the supplementary crystallographic
data of 5d for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(5) The (E)-2-(2-nitrovinyl)phenols were prepared from the
corresponding substituted salicylaldehydes and
nitromethane in AcOH/NH4OAc according to the literature
Synthesis 2012, 44, 773–782
© Thieme Stuttgart · New York