Synthesis of Highly Functionalized Chiral Benzopyrano[3,4-c]pyrrolidines Bearing Five Contiguous Stereogenic Centers

Article abstract of DOI:10.1021/acs.joc.5b01445

A chiral bis(imidazolidine)pyridine-Cu complex smoothly catalyzed the asymmetric [3 + 2] cycloaddition reaction of α,β-unsaturated ester-containing nitroalkenes with imino esters to give endo-pyrrolidine products in a highly enantioselective manner while maintaining the α,β-unsaturated ester functionality. Subsequent intramolecular diastereoselective cyclizations of the obtained pyrrolidine products were accomplished by treatment with KF/Al₂O₃ in toluene/EtOH (4:1) to give highly functionalized benzopyrano[3,4-c]pyrrolidines bearing five contiguous stereogenic centers.

Full text of DOI:10.1021/acs.joc.5b01445

Subscriber access provided by UNIV PRINCE EDWARD ISLAND
Note
Synthesis of Highly Functionalized Chiral Benzopyrano[3,4-
c]pyrrolidines Bearing Five Contiguous Stereogenic Centers
Toru Sato, Tomoya Miyazaki, and Takayoshi Arai
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01445 • Publication Date (Web): 21 Sep 2015
Downloaded from http://pubs.acs.org on September 23, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Synthesis of Highly Functionalized Chiral Benzopyrano[3,4-c]pyrrolidines Bearing Five
8
9
Contiguous Stereogenic Centers
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Toru Sato, Tomoya Miyazaki and Takayoshi Arai*
Molecular Chirality Research Center, and Department of Chemistry, Graduate School of
Science, Chiba University, Inage 263-8522, Japan
ABSTRACT: A chiral bis(imidazolidine)pyridine–Cu complex smoothly catalyzed the
asymmetric [3+2] cycloaddition reaction of α,β-unsaturated ester-containing
nitroalkenes with imino esters to give the endo-pyrrolidine products in a highly
enantioselective manner while maintaining the α,β-unsaturated ester functionality.
Subsequent intramolecular diastereoselective cyclizations of the obtained pyrrolidine
products were accomplished by treatment with KF/Al2O3 in toluene/EtOH (4:1) to give
highly functionalized benzopyrano[3,4-
stereogenic centers.
c]pyrrolidines bearing five contiguous
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 35
1
2
3
4
5
6
7
Benzopyrano[3,4-
c]pyrrolidine is a unique and important core structure in medicinal
8
9
chemistry (Figure 1). For example, S33138, a dopamine-D3-receptor antagonist, has a
]pyrrolidine framework as the pharmacophore.1 Abbott Co., Ltd.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
trans-benzopyrano[3,4-
c
adopted the cis-benzopyrano[3,4-c]pyrrolidine framework to develop Fiduxosin as an
α1-adrenoceptor antagonist.2
Figure 1. Biologically important chiral benzopyrano[3,4-c]pyrrolidine derivatives.
In spite of the crucial role of benzopyrano[3,4-c]pyrrolidines in medicinal chemistry,
there are a limited number of catalytic asymmetric synthetic methods to prepare
]pyrrolidine derivatives.1b,2b For an example, in 2012, Enders et al
.
benzopyrano[3,4-
c
reported a short and highly stereoselective synthesis of a decyano derivative of S33138
via a catalytic asymmetric domino oxa-Michael/Michael reaction of nitrovinylphenol
with acrolein.3 Considering the fascinating structure and bioactivity, further diversified
ACS Paragon Plus Environment

