Efficient kinetic resolution of racemic 3-nitro-2H-chromene derivatives catalyzed by Takemoto's organocatalyst

Article abstract of DOI:10.1039/b922668k

Efficient kinetic resolution of racemic 3-nitro-2H-chromenes by bifunctional thiourea afforded optically active (R)-3-nitro-2H-chromene derivatives with moderate to good enantioselectivities, which simultaneously gave the multifunctional 3,4-diphenyl-3a-n

Full text of DOI:10.1039/b922668k

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Efficient kinetic resolution of racemic 3-nitro-2H-chromene derivatives
catalyzed by Takemoto’s organocatalyst†
Jian-Wu Xie,* Li-Ping Fan, Hong Su, Xin-Sheng Li and Dong-Cheng Xu
Received 29th October 2009, Accepted 22nd February 2010
First published as an Advance Article on the web 11th March 2010
DOI: 10.1039/b922668k
Efficient kinetic resolution of racemic 3-nitro-2H-chromenes by bifunctional thiourea afforded
optically active (R)-3-nitro-2H-chromene derivatives with moderate to good enantioselectivities,
which simultaneously gave the multifunctional 3,4-diphenyl-3a-nitrobenzopyrano-[3,4-c]-
pyrrolidine-1,1-dicarboxylate derivatives with four vicinal chiral carbon centers.
tertiary amine catalyzed reactions, such as Michael additions, aza-
Henry reactions, domino reactions and dynamic kinetic resolution
Introduction
(DKR).12 Motivated by our success in the thiourea-catalyzed
asymmetric formal [3+2] cycloaddition of azomethine ylides
with nitroolefins to provide highly functionalized pyrrolidines
with high diastereo- and enantioselectivities.14 We hoped that
the bifunctional thiourea catalysts 1a–1d, which proved to be
highly effective in the Michael addition,12 would effect a kinetic
resolution (KR) of racemic 3-nitro-2H-chromene derivatives. If
the selectivity of the catalyst is sufficiently high, a KR process
will be of practical significance, for both the remaining 4 and
the converted substrate enantiomers 5 have a wide range of
potential applications in pharmaceutical chemistry (Scheme 1).
Herein, we set out to expand this methodology to synthesis of
chiral 3-nitro-2H-chromene derivatives by kinetic resolution of
racemic 3-nitro-2H-chromene derivatives. Notably, the kinetic
resolution gave the 3-nitro-2H-chromene derivatives with good
enantioselectives, which simultaneously gave the multifunctional
diethyl 3,4-diphenyl-3a-nitro-benzopyrano[3,4-c] pyrrolidine-1,1-
dicarboxylate derivatives with four vicinal chiral carbon centers
for the first time.
The chiral chroman unit is the core structure in a number of natural
products.1 Many chiral chroman derivatives are known to exhibit
a wide range of biological properties,2 for example anticancer,
diuretic, anticoagulant, and anti-anaphylactic activity.3 Particu-
larly, many chiral chroman units are also the most significant
member of the vitamin E family serving as a natural lipophilic
antioxidant and radical scavenger.4 Thus, continuous efforts have
been devoted to the development of more general and versatile
synthetic methodologies to this class of compounds.5,6 Among
this class of compounds, 3-nitro-2H-chromenes are very impor-
tant units, which are recognized due to their biological activity
and their importance as precursors of flavonols, amines, and other
important targets.7 Recently, Xu’s group and Sankararaman’s
group reported the enantioselective tandem oxa-Michael–Henry
reaction of salicylaldehyde derivatives to nitroolefins for chiral
3-nitro-2H-chromene derivatives catalyzed by a chiral amine.8
Unfortunately, low ees were observed for a range of substrates, and
in general over 96 h were required in order to achieve good yields
at room temperature. In addition, although 3-nitro-chromene
derivatives as 2p components in 1,3-dipolar cycloadditions of
azomethine ylides has been reported,9 to the best of our knowl-
edge, there is no report on the direct catalytic asymmetric 1,3-
dipolar cycloaddition of 2-aryl-3-nitrochromenes with azomethine
ylides. These encouraged us to explore a more general and
versatile synthetic methodologies to this class of compounds.
Besides chiral pool strategies (use of enantiopure starting materials
provided by nature) and enantioselective synthesis (preparation
from achiral precursors using chiral reagents or catalysts),10 the
kinetic resolution of racemates has always played a central role
in the preparation of optically active compounds.11,12 Recently,
thiourea–tertiary amines were investigated and established as
effective bifunctional organocatalysts in asymmetric catalysis13
and many exciting discoveries have been made in the thiourea–
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces,
Department of Chemistry and Life Science, Zhejiang Normal University,
Jinhua, 321004, China. E-mail: xiejw@zjnu.cn; Fax: 86 579 82282610
† Electronic supplementary information (ESI) available: 1H and 13C
NMR, and HPLC spectra. CCDC reference numbers 752804. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b922668k
Scheme 1 Kinetic resolution of 3-nitro-2H-chromene derivatives 2 via
[3+2] cycloaddition catalyzed by thiourea–tertiary amine bifunctional
organocatalysts.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2117–2122 | 2117
©

View Article Online
Table 1 Optimization of the reaction conditionsa
Table 2 Asymmetric kinetic resolution of racemic 3-nitro-2H-chromene
derivativesa
Entry Catalyst Solvent Ee (%)b/yield (%)c4 Ee (%)b/yield (%)c 5d
Entry Ar (2)
Ee (%)b/yield (%)c 4 Ee (%)b/yield (%)c 5d
1
2
3
4
5
6
1a
1b
1c
1d
1c
1c
1c
1c
1c
DCM
DCM
DCM
DCM
Toluene 87/41
THF 51/53
Ethanol 15/31
Toluene 81/43
Toluene 78/46
29/42
42/41
65/46
37/40
1/40
9/35
13/11
21/49
19/25
7/40
0/62
25/25
31/28
1
2
3
4
C6H5
2a 87/41 4a
19/25 5a
17/26 5b
35/40 5c
49/31 5d
45/27 5e
21/23 5f
53/47 5g
33/29 5h
57/35 5i
70/36 5j
51/41 5k
13/32 5l
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-MeC6H4
2b 77/42 4b
2c 79/41 4c
2d 85/46 4d
2e 82/47 4e
5
7
6
4-MeOC6H4 2f 68/49 4f
8e
9f
7e
8f
9f
10f
11f
12f
C6H5
2g 73/37 4g
2h 86/43 4h
C6H5
4-MeC6H4
4-MeOC6H4 2j
4-ClC6H4
4-BrC6H4
2i
87/45 4i
83/47 4j
a Unless otherwise noted, reactions were performed with 0.1 mmol of 2a,
0.1 mmol of 3a, 10 mol% catalyst, in 1 mL solvent at 0 ◦C. b Determined by
chiral HPLC analysis. c Isolated yield. d The diastereoselectivities (>99 : 1)
were determined after isolation. e Reaction with 3b. f Reaction with 3c.