Page 3 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
benzopyrano[3,4-
c
]pyrrolidine derivatives having multiple arrays of stereogenic centers
8
9
are important for investigating unsolved biological phenomena, and for enhancing the
biological selectivity of drug candidates.4,5 Because [3+2] cycloaddition is a powerful tool
for the construction of highly functionalized chiral five-membered pyrrolidines, here we
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
present a concise synthesis of benzopyrano[3,4-c]pyrrolidines bearing five contiguous
stereogenic centers via the catalytic asymmetric [3+2] cycloaddition of imino esters with
nitroalkenes.6,7
We previously succeeded in the development of
a
chiral N,N,N-tridentate
bis(imidazolidine)pyridine (PyBidine)–Cu complex8 for the catalytic asymmetric [3+2]
cycloaddition using imino esters. The PyBidine-Cu(OTf)2 complex catalyzed the
asymmetric [3+2] cycloaddition of imino esters with nitroalkenes in a highly
endo-selective manner to give the chiral pyrrolidines with up to 99% ee (Scheme 1).8a
Ph
Bn
Ph
Bn
NH
HN
Ph
Ph
N
N
N
NO2
R3
R4
R4
R3
R2
CO2Me
PyBidine
Cu(OTf)2 (5 mol%)
O2N
R1
+
R2
Cs2CO3, dioxane, rt
N
H
R1
N
CO2Me
highly endo-selective
up to 99% ee
Scheme 1. PyBidine–Cu-catalyzed asymmetric endo-selective [3+2]cycloaddition.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 35
1
2
3
4
5
6
7
The chiral benzopyrano[3,4-c]pyrrolidine derivatives (1) bearing five contiguous
8
9
stereogenic centers were designed as shown in Scheme 2. Because the
PyBidine-Cu(OTf)2-catalyzed [3+2] cycloaddition of imino esters with nitrostyrenes can
provide 3-aryl-4-nitropyrrolidines, the construction of a chroman ring was planned by
diastereoselective cyclization using conjugate addition at the 4-position of pyrrolidine to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
the
β-oxo-α,β-unsaturated
ester
side
chain
in
intermediate
2.
The
3-phenyl-4-nitropyrrolidine intermediates 2 having the β-oxo-α,β-unsaturated ester at
the ortho-position of the benzene ring would be provided by the endo-selective [3+2]
cycloaddition of imino esters (4) with ortho-nitrovinyl phenoxyacrylates (3).
Scheme
2.
Retrosynthesis
c]pyrrolidines.
of
highly
functionalized
chiral
benzopyrano[3,4-
The ortho-nitrovinyl phenoxyacrylate (3a: R1=H, R4=Et) was prepared from
ACS Paragon Plus Environment

Page 5 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
salicylaldehyde according to a known procedure (see Supporting Information).9 Under
the original conditions, the PyBidine–Cu complex smoothly catalyzed the asymmetric
[3+2] cycloaddition reaction of 3a with imino ester (4a: R2=Ph, R3=Et) in dioxane to give
the pyrrolidine product (2a) with the phenoxyacrylate functionality intact in 77% yield
in an endo-selective manner (endo:exo = 97:3). The enantioselectivity of the endo-adduct
was 97% ee. When the reaction was carried out in CH2Cl2 at 0 °C, 72% of endo-2a was
obtained in excellent diastereoselectivity (endo:exo = >99:1) with 99% ee.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The scope of the PyBidine-Cu(OTf)2-catalyzed endo-selective asymmetric [3+2]
cycloaddition reaction of ortho-nitrovinyl phenoxyacrylates (3) with imino esters (4) is
summarized in Scheme 3. Both electron-deficient and electron-donating aryl
functionalities were successfully employed as the R2-substituents of the imino esters to
provide the endo-products in 94-99% ee, though the introduction of an electron-deficient
substituent reduced the chemical yields. An ortho-fluorinated phenyl substrate was also
compatible in the PyBidine-Cu(OTf)2-catalyzed asymmetric [3+2] cycloaddition to give
the product endo-2e in 59% yield with 97% ee. For the ortho-nitrovinyl
phenoxyacrylates, the substrates having additional alkyl substituents on the benzene
ring were converted to the endo-products 2f and 2g with 95% ee and 98% ee,
respectively.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 35
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment

Page 7 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Scheme 3. endo-Selective asymmetric [3+2] cycloaddition reaction of ortho-nitrovinyl
8
9
phenoxyacrylate with imino esters catalyzed by PyBidine–Cu(OTf)2 complex.a-c)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
Br
EtO2C
H
EtO2C
H
EtO2C
H
NH
NH
NH
NO2
CO2Et
NO2
CO2Et
NO2
CO2Et
O
O
O
2a: 72%
endo:exo = >99:1
99% ee
(77%, endo:exo = 97:3
97% ee)d)
2b: 83%
endo:exo = >99:1
94% ee
2c: 57%
endo:exo = >99:1
98% ee
(60%, endo:exo = 94:6
95% ee)d)
OCH3
F
EtO2C
EtO2C
EtO2C
NH
NH
NH
H
H
H
H3C
NO2
NO2
NO2
CO2Et
CO2Et
CO2Et
O
O
O
2d: 80%
endo:exo = >99:1
93% ee
2e: 59%
endo:exo = >99:1
97% ee
2f: 50%
endo:exo = >99:1
95% ee
(49%, endo:exo = 88:12
60% ee)d)
(56%, endo:exo = 96:4
83% ee)d)
Br
EtO2C
NH
H
H3C
NO2
CO2Et
O
2g: 58%
endo:exo = >99:1
98% ee
1
a) Isolated yield. b) Diastereoselectivity (dr) was determined by evaluation of H-NMR
spectra of the crude products. c) Enantiomeric excess (ee) was determined by chiral
HPLC analysis of the product using a Daicel Chiralcel OD-H and Chiralpak AD-H
columns (hexane/2-propanol). The absolute configuration is presented by analogy with
the product synthesized from nitroalkene without α,β-unsaturated ester.8a d) Values of
parenthesis are the results carried in dioxane.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 35
1
2
3
4
5
6
7
Next, we focused on the cyclization of endo-[3+2] cycloaddition adducts 2 by conjugate
8
9
addition of pyrrolidine at the 4-position to a β-oxo-α,β-unsaturated ester side chain. The
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
cyclization was examined using 2a (endo:exo = 97:3) as the test sample, and the results
are shown in Table 1. DBU and KOtBu as the base resulted in the formation of a
complex mixture. TBAF did not promote the reaction at all.
Table 1. Optimization of cyclization of endo-[3+2] cycloaddition adducts 2.
Entry
Base
Solvent
EtOH
EtOH
EtOH
EtOH
Time (h)
yielda (%)
drb
c)
1
2
3
4
5
6
7
8
9
DBU
2
-
-
KOtBu
TBAF
K2CO3
2
-
-
c)
5.5
5.5
5.5
17
17
18
18
nrd)
<82
>99
89
-
75:25
75:25
91:9
94:6
96:4
97:3
KF/Al2O3 EtOH
KF/Al2O3 CH2Cl2-EtOH (4 : 1)
KF/Al2O3 Toluene-EtOH (4 : 1)
KF/Al2O3 Toluene-EtOH (9 : 1)
KF/Al2O3 Toluene-EtOH (19 : 1)
>99
96
76
1
1
a) Determined by H-NMR spectrums of crude products. b) Determined by H-NMR
spectra. c) Complex mixture was obtained. d) No reaction proceeded.
ACS Paragon Plus Environment

Page 9 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
When pyrrolidine product 2a was treated with KF/Al2O3 in EtOH, the desired
8
9
benzopyrano[3,4-c]pyrrolidine 1a was obtained in 99% yield in a diastereoselective
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
manner in a ratio of 75:25. Fortunately, 1a retained the 97% ee from the starting
material 2a. To improve the diastereoselectivity, detailed examination of the solvent
effects was conducted for the KF/Al2O3 promoted cyclization. The combined use of an
aprotic solvent with EtOH was effective for improving the diastereoselectivity, although
increasing the ratio of the aprotic solvent prolonged the reaction time. Finally, the
toluene-EtOH (4:1) solvent system was selected as the best choice for producing 1a in
>99% yield with 94:6 diastereoselectivity.
Under the optimized conditions, a series of chiral benzopyrano[3,4-c]pyrrolidines 1 was
synthesized from the endo-[3+2] cycloaddition adducts 2 obtained in Scheme 3 (Scheme
4). A simple filtering KF/Al2O3 out gave 1 with satisfied purities, and the further
purification wasn’t effective. After the concentration of filtrate, the isolated yield of 1
was reported with the purity in Scheme 3. All substrates (2a-g) were successfully
converted to benzopyrano[3,4-c]pyrrolidines (1a-g) with high diastereoselectivities while
maintaining the enantiomeric purities.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 35
1
2
3
4
5
6
7
8
9
Scheme 4. Synthesis of chiral benzopyrano[3,4-
stereogenic centers.a-d)
c]pyrrolidines having five contiguous
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a) Value of parenthesis is ee of 2. b) Isolated yield. c) Diastereoselectivity (dr) was
1
determined by evaluation of H-NMR spectra of the crude products. d) Enantiomeric
excess (ee) was determined by chiral HPLC analysis of the product using Daicel
Chiralcel OD-H and Chiralpak AD-H columns. e) Purity of products was evaluated by
1H-NMR spectra.
ACS Paragon Plus Environment