2k 73/45 4k
2l 82/39 4l
a Unless otherwise noted, reactions were performed with 0.1 mmol of 2a–l,
0.1 mmol of 3a, 10 mol% 1c, in 1 mL toluene at 0 ◦C. b Determined by
chiral HPLC analysis. c Isolated yield. d T◦he diastereoselectivit◦ies (>99 : 1)
were determined after isolation. e At -10 C for 12 h. f At -10 C for 36 h
Results and discussion
Our studies began with the identification of the best catalyst
and reaction conditions for this kinetic resolution using racemic
3-nitro-2H-chromene 2a as a model substrate (Table 1). We
first investigated the catalytic activity of thiourea for the [3+2]
cycloaddition of 3-nitro-2H-chromene 2a with azomethine ylides.
We found that the catalysts 1a and 1b (Scheme 2), which have
been successfully used in the asymmetric Michael reactions,13e,f
were found to be highly active catalysts at 0 ◦C. Clean products 4a
and 5 were obtained, while the ees were very low (Table 1, entries
1 and 2). Subsequently, we were pleased to find that Takemoto’s
catalsyst 1c exhibited higher catalytic activity, and 41% yield with
65% ee could be obtained under the same conditions (Table 1,
entry 3). Low enantioselectivity was obtained using catalyst 1d
derived from L-proline (Table 1, entry 4). In the next stage of the
studies, different solvents were screened. The kinetic resolution
could be efficiently performed in all solvents tested affording 4a
and 5 but with low enantioselectivity. Gratifyingly, we achieved an
good ee (87%) with 43% yield by utilizing the toluene as solvent,
under the same conditions. Using other azomethine ylides as the
1,3-dipoles gave a similar enantioselectivity (entries 8 and 9).
To test the substrate scope of our kinetic resolution process, the
reaction of various 3-nitro-2H-chromene derivatives (2a–2l) and
a-amino malonate imine (3a) was studied under the optimized
conditions using 10 mol% of Takemoto’s catalyst (1c) as the
catalyst. The results are collected in Table 2.
As shown in Table 2, the kinetic resolution of various 3-nitro-
2H-chromene derivatives with a-amino malonate imine (3a) all
gave excellent yields and good enantioselectivities of the desired
products 4a–4l and 5a–5l. The kinetic resolution of 3-nitro-2H-
chromene derivatives with electron-withdrawing substituents or
electron-donating groups on the Ar group afford the desired
products with a slight effect on enantioselectivities (Table 2, entries
2–6, 77–85% ee), except for the substrate 2f (Table 2, entry 6), for
which the product was obtained in moderate enantioselectivity
(68% ee). In addition, the electronic nature of a substituent on
the aromatic moiety of 2g–2l (Fig. 1) affects the asymmetric
induction of the kinetic resolution. The substrate 2g with a strong
electron-withdrawing substituent (–F) showed high reactivity—
the kinetic resolution could proceed smoothly with good ee even
◦
at -10 C in a short time (Table 2, entry 7). On the other hand,
Scheme 2 The structure of thiourea catalysts.
Fig. 1 Structures of the 3-nitro-2H-chromene derivatives.
2118 | Org. Biomol. Chem., 2010, 8, 2117–2122
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
the substrates 2h–2l with an electron-donating group (–MeO)
led to an increase in enantioselectivity (entries 9–12). Notably,
the kinetic resolution gave the 3-nitro-2H-chromene derivatives
with good enantioselectivities, which simultaneously gave the
multifunctional diethyl 3,4-diphenyl-3a-nitrobenzopyrano[3,4-c]-
pyrrolidine-1,1-dicarboxylate derivatives 5a–5l with moderate
enantioselectivities (up to 70% ee) possess four vicinal chiral
carbon centers. To the best of our knowledge, the chiral multi-
functional chroman derivatives 5a–5l were obtained for the first
time.
To determine the absolute configuration of the [3+2] cy-
cloadducts 5, single crystal suitable for X-ray crystallographic
analysis was fortunately obtained from 5c that bears a bromide
atom.‡ As shown in Fig. 2, it is composed of (C7-S, C8-R, C9-S,
C22-R) configuration.
centers. The KR process was of practical significance, for both
the 3-nitro-2H-chromene derivatives 4 and chroman derivatives
5 have a wide range of potential applications in pharmaceutical
chemistry.
Experimental
General methods
NMR spectra were recorded with tetramethylsilane as the internal
standard. TLC was performed on glass-backed silica plates.
Column chromatography was performed using silica gel (200–
300 mesh) eluting with ethyl acetate and petroleum ether. 1H
NMR spectra were recorded at 400 MHz, and 13C NMR spectra
were recorded at 100 MHz (Bruker Avance). Chemical shifts (d)
are reported in ppm downfield from CDCl3 (d = 7.26 ppm) for
1H NMR and relative to the central CDCl3 resonance (d =
77.0 ppm) for 13C NMR spectroscopy. Coupling constants (J)
are given in Hz. ESI-HRMS spectrometer was measured with a
Finnigan LCQDECA ion trap mass spectrometer. Optical rotations
were measured at 589 nm at 25 ◦C. Enantiomeric excess was
determined by HPLC analysis on Chiralpak AD and OJ columns.
General procedure for kinetic resolution racemic
3-nitro-2H-chromene derivatives with a chiral thiourea
General procedure: 2a 25 mg (0.1 mmol), 3a 20 mg (0.1 mmol),
thiourea 4.1 mg (0.01 mmol) were stirred in toluene (1 ml) at -10 ◦C
for 60 h. Then flash chromatography on silica gel (PE : EA=10 : 1)
gave 4a as a pale yellow solid and 5a as a white solid.
Fig. 2 Molecular structure of enantiopure 5c.