Page 11 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
The stereochemistry of the cis-benzopyrano[3,4-c]pyrrolidine product was determined
8
9
1
by 2D H–1H NOESY experiments on 1b (Figure 2). Because all substituents on the
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
benzopyrano[3,4-
benzopyrano[3,4-
compounds.
c
]pyrrolidine ring system were present on the convex phase, the
]pyrrolidines (1a-g) were obtained as thermodynamically stable
c
Figure 2. nOe connectivities of benzopyrano[3,4-c]pyrrolidine product (1b).
In conclusion, the PyBidine-Cu(OTf)2-catalyzed highly endo-selective asymmetric [3+2]
cycloaddition of nitroalkenes with imino esters was applied to the synthesis of novel chiral
benzopyrano[3,4-c]pyrrolidines bearing five contiguous stereogenic centers. The biological activity
of these unique molecules is being examined in our group.10
EXPERIMENTAL SECTION
General Information
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 35
1
2
3
4
5
6
7
8
9
Dry solvents were purchased from commercial suppliers and used without further purification.
Analytical thin-layer chromatography (TLC) was performed on glass plates coated with 0.25 mm
230-400 mesh silica gel containing a fluorescent indicator (Merck, #1.05715.0009). Silica gel
column chromatography was performed on Kanto silica gel 60 (spherical, 100-210 ꢀm). IR spectra
were recorded using ATR. Chemical shifts of 1H-NMR spectra were reported relative to tetramethyl
silane (δ 0). Chemical shifts of 13C-NMR spectra were reported relative to CDCl3 (δ 77.0). Splitting
patterns were reported as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Ethyl
(E)-3-{2-[(E)-2-nitrovinyl]phenoxy}prop-2-enoate were synthesized according to known procedure.9
Iminoesters were synthesized according to known procedure.11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Synthesis of Substrates
General synthetic routes of substrate 3
Substrates 3 were prepared by following the procedures.
ACS Paragon Plus Environment

Page 13 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of intermediate 4
To a solution of salicylaldehydes (26 mmol) in dry MeCN (130 mL), ethyl propiolate (1.1
eq) and
N-methylmorpholine (6 mol %) were added at 0 °C and the resultant mixture
was stirred at rt for 24 h. After evaporation, the residue was purified by silica-gel
column
chromatography
(hexane/ethyl
acetate=6/1)
to
afford
ethyl
(E)-3-{2-[(E)-2-formyl]phenoxy}prop-2-enoates (4).
Analytical data of ethyl (E)-3-(2-formylphenoxy)prop-enoate (4a):
1H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 7.93 (dd,
J
= 7.8, 1.7 Hz, 1H), 7.85 (d, J =
12.2 Hz, 1H), 7.67-7.63 (m, 1H), 7.32 (t,
J
= 7.7, 7.5 Hz, 1H), 7.16 (d,
J = 8.3 Hz, 1H), 5.64
(d,
J = 12.2 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.30 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 188.1, 166.5, 157.9, 157.5, 136.0, 128.9, 126.5, 125.3, 118.3, 104.2, 60.4, 14.3;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 35
1
2
3
4
5
6
7
8
FTMS (ESI) calcd for C12H12O4– [M – H]– 221.0808; found, 221.0804; FTIR (neat) 1715,
1697, 1228, 934, 824 cm-1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for the synthesis of intermediate 5
To a solution of ethyl (E)-3-{2-[(E)-2-formyl]phenoxy}prop-2-enoates (24 mmol) in t-BuOH
(24 mL) and THF (24 mL), CH3NO2 (5 eq) and t-BuOK (10 mol %) were added at 0 °C.
The resultant solution was stirred at rt for 16 h. The reaction mixture was diluted with
H2O and extracted with AcOEt. The combined organic layers were washed with brine,
dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica-gel
column chromatography (hexane/ethyl acetate=5/1) to afford the nitroaldols 5.
Analytical data of ethyl (
E)-3-[2-(1-hydroxy-2-nitroethyl)phenoxy]prop-enoate (5a):
1H NMR (400 MHz, CDCl3) δ 7.79 (d,
J
= 12.2 Hz, 1H), 7.63 (d,
J
= 7.7 Hz, 1H), 7.40 (t,
J
J
= 7.81 Hz, 1H), 7.23 (t,
J = 7.48 1H), 7.07 (d, J = 8.2 Hz, 1H), 5.73-5.69 (m, 1H), 5.60 (d,
= 12.2 Hz, 1H), 4.62-4.5 (m, 2H), 4.20 (t
J = 7.1 Hz 2H), 3.16 (J = 4.8 Hz), 1.29 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 157.9, 152.0, 130.2, 128.4, 127.6, 125.7,
117.5, 103.5, 65.8, 60.4, 30.9, 14.2; FTMS (ESI) calcd for C13H14NO6– [M – H]– 280.0827;
found, 280.0846; FTIR (neat) 3450, 1709, 1557, 1322, 932, 854 cm-1.
ACS Paragon Plus Environment

Page 15 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
General procedure for the synthesis of substrate 3
8
9
To a solution of nitroaldols (14 mmol) and NEt3 (2.1 eq) in CH2Cl2 (14 mL), MeSO2Cl (1.05
eq) was added dropwise at 0 °C. The resultant solution was stirred at rt for 1 h. The
reaction mixture was diluted with H2O and extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by silica-gel column chromatography (hexane/ethyl acetate=6/1). The
resulting residue was washed with hexane to afford substrate 3.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Analytical data of ethyl (E)-3-{2-[(E)-2-nitrovinyl]phenoxy}prop-2-enoate (3a):
1H NMR (400 MHz, CDCl3) δ 8.14 (d,
J
= 13.7 Hz, 1H), 7.77 (d, J = 12.2 Hz, 1H), 7.69 (d,
J
= 13.7 Hz, 1H), 7.59-7.51 (m, 2H), 7.29 (dd,
J
= 7.5, 0.9 Hz, 1H), 7.16 (dd,
J = 8.4, 0.9
Hz, 1H), 5.69 (d,
J
= 12.2 Hz, 1H), 4.22 (q,
J
= 7.1 Hz, 2H), 1.31 (t,
J
= 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 166.4, 157.2, 155.0, 139.0, 133.5, 133.1, 130.7, 125.5, 121.1,
–
118.3, 104.6, 60.4, 14.3; FTMS (ESI) calcd for C13H12NO5 [M – H]– 262.0721; found,
262.0734; FTIR (neat) 2986, 1715, 1577, 1346, 1126, 976, 852, 824 cm-1.
Analytical data of Ethyl (E)-3-{4-methyl-2-[(E)-2-nitrovinyl]phenoxy}prop-2-enoate (3b):
1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 13.8 Hz, 1H), 7.75 (d, J = 12.2 Hz, 1H), 7.67 (d, J = 13.8
Hz, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.32 (dd, J = 8.4, 1.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 5.63 (d, J
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 35
1
2
3
4
5
6
7
8
= 12.2 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.6, 157.8, 153.0, 138.8, 133.4, 134.2, 133.3, 130.9, 120.8, 118.4, 104.0, 60.4, 20.6,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
–
14.3; FTMS (ESI) calcd for C14H14NO5 [M – H]– 276.0877; found, 276.0896; FTIR (neat) 2923,
1708, 1582, 1517, 1369, 1236, 970, 843 cm-1.
General procedure of PyBidine-Cu(OTf)
2
catalyzed asymmetric [3+2]-cycloaddition
PyBidine (0.011 mmol) and Cu(OTf)
2
(0.01 mmol) were added to a round flask
containing a stir bar under Ar. CH
2Cl (1 mL) was added to the flask, and the mixture
2
was stirred for
1
hour. To the resulting solution were added ethyl
(E)-3-{2-[(E)-2-nitrovinyl]phenoxy}prop-2-enoate (0.2 mmol) and Cs2CO3 (0.02 mmol) at
rt. After cooling to 0 °C, to the mixture was added iminoester (0.22 mmol). After stirring
for appropriate time, the reaction mixture was diluted with sat. NaHCO3 aq. and
extracted with AcOEt. The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica-gel column
chromatography (hexane/ethyl acetate=3/1) to afford the pyrrolidine product 2.
General procedure of intramolecular diastreoselective cyclization of pyrrolidine product
2
ACS Paragon Plus Environment