(R)-3-Nitro-2-phenyl-2H-chromene (4a). 1H NMR (400 MHz,
CDCl3) d (ppm) 8.02 (s, 1H), 7.38-7.22 (m, 7H), 6.98-6.94 (m,
1H), 6.85-6.83 (m, 1H), 6.57 (s, 1H); 13C NMR (100 MHz, CDCl3)
d (ppm) 153.6, 136.8, 134.3, 130.5, 129.5, 129.3, 128.9, 128.9,
128.9, 127.1,127.1, 127.1, 122.6, 118.0, 117.3, 74.3; ESI-HRMS:
calcd. for C15H11NO3+H Exact Mass: 254.08216, found 254.08099;
[a]2D5 = -33.0 (c 0.27, ethanol), 87% ee; The enantiomeric ratio
was determined by HPLC on Chiralpak AS-RH column (10%
Conclusions
In conclusion, we have described a novel and practical organocat-
alytic method for the synthesis of optically active 3-nitro-2H-
chromene derivatives. To the best of our knowledge, this is
the first time that kinetic resolution of racemic 3-nitro-2H-
chromene derivatives catalyzed by Takemoto’s catalyst afford
the 3-nitro-2H-chromene derivatives with good enantioselectiv-
ities. Notably, the kinetic resolution gave the optically active 3-
nitro-2H-chromene derivatives, which simultaneously gave the
multifunctional diethyl 3,4-diphenyl-3a-nitrobenzopyrano [3,4-c]-
pyrrolidine-1,1-dicarboxylate derivatives 5 with moderate enan-
tioselectivities (up to 70% ee) possessing four vicinal chiral carbon
2-propanol–hexane, 1 mL min-1), tminor = 9.052 min, tmajor
=
15.732 min.
(R)-2-(4-Chlorophenyl)-3-nitro-2H-chromene (4b). 1H NMR
(400 MHz, CDCl3) d (ppm) 8.05 (s, 1H), 7.34-7.26 (m, 6H), 7.02-
6.84 (m, 2H), 6.54 (s, 1H); 13C NMR (100 MHz, CDCl3) d (ppm)
153.3, 135.5, 135.3, 134.5, 130.5, 129.5, 129.1, 128.4, 122.8, 117.8,
117.3, 73.5. IR (KBr) cm-1 1639, 1603, 1499; ESI-HRMS: calcd.
for C15H10ClNO3+H 288.04378, found 288.04069; [a]2D5 = -20.0
(c 0.19, ethanol), 77% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak OJ-RH column (10% 2-propanol–hexane,
1 mL min-1), tminor = 8.00 min, tmajor = 9.69 min.
(R)-2-(4-Bromophenyl)-3-nitro-2H-chromene (4c). 1H NMR
(400 MHz, CDCl3) d (ppm) 8.08 (s, 1H), 7.48-7.25 (m, 6H),
7.05-7.02 (m, 1H), 6.90-6.88 (m, 1H), 6.55 (s, 1H); 13C NMR
(100 MHz, CDCl3) d (ppm) 153.3, 135.8, 134.5, 132.1, 132.1,
130.5, 129.5, 128.7, 128.7, 117.8, 117.3, 73.5; ESI-HRMS: calcd.
for C15H10BrNO3 330.98396, found 330.98215; [a]2D5 = -33.8 (c
0.34, ethanol), 79% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak OJ-RH column (10% 2-propanol–hexane,
1 mL min-1), tminor = 9.26 min, tmajor = 10.90 min.
‡ Crystal data for 5c C29H27BrN2O7 (595.44), Monoclinic, space group P21,
3
˚
˚
˚
˚
a = 11.2327(3) A, b = 10.1083(3) A, c = 12.0414(3) A, V = 1333.26(6) A ,
Z = 2, specimen 0.25 ¥ 0.07 ¥ 0.06 mm3, T = 296(2) K, SIEMENS
P4 diffractometer, absorption coefficient 1.593 mm-1, reflections collected
20 445, independent reflections 6121 [R(int) = 0.0338], refinement by
Full-matrix least-squares on F2, data/restraints/parameters 6121/1/352,
goodness-of-fit on F2 = 1.032, final R indices [I > 2s(I)] R1 = 0.0378,
wR2 = 0.0873, R indices (all data) R1 = 0.0563, wR2 = 0.0935, largest diff.
-3
˚
peak and hole 0.342 and -0.664 e A , Flack = 0.015(6). Crystallographic
data for the structure 5c have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication no. CCDC
752804. Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax.: (internet.) +
44 1223/336-033; e-mail: deposit@ccdc.cam.ac.uk]. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/b922668k
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2117–2122 | 2119
©

View Article Online
(R)-2-(4-(Trifluoromethyl)phenyl)-3-nitro-2H-chromene
(4d).
13C NMR (100 MHz, CDCl3) d (ppm) 165.1, 131.6, 130.0,
129.2, 128.5, 114.2, 111.2, 109.7, 102.2, 74.3, 55.6, 55.3; ESI-
HRMS: calcd. for C17H15NO5+Na 336.08547, found 336.08395;
[a]2D5 = -19.7 (c 0.11, ethanol), 83% ee; The enantiomeric ratio
was determined by HPLC on Chiralpak OJ-RH column (10%
1H NMR (400 MHz, CDCl3) d (ppm) 8.08 (s, 1H), 7.58-7.33
(m, 6H), 7.04-6.88 (m, 2H), 6.63 (s, 1H); 13C NMR (100 MHz,
CDCl3) d (ppm) 153.3, 134.7, 130.7, 129.8, 127.4, 127.4, 126.0,
126.0, 125.9, 125.9, 123.0, 117.7, 117.3, 73.5; ESI-HRMS: calcd.
for C16H10F3NO3+Na 344.05215, found 344.05117; [a]2D5 = -31.0
(c 0.28, ethanol), 85% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak OJ-RH column (10% 2-propanol–hexane,
1 mL min-1), tminor = 6.57 min, tmajor = 8.40 min.
2-propanol–hexane, 1 mL min-1), tmajor = 25.77 min, tminor
=
28.10 min.
(R)-7-Methoxy-2-(4-chlorophenyl)-3-nitro-2H-chromene (4k).