Page 17 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
To a solution of pyrrolidine product 2 (0.18 mmol) in toluene/EtOH (4 : 1) was added KF/Al2O3
(0.18 mmol, Aldrich). After stirring at rt for appropriate time, the reaction mixture was filtered and
concentrated in vacuo to afford benzopyrano[3,4-c]pyrrolidine 1. (A simple filtering KF/Al2O3 out
gave 1 with satisfied purities. Further purification (e.g. silica-gel column chromatography, alumina
column chromatography, and preparative TLC) wasn’t effective. After the concentration of filtrate,
the isolated yield of 1 was reported with the purity in Scheme 3.)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl (2S,3R,4S,5S)-3-{2-[(E)-
2-carbethoxy-eth-1-enoxy]phenyl}-4-nitro-5-phenyl-pyrrolidine-2-carboxylate (2a)
67 mg, 72% yield; 1H NMR (400 MHz, CDCl3) δ 7.79 (d,
J
= 12.1 Hz, 1H), 7.42-7.31 (m,
7H), 7.22 (dd,
J = 7.5, 0.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 5.66 (d, J = 12.1 Hz, 1H), 5.36
(dd,
J
= 6.7, 3.6 Hz, 1H), 4.92 (dd,
J
= 10.3, 6.7 Hz, 1H), 4.29-4.18 (m, 5H), 4.13 (t,
J = 7.9
Hz, 1H), 3.36 (t,
J
= 10.3 Hz, 1H), 1.30 (t,
J
= 7.3 Hz, 3H), 1.23 (t,
J
= 7.0 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 170.9, 166.5, 157.4, 153.7, 134.1, 130.4, 129.9, 128.7, 128.0,
126.4, 125.4, 117.6, 104.0, 96.4, 67.6, 65.6, 61.7, 60.4, 53.4, 52.4, 14.2, 14.1; FTMS (ESI)
–
calcd for C24H25N2O7 [M – H]– 453.1667; found, 453.1683; Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H column (70:30 hexane:2-propanol, 1.0
mL/min, 254 nm); minor enantiomer tr = 16.9 min, major enantiomer tr = 25.2 min;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 35
1
2
3
4
5
6
7
[α]D21 –89.4 (c 1.0, CHCl3, 99% ee); FTIR (neat) 3774, 3663, 1710, 1550, 1223, 1124, 756,
8
9
699 cm-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl
(
2S,3R,4S,5S)-5-(4-chlorophenyl)-3-{2-[(E)-2-carbethoxy-eth-1-enoxy]phenyl}-4-nitro-py
rrolidine-2-carboxylate (2b)
81 mg, 83% yield; 1H NMR (400 MHz, CDCl3) δ 7.79 (d,
J
= 12.2 Hz, 1H), 7.40 (td, J = 8.1,
1.4 Hz, 1H), 7.36-7.27 (m, 5H), 7.21 (t,
J = 7.5 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.65 (d, J
= 12.2 Hz, 1H), 5.34 (dd,
J = 6.7, 4.0 Hz, 1H), 4.88 (dd, J = 9.9, 4.0 Hz, 1H), 4.30-4.18 (m,
5H), 4.12 (t,
J = 8.1 Hz, 1H), 3.26 (t, J = 9.9 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.22 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 166.4, 157.3, 153.6, 134.5, 132.8, 130.4,
130.0, 128.9, 127.8, 127.7, 125.4, 117.6, 104.0, 96.1, 66.7, 65.3, 61.7, 60.4, 52.0, 14.2,
14.0; FTMS (ESI) calcd for C24H26ClN2O7+ [M + H]+ 489.1423; found, 489.1409; calcd for
C24H26Cl37N2O7 [M + H]+ 491.1394; found, 491.1380; Enantiomeric excess was
+
determined by HPLC with a Chiralcel AD-H column (70:30 hexane:2-propanol, 1.0
mL/min, 254 nm); minor enantiomer tr = 26.1 min, major enantiomer tr = 53.2 min;
[α]D20 –72.8 (c 1.0, CHCl3, 94% ee); FTIR (neat) 3774, 3663, 1709, 1549, 1224, 1122, 758
cm-1.
ACS Paragon Plus Environment