1H NMR (400 MHz, CDCl3) d (ppm) 8.05 (s, 1H), 7.33-7.23 (m,
5H), 6.60-6.40 (m, 3H), 3.00 (s, 1H); 13C NMR (100 MHz, CDCl3)
d (ppm) 165.2, 155.4, 135.6, 135.3, 131.8, 130.0, 129.1, 129.0,
128.5, 128.5, 128.4, 128.4, 111.0, 111.0, 102.3, 73.8, 56.7; ESI-
HRMS: calcd. for C16H12ClNO4+H 317.04609, found 317.04446;
[a]2D5 = -37.6 (c 0.27, ethanol), 73% ee; The enantiomeric ratio
was determined by HPLC on Chiralpak OJ-RH column (10%
(R)-3-Nitro-2-p-tolyl-2H-chromene (4e). 1H NMR (400 MHz,
CDCl3) d (ppm) 8.02 (s, 1H), 7.30-7.24 (m, 4H), 7.10-6.82 (m, 4H),
6.53 (s, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) d (ppm)
134.3, 130.4, 129.6, 129.2, 127.0, 122.5, 117.3, 74.1, 21.2; ESI-
HRMS: calcd. for C16H14NO3+H 268.09805, found 268.09793;
[a]2D5 = -34.5 (c 0.35, ethanol), 82% ee; The enantiomeric ratio
was determined by HPLC on Chiralpak OJ-RH column (10% 2-
propanol–hexane, 1 mL min-1), tminor = 6.59 min, tmajor = 9.56 min.
2-propanol–hexane, 1 mL min-1), tmajor = 13.81 min, tminor
=
17.47 min.
(R)-2-(4-Methoxyphenyl)-3-nitro-2H-chromene (4f). 1H NMR
(400 MHz, CDCl3) d (ppm) 8.03 (s, 1H), 7.32-7.25 (m, 4H), 7.00-
6.96 (m, 1H), 6.84-6.80 (m, 3H), 6.52 (s, 1H), 3.75 (s, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm) 180.5, 134.2, 130.3, 129.1, 128.9, 128.5,
128.5, 122.4, 118.0, 117.3, 114.2, 73.9, 55.3; ESI-HRMS: calcd.
for C16H13NO4+Na 307.08317, found 307.08306; [a]2D5 = -20.0
(c 0.22, ethanol), 68% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak OJ-RH column (10% 2-propanol–hexane,
1 mL min-1), tminor = 12.29 min, tmajor = 19.91 min.
(R)-7-Methoxy-2-(4-bromophenyl)-3-nitro-2H-chromene (4l).
1H NMR (400 MHz, CDCl3) d (ppm) 8.05 (s, 1H), 7.47-7.23
(m, 5H), 6.59-6.40 (m, 3H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3) d (ppm) 165.3, 136.0, 135.2, 132.0, 131.8, 130.0, 128.7,
110.0, 110.0, 108.4, 102.2, 100.7, 55.7, 55.7; ESI-HRMS: calcd.
for C16H12BrNO4+Na 383.98503, found 383.98497; [a]2D5 = -29.0
(c 0.36, ethanol), 82% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak OJ-RH column (10% 2-propanol–hexane,
1 mL min-1), tmajor = 15.05 min, tminor = 19.78 min.
(R)-6-Fluoro-2-phenyl-3-nitro-2H-chromene (4g). 1H NMR
(400 MHz, CDCl3) d (ppm) 8.01 (s, 1H), 7.38-7.33 (m, 5H), 7.07-
7.01 (m, 2H), 6.86-6.83 (m, 1H), 6.58 (s, 1H); 13C NMR (100 MHz,
CDCl3) d (ppm) 158.9, 136.2, 129.6, 128.9, 128.3, 128.2, 127.0,
120.9, 120.6, 118.6, 118.5, 115.9, 115.7, 74.2; ESI-HRMS: calcd.
for C15H10FNO3+H 272.04432, found 272.04419; [a]2D5 = -35.5
(c 0.38, ethanol), 73% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak OJ-RH column (10% 2-propanol–hexane,
1 mL min-1), tminor = 9.84 min, tmajor = 12.43 min.
(R)-7-Methoxy-2-phenyl-3-nitro-2H-chromene (4h). 1H NMR
(400 MHz, CDCl3) d (ppm) 8.05 (s, 1H), 7.39-7.22 (m, 6H), 6.57-
6.54 (m, 2H), 6.79 (d, J = 2.4 Hz, 1H), 6.57 (s, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm) 165.1, 155.6, 137.9, 131.7, 129.8, 129.3,
128.8, 127.0, 111.1, 109.8, 102.2, 74.5, 55.6; ESI-HRMS: calcd.
for C16H13NO4+Na 307.08317, found 307.08303; [a]2D5 = -26.3
(c 0.51, ethanol), 86% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak OJ-RH column (10% 2-propanol–hexane,
1 mL min-1), tmajor = 15.93 min, tminor = 19.65 min.
(R)-7-Methoxy-2-p-tolyl-3-nitro-2H-chromene (4i). 1H NMR
(400 MHz, CDCl3) d (ppm) 8.08 (s, 1H), 7.31-7.15 (m, 5H), 6.60-
6.42 (m, 3H), 3.81 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3) d (ppm) 165.0, 155.6, 138.4, 134.1, 131.6, 130.0, 127.0,
127.0, 111.0, 109.7, 102.2, 74.4, 56.6, 21.2; ESI-HRMS: calcd.
for C17H15NO4+Na 320.09006, found 320.08917; [a]2D5 = -31.8
(c 0.21, ethanol), 87% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak OJ-RH column (10% 2-propanol–hexane,
1 mL min-1), tmajor = 13.40 min, tminor = 15.43 min.
Diethyl 3-phenyl-4-phenyl-3a-nitrobenzopyrano[3,4-c]-pyrroli-
dine-1,1-dicarboxylate (5a). 1H NMR (400 MHz, CDCl3) d
(ppm) 7.52 (d, J = 7.6 Hz, 1H), 7.34-7.05 (m, 11H), 6.94 (t, J =
7.6 Hz, 1H), 6.73 (d, J = 8.4 Hz, 1H), 5.68 (s, 1H), 5.64 (s, 1H),
5.55 (d, J = 9.6 Hz, 1H), 5.55 (d, J = 8.4 Hz, 1H), 4.47-4.42
(m, 2H), 3.73-3.62 (m, 2H), 3.19 (d, J = 5.2 Hz, 1H), 1.38 (t,
J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d (ppm) 170.7, 169.8, 152.0, 136.0, 134.5, 130.0, 129.3,
129.1, 128.9, 128.8, 128.4, 128.3, 127.7, 122.2, 121.6, 118.2, 96.9,
69.0, 62.7, 62.1, 47.6, 14.1; ESI-HRMS: calcd. for C29H28N2O7+H
517.19873, found 517.19693; [a]2D5 = -22.5 (c 0.70, ethanol),
19% ee; The enantiomeric ratio was determined by HPLC on
Chiralpak AD column (30% 2-propanol–hexane, 1 mL min-1),
tminor = 9.07 min, tmajor = 14.57 min.
3-Phenyl-4-(4-chlorophenyl)-3a-nitrobenzopyrano[3,4-c]-pyrroli-
dine-1,1-dicarboxylate (5b). 1H NMR (400 MHz, CDCl3) d
(ppm) 7.52 (d, J = 7.6 Hz, 1H), 7.36-7.07 (m, 10H), 6.98-6.94 (m,
1H), 6.74-6.72 (m, 1H), 5.65(s, 1H), 5.61(s,1H), 5.50(s,1H), 4.49-
4.39 (m, 2H), 3.77-3.59(m, 2H), 3.17 (s, 1H), 1.38 (t, J = 7.2 Hz,
3H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
(ppm) 170.6,168.7, 151.9, 134.9, 133.1, 130.1, 129.7, 129.4, 129.2,
128.8, 128.5, 127.3, 122.4, 121.3, 118.1, 96.8, 68.9, 62.7, 62.1, 47.4,
14.1, 13.5; ESI-HRMS: calcd. for C29H27ClN2O7+H 551.16003,
found 551.15796; [a]D25 = -11.3 (c 0.80, CH2Cl2), 17% ee; The
enantiomeric ratio was determined by HPLC on Chiralpak AD
column (30% 2-propanol–hexane, 1 mL min-1), tminor = 9.17 min,
tmajor = 19.75 min.
(R)-7-Methoxy-2-(4-methoxyphenyl)-3-nitro-2H-chromene (4j).
1H NMR (400 MHz, CDCl3) d (ppm) 8.05 (s, 1H), 7.32-7.23 (m,
3H), 6.85-6.83 (m, 2H), 6.57-6.38 (m, 3H), 3.79-3.77 (m, 6H);
3-Phenyl-4-(4-bromophenyl)-3a-nitrobenzopyrano[3,4-c]-pyrro-
lidine-1,1-dicarboxylate (5c). 1H NMR (400 MHz, CDCl3) d
(ppm) 7.52 (d, J = 7.6 Hz, 1H), 7.35-7.06 (m, 10H), 6.97
2120 | Org. Biomol. Chem., 2010, 8, 2117–2122
This journal is
The Royal Society of Chemistry 2010
©

View Article Online
(t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 5.65 (s, 1H),
5.60 (s, 1H), 5.51 (d, J = 5.2 Hz, 1H), 4.48-4.41 (m, 2H), 3.59-
3.37 (m, 2H), 3.18 (d, J = 5.2 Hz, 1H), 1.38 (t, J = 7.2 Hz,
3H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
(ppm) 170.6, 168.7, 151.7, 135.9, 133.6, 131.4, 130.1, 130.0, 129.4,
129.3, 127.3, 123.2, 121.3, 118.1, 76.7, 69.0, 62.7, 62.1, 47.4, 45.8,
14.1, 13.4; ESI-HRMS: calcd. for C29H27BrN2O7+Na 617.09180,
found 617.08938; [a]D25 = -18.3 (c 0.76, CH2Cl2), 35% ee; The
enantiomeric ratio was determined by HPLC on Chiralpak AD
column (30% 2-propanol–hexane, 1 mL min-1), tminor = 10.45 min,
tmajor = 21.37 min.
3-Phenyl-4-(4-(trifluoromethyl)phenyl)-3a-nitrobenzopyrano-
[3,4-c]-pyrrolidine-1,1-dicarboxylate (5d). 1H NMR (400 MHz,
CDCl3) d (ppm) 7.58-7.29 (m, 10H), 7.14-6.99 (m, 2H), 6.78 (d, J =
8.0 Hz, 1H), 5.73-5.71 (m, 2H), 5.56 (d, J = 4.8 Hz, 1H), 4.51-4.46
(m, 2H), 3.84-3.64 (m, 2H), 3.24 (d, J = 4.8 Hz, 1H), 1.42 (t, J =
7.2 Hz, 3H), 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d (ppm) 170.6, 168.7, 151.8, 138.5, 131.0, 130.8, 129.5, 129.3,
128.9, 128.8, 127.3, 125.3,125.2, 125.1, 125.0, 122.6, 122.4, 121.1,
118.1, 96.7, 68.9, 62.8, 62.2, 47.3, 14.1, 13.5; ESI-HRMS: calcd.
for C30H27F3N2O7+Na 607.16791, found 607.16626; [a]2D5 = -22.6
(c 0.69, ethanol), 49% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak AD column (30% 2-propanol–hexane,
1 mL min-1), tminor = 7.16 min, tmajor = 13.53 min.
3-Phenyl-4-(4-methylphenyl)-3a-nitrobenzopyrano[3,4-c]-pyrro-
lidine-1,1-dicarboxylate (5e). 1H NMR (400 MHz, CDCl3) d
(ppm) 7.50 (d, J = 7.6 Hz, 1H), 7.35-6.91 (m, 11H), 6.72 (d,
J = 8.0 Hz, 1H), 5.67 (s, 1H), 5.64 (s, 1H), 5.53 (d, J = 1.6 Hz,
1H), 4.47-4.42 (m, 2H), 3.72-3.59 (m, 2H), 3.17 (d, J = 3.6 Hz,
1H), 2.21 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz, CDCl3) d (ppm) 170.7, 169.8, 152.0,
138.7, 136.0, 131.4, 130.0, 129.3, 129.0, 128.8, 128.2, 127.3, 121.7,
118.2, 96.9, 68.1, 62.7, 62.1, 47.6, 21.1, 14.1, 13.5. IR (KBr) cm-1
3345, 1741, 1712, 1582, 1489, 1458, 768; ESI-HRMS: calcd. for
C30H30N2O7+H 531.21415, found 531.21407; [a]2D5 = -28.6 (c
0.48, ethanol), 45% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak AD column (30% 2-propanol–hexane,
1 mL min-1), tminor = 8.96 min, tmajor = 11.52 min.
3-Phenyl-4-(4-methoxyphenyl)-3a-nitrobenzopyrano[3,4-c]-
pyrrolidine-1,1-dicarboxylate (5f). 1H NMR (400 MHz, CDCl3)
d (ppm) 7.53 (d, J = 7.6 Hz, 1H), 7.36-7.09 (m, 10H), 6.97 (t, J =
7.6 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.64 (d, J = 10.2 Hz, 2H),
5.51 (d, J = 7.6 Hz, 1H), 4.50-4.40 (m, 2H), 3.78-3.60 (m, 2H),
3.19-3.17 (m, 3H), 1.42-1.37 (m, 3H), 0.94 (t, J = 10.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d (ppm) 170.6, 168.7, 151.9, 134.9,
133.1, 130.1, 129.7, 129.4, 129.2, 128.8, 128.4, 127.3, 122.4, 121.3,
118.1, 96.8, 68.9, 62.7, 62.1, 47.4, 14.0, 13.8; ESI-HRMS: calcd.
for C30H30N2O8+Na 541.97903, found 541.97815; [a]2D5 = -28.6 (c
0.50, ethanol), 21% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak AD column (30% 2-propanol–hexane,
1 mL min-1), tminor = 11.13 min, tmajor = 14.13 min.
128.8, 128.3, 128.3, 127.3, 119.3, 119.2, 116.4, 116.2, 116.1, 115.8,
96.5, 68.8, 62.8, 62.3, 47.6, 14.0, 13.4; ESI-HRMS: calcd. for
C29H27FN2O7+Na 557.17051, found 557.16945; [a]2D5 = -23.3 (c
0.56, ethanol), 53% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak AD column (30% 2-propanol–hexane,
1 mL min-1), tminor = 10.78 min, tmajor = 23.81 min.
Diethyl 9-methoxy-3-phenyl-4-phenyl-3a-nitrobenzopyrano[3,4-
c]-pyrrolidine-1,1-dicarboxylate (5h). 1H NMR (400 MHz,
CDCl3) d (ppm) 7.42-7.22 (m, 12H), 6.55-6.52 (m, 1H), 6.29 (d,
J = 2.4 Hz, 1H), 5.62 (d, J = 2.8 Hz, 1H), 5.50 (d, J = 4.2 Hz,
1H), 4.47-4.42 (m, 2H), 3.84-3.65 (m, 5H), 3.16 (d, J = 4.2 Hz,
1H), 1.38 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm) 170.8, 168.9, 160.2, 153.0, 134.5, 130.7,
129.3, 128.8, 128.3, 127.3, 96.9, 62.8, 62.5, 62.1, 56.3, 47.2, 14.1,
13.6; C30H30N2O8+Na 541.97917, found 541.97873; [a]2D5 = -13.1
(c 0.70, ethanol), 33% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak AD column (30% 2-propanol–hexane,
1 mL min-1), tminor = 11.1 min, tmajor = 18.41 min.
Diethyl 9-methoxy-3-phenyl-4-(4-methylphenyl)-3a-nitrobenzo-
pyrano[3,4-c]-pyrrolidine-1,1-dicarboxylate
(5i). 1H
NMR
(400 MHz, CDCl3) d (ppm) 7.40-7.26 (m, 6H), 7.09-7.00 (m, 4H),
6.55-6.52 (m, 1H), 6.30 (d, J = 1.2 Hz, 1H), 5.60 (d, J = 7.2 Hz,
2H), 6.51 (s, 1H), 4.47-4.42 (m, 2H), 3.81-3.66 (m, 5H), 3.16 (d,
J = 5.2 Hz, 1H), 2.25 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H), 1.00 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) d (ppm) 170.8,
169.9, 160.2, 153.3, 138.7, 136.2, 131.4, 130.6, 129.2, 128.9, 128.7,
127.3, 113.4, 109.1, 102.1, 96.9, 68.9, 62.6, 62.1, 55.3, 47.2, 21.1,
14.1, 13.6; ESI-HRMS: calcd. for C31H32N2O8+H 561.22455,
found 561.22391; [a]2D5 = -19.6 (c 0.65, ethanol), 57% ee; The
enantiomeric ratio was determined by HPLC on Chiralpak AD
column (10% 2-propanol–hexane, 1 mL min-1), tmajor = 5.69 min,
tminor = 7.04 min.
Diethyl
9-methoxy-3-phenyl-4-(4-methoxyphenyl)-3a-nitro-
benzopyrano[3,4-c]-pyrrolidine-1,1-dicarboxylate (5j). 1H NMR
(400 MHz, CDCl3) d (ppm) 7.41-7.11 (m, 8H), 6.74-6.52 (m,
3H), 6.30 (d, J = 2.4 Hz, 1H), 5.61 (s, 1H), 5.58 (s, 1H), 5.49 (s,
1H), 4.46-4.42 (m, 2H), 3.84-3.62 (m, 8H), 3.15 (s, 1H), 1.39 (t,
J = 7.6 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d (ppm) 160.2, 159.8, 130.5, 129.7, 129.2, 128.7, 127.3,
126.6, 113.7, 110.1, 109.1, 102.7, 97.0, 68.9, 62.5, 55.2, 55.1, 47.1,
14.1, 13.6; ESI-HRMS: calcd. for C31H32N2O9+Na 599.20127,
found 599.20095; [a]2D5 = -21.1 (c 0.540, ethanol), 70% ee; The
enantiomeric ratio was determined by HPLC on Chiralpak AD
column (10% 2-propanol–hexane, 1 mL min-1), tminor = 5.71 min,
tmajor = 7.08 min.
9-Methoxy-3-phenyl-4-(4-chlorophenyl)-3a-nitrobenzopyrano-
[3,4-c]-pyrrolidine-1,1-dicarboxylate (5k). 1H NMR (400 MHz,
CDCl3) d (ppm) 7.42-7.14 (m, 10H), 6.56-6.33 (m, 1H), 6.28 (d,
J = 2.4 Hz, 1H), 5.59 (d, J = 6.0 Hz, 2H), 5.47 (d, J = 4.0 Hz, 1H),
4.47-4.39 (m, 2H), 3.85-3.65 (m, 5H), 3.15 (d, J = 4.0 Hz, 1H), 1.38
(t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d (ppm) 169.9, 160.3, 134.9, 133.1, 130.7, 129.7, 129.3,
128.8, 128.5, 127.3, 109.4, 102.6, 96.7, 68.8, 62.6, 62.1, 55.2, 47.0,
14.0, 13.5; ESI-HRMS: calcd. for C30H29ClN2O8+H 581.16998,
found 581.16879; [a]2D5 = -15.8 (c 0.40, ethanol), 51% ee; The
enantiomeric ratio was determined by HPLC on Chiralpak AD
Diethyl 8-fluoro-3-phenyl-4-phenyl-3a-nitrobenzopyrano[3,4-c]-
pyrrolidine-1,1-dicarboxylate (5g). 1H NMR (400 MHz, CDCl3)
d (ppm) 7.35-7.18 (m, 12H), 6.80-6.68 (m, 2H), 5.65-5.51 (m, 3H),
4.51-4.40 (m, 2H), 3.87-3.71 (m, 2H), 3.19 (d, J = 4.8 Hz, 1H),
1.39 (t, J = 5.2 Hz, 3H), 0.92 (t, J = 3.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d (ppm) 170.5, 169.6, 135..0, 134.2, 129.3,
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2117–2122 | 2121
©

View Article Online
column (10% 2-propanol–hexane, 0.5 mL min-1), tmajor = 6.26 min,
tminor = 7.00 min.
Arvidsson, Tetrahedron: Asymmetry, 2006, 17, 1763; (c) H. Li, J. Wang,
T. ENunu, L. Zu, W. Jiang, S. Wei and W. Wang, Chem. Commun.,
2007, 507; (d) H. Sunde´n, I. Ibrahem, G.-L. Zhao, L. Eriksson and
A. Co´rdova, Chem.–Eur. J., 2007, 13, 574; (e) R. Rios, H. Sunde´n,
I. Ibrahem and A. Co´rdova, Tetrahedron Lett., 2007, 48, 2181.
7 (a) H. Booth, D. Huckle and I. M. Lockhart, J. Chem. Soc., Perkin
Trans. 2, 1973, 227; (b) L. Rene, L. Blanco, R. Royer, R. Cavier and J.
Lemoine, Eur. J. Med. Chem., 1977, 12, 385; (c) L. Rene and R. Royer,
Eur. J. Med. Chem-Chim. Ther., 1982, 17, 89; (d) S. R. Deshpande, H. H.
Mathur and G. K. Trivedi, Synthesis, 1983, 835; (e) N. Ono, K. Sugi,
T. Ogawa and S. Aramaki, J. Chem. Soc., Chem. Commun., 1993, 1781;
(f) L. Johansson, D. Sohn, S.-O. Thorberg, D. M. Jackson, D. Kelder,
L.-G. Larsson, L. Renyi, S. B. Ross, C. Wallsten, H. Eriksson, P.-S. Hu,
E. Jerning, N. Mohell and A. Westlind-Danielsson, J. Pharmacol. Exp.
Ther., 1997, 283, 216; (g) M. Nyerges, A. Vira´nyi, G. Marth, A. Dancso´,
G. Blasko´ and L. To¨ke, Synlett, 2004, 2761; (h) R. Muruganantham,
S. M. Mobin and I. N. N. Namboothiri, Org. Lett., 2007, 9, 1125; (i) G.
Kolokythas, I. K. Kostakis, N. Pouli, P. Marakos, O. C. Kousidou, G. N.
Tzanakakis and N. K. Karamanos, Eur. J. Med. Chem., 2007, 42, 307;
(j) T. Furuta, Y. Hirooka, A. Abe, Y. Sugata, M. Ueda, K. Murakami,
T. Suzuki, K. Tanaka and T. Kan, Bioorg. Med. Chem. Lett., 2007, 17,
3095.
8 (a) D.-Q. Xu, Y.-F. Wang, S.-P. Luo, S. Zhang, A.-G. Zhong, H. Chen
and Z.-Y. Xu, Adv. Synth. Catal., 2008, 350, 2610; (b) T. Karthikeyan
and S. Sankararaman, Tetrahedron: Asymmetry, 2008, 19, 2741.
9 A. Vira´nyi, G. Marth, A. Dancsa´, G. Blaska´, L. To¨ke and M. Nyerges,
Tetrahedron, 2006, 62, 8720.
10 (a) J.-A. Ma, Angew. Chem., 2003, 115, 4426, (Angew. Chem., Int. Ed.,
2003, 42, 4290); (b) S. Kobayashi and H. Ishitani, Chem. Rev., 1999, 99,
1069; (c) H. Ishitani, M. Ueno and S. Kobayashi, J. Am. Chem. Soc.,
1997, 119, 7153; (d) M. P. Sibi, J. J. Shay, M. Liu and C. P. Jasperse,
J. Am. Chem. Soc., 1998, 120, 6615; (e) J. K. Myers and E. N. Jacobsen,
J. Am. Chem. Soc., 1999, 121, 8959; (f) A. G. Wenzel and E. N. Jacobsen,
J. Am. Chem. Soc., 2002, 124, 12964.
11 For reviews, see: (a) E. Vedejs and M. Jure, Angew. Chem., Int. Ed.,
2005, 44, 3974; (b) J. M. Keith, J. F. Larrow and E. N. Jacobsen, Adv.
Synth. Catal., 2001, 343, 5; (c) D. E. J. E. Robinson and S. D. Bull,
Tetrahedron: Asymmetry, 2003, 14, 1407.
12 (a) A. Berkessel, F. Cleemann, S. Mukherjee, T. N. Mu¨ller and J. Lex,
Angew. Chem., Int. Ed., 2005, 44, 807; (b) A. Berkessel, S. Mukherjee,
F. Cleemann, T. N. Mu¨ller and J. Lex, Chem. Commun., 2005, 1898;
(c) A. Berkessel, F. Cleemann and S. Mukherjee, Angew. Chem., Int.
Ed., 2005, 44, 7466; (d) A. Berkessel, S. Mukherjee, T. N. Mu¨ller, F.
Cleemann, K. Roland, M. Brandenburg, J.-M. Neudo¨rfl and J. Lex,
Org. Biomol. Chem., 2006, 4, 4319.
13 For other applications of thiourea–tertiary amine bifunctional
organocatalysts see: (a) T. Okino, Y. Hoashi and Y. Takemoto, J. Am.
Chem. Soc., 2003, 125, 12672; (b) T. Okino, Y. Hoashi, T. Furukawa, X.
Xu and Y. Takemoto, J. Am. Chem. Soc., 2005, 127, 119; (c) Y. Hoashi,
T. Yabuta, P. Yuan, H. Miyabe and Y. Takemoto, Tetrahedron, 2006,
62, 365; (d) Y. Hoashi, T. Yabuta and Y. Takemoto, Tetrahedron Lett.,
2004, 45, 9185; (e) B.-J. Li, L. Jiang, M. Liu, Y.-C. Chen, L.-S. Ding
and Y. Wu, Synlett, 2005, 603; (f) B. Vakulya, S. Varga, A. Csampai
and T. Soos, Org. Lett., 2005, 7, 1967; (g) J. Ye, D. J. Dixon and P. S.
Hynes, Chem. Commun., 2005, 4481; (h) J. Wang, H. Li, X. Yu, L. Zu
and W. Wang, Org. Lett., 2005, 7, 4293; (i) S. H. McCooey and S. J.
Connon, Angew. Chem., Int. Ed., 2005, 44, 6367; (j) J. Wang, H. Li, W.
Duan, L. Zu and W. Wang, Org. Lett., 2005, 7, 4713; (k) D. E. Fuerst
and E. N. Jacobsen, J. Am. Chem. Soc., 2005, 127, 8964; (l) A. P. Dove,
R. C. Pratt, B. G. G. Lohmeijer, R. M. Waymouth and J. L. Hedrick,
J. Am. Chem. Soc., 2005, 127, 13798; (m) X. Xu, T. Yabuta, P. Yuan
and Y. Takemoto, Synlett, 2006, 137; (n) A. L. Tillman, J. Ye and D. J.
Dixon, Chem. Commun., 2006, 1191; (o) J. Wang, H. Li, L. Zu, W. Jiang,
H. Xie, W. Duan and W. Wang, J. Am. Chem. Soc., 2006, 128, 12652.
14 J. W. Xie, K. Yoshida, K. Takasu and Y. Takemoto, Tetrahedron Lett.,
2008, 49, 6910.
9-Methoxy-3-phenyl-4-(4-bromophenyl)-3a-nitrobenzopyrano-
[3,4-c]-pyrrolidine-1,1-dicarboxylate (5l). 1H NMR (400 MHz,
CDCl3) d (ppm) 7.43-7.26 (m, 8H), 7.10-7.08 (m, 2H), 6.56-6.54
(m, 1H), 6.29 (d, J = 6.4 Hz, 1H), 5.59 (s, 2H), 5.48 (s, 1H),
4.48-4.41 (m, 2H), 3.85-3.66 (m, 5H), 3.16 (s, 1H), 1.39 (t, J =
7.2 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d (ppm) 170.7, 168.8, 160.3, 152.9, 136.0, 133.6, 131.5,
130.7, 130.0, 129.4, 128.8, 127.3, 123.2, 113.0, 109.4, 102.7,
96.7, 68.8, 62.6, 62.1, 55.3, 47.0, 14.1, 13.6; ESI-HRMS: calcd.
for C30H29BrN2O8+H 625.11800, found 625.11820; [a]2D5 = -17.2
(c 0.34, ethanol), 13% ee; The enantiomeric ratio was determined
by HPLC on Chiralpak AD column (10% 2-propanol–hexane,
0.5 mL min-1), tmajor = 13.78 min, tminor = 24.97 min.
Acknowledgements
We are grateful for the financial support from the National Natural
Science Foundation of China (20902083, 20672101), Province
Natural Science Foundation of Zhejiang (Y4090082) and Zhejiang
Normal University.
Notes and references
1 J. Nareshkumar, M. K. Ramesh, X. Jiayi, G. Jian-Zhong, P. Emmanuel,
L. Muh-Tsann, D. Fuyong, M. Amy, A. George, H. DoWon, L. Scott
and S. Zhihua, J. Med. Chem., 2006, 49, 3056.
2 (a) K. C. Nicolaou, J. A. Pfefferkorn, A. J. Roecker, G.-Q. Cao, S.
Barluenga and H. J. Mitchell, J. Am. Chem. Soc., 2000, 122, 9939;
(b) K. C. Nicolaou, J. A. Pfefferkorn, H. J. Mitchell, A. J. Roecker, S.
Barluenga, G.-Q. Cao, R. L. Affleck and J. E. Lillig, J. Am. Chem. Soc.,
2000, 122, 9954; (c) K. C. Nicolaou, J. A. Pfefferkorn, S. Barluenga,
H. J. Mitchell, A. J. Roecker and G.-Q. Cao, J. Am. Chem. Soc., 2000,
122, 9968; (d) G. Zeni and R. C. Larock, Chem. Rev., 2004, 104, 2285;
(e) J. Mori, M. Iwashima, M. Takeuchi and H. Saito, Chem. Pharm.
Bull., 2006, 54, 391; (f) Y. Kashiwada, K. Yamazaki, Y. Ikeshiro, T.
Yamasisbi, T. Fujioka, K. Milashi, K. Mizuki, L. M. Cosentino, K. S.
Fowke, L. M. Natschke and K.-H. Lee, Tetrahedron, 2001, 57, 1559.
3 (a) W. O. Foye, Principi Di Chemico Farmaceutica, Piccin, Padova, Italy,
1991, p 416; (b) L. L. Andreani and E. Lapi, Bull. Chim. Farm., 1960,
99, 583; (c) Y. L. Zhang, B. Z. Chen, K. Q. Zheng, M. L. Xu and X. H.
Lei, Yao Xue Bao, 1982, 17, 17; Chem. Abstr, 1982, 96, 135383e; (d) L.
Bonsignore, G. Loy, D. Secci and A. Calignano, Eur. J. Med. Chem.,
1993, 28, 517; (e) E. C. Witte, P. Neubert and A. Roesch, Ger. Offen DE
(Cl. C07D405/12), 1986, p 25; Chem. Abstr., 1986, 104, 224915f.
4 L. J. Machlin, a-Tocopherol, Marcel Dekker, New York, NY, 1980.
5 (a) B. Lesch and S. Bra¨se, Angew. Chem., 2004, 116, 118, (Angew. Chem.,
Int. Ed., 2004, 43, 115); (b) P. T. Kaye and M. A. Musa, Synthesis, 2002,
2701; (c) P. T. Kaye and X. W. Nocanda, Synthesis, 2001, 2389; (d) R.
Ballini, G. Bosica, D. Fiorini and A. Palmieri, Green Chem., 2005, 7,
825; (e) M.-C. Yan, Y.-J. Jang, W.-Y. Kuo, Z. Tu, K.-H. Shen, T.-S. Cuo,
C.-H. Ueng and C.-F. Yao, Heterocycles, 2002, 57, 1033; (f) M.-C. Yan,
Y.-J. Jang and C.-F. Yao, Tetrahedron Lett., 2001, 42, 2717; (g) R. S.
Varma and G. W. Kabalka, Heterocycles, 1985, 23, 139; (h) T. S. Rao,
S. Deshpande, H. H. Mathur and G. K. Trivedi, Heterocycles, 1984, 22,
1943.
6 (a) W. Wang, H. Li, J. Wang and L. Zu, J. Am. Chem. Soc., 2006,
128, 10354; (b) T. Govender, L. Hojabri, F. M. Moghaddam and P. I.
2122 | Org. Biomol. Chem., 2010, 8, 2117–2122
This journal is
The Royal Society of Chemistry 2010
©