Page 19 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Ethyl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
2S,3R,4S,5S)-5-(4-bromophenyl)-3-{2-[(E)-2-carbethoxy-eth-1-enoxy]phenyl}-4-nitro-py
rrolidine-2-carboxylate (2c)
62 mg, 57% yield; 1H NMR (400 MHz, CDCl3) δ 7.78 (d,
J
= 12.2 Hz, 1H), 7.49 (d, J = 8.3
Hz, 2H), 7.40 (td,
J = 7.7, 1.5 Hz, 1H), 7.31 (dd, J = 7.7, 1.5 Hz, 1H), 7.24-7.19 (m, 3H),
7.12 (d,
J = 8.3 Hz, 1H), 5.65 (d, J = 12.2 Hz, 1H), 5.33 (dd, J = 6.6, 3.9 Hz, 1H), 4.86 (dd,
J
= 6.6 Hz, 1H), 4.29-4.17 (m, 5H), 4.12 (d,
J = 8.6 Hz, 1H), 3.26 (br, 1H), 1.29 (t, J = 7.0
Hz, 3H), 1.22 (t,
J
= 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.8, 166.4, 157.3, 153.6,
133.3, 131.8, 130.4, 130.0, 128.1, 127.7, 125.4, 122.7, 117.6, 104.0, 96.0, 66.7, 65.3, 61.7,
60.4, 52.0, 14.2, 14.0; FTMS (ESI) calcd for C24H26BrN2O7 [M + H]+ 533.0918; found,
+
533.0901; calcd for C24H26Br81N2O7+ [M + H]+ 535.0897; found, 535.0883; Enantiomeric
excess was determined by HPLC with
a
Chiralcel AD-H column (70:30
hexane:2-propanol, 1.0 mL/min, 254 nm); minor enantiomer tr = 18.5 min, major
enantiomer tr = 30.8 min; [α]D20 –119.5 (c 0.50, CHCl3, 98% ee); FTIR (neat) 2982, 1706,
1548, 1121, 757 cm-1.
Ethyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 35
1
2
3
4
5
6
7
(
2S
,
3R
,
4S
,
5S)-3-{2-[(E)-2-carbethoxy-eth-1-enoxy]phenyl}-5-(3-methoxyphenyl)-4-nitro-
8
9
pyrrolidine-2-carboxylate (2d)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
78mg, 80% yield; 1H NMR (400 MHz, CDCl3) δ 7.79 (d,
J = 12.1 Hz, 1H), 7.40 (td, J = 7.7,
1.6 Hz, 1H), 7.32 (dd,
J = 7.7, 1.6 Hz, 1H), 7.27 (t, J = 7.7 z, 1H), 7.22 (td, J = 7.5, 0.9 Hz,
1H), 7.12 (d,
J = 8.0 Hz), 6.92-6.84 (m, 3H), 5.65 (d, J = 12.1 Hz, 1H), 5.35 (dd, J = 6.6,
4.0 Hz, 1H), 4.89 (dd,
J
= 10.9, 6.6 Hz, 1H), 4.30-4.17 (m, 5H), 4.12 (t,
J = 8.9 Hz, 1H),
3.80 (s, 3H), 3.34 (t,
J
= 10.9 Hz, 1H), 1.29 (t,
J
= 7.1 Hz, 3H), 1.23 (t,
J
= 7.1 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) δ 170.9, 166.5, 159.7, 157.4, 153.6, 135.7, 130.4, 129.4, 129.7,
128.0, 125.4, 118.6, 117.6, 114.0, 112.2, 104.0, 96.2, 67.5, 65.6, 61.7, 60.4, 55.2, 52.3, 14.2,
+
14.0; FTMS (ESI) calcd for C25H29N2O8 [M + H]+ 485.1918; found, 485.1901;
Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column (70:30
hexane:2-propanol, 1.0 mL/min, 254 nm); minor enantiomer tr = 13.5 min, major
enantiomer tr = 26.7 min; [α]D20 –77.8 (c 0.50, CHCl3, 96% ee); FTIR (neat) 2982, 1709,
1550, 1123, 756 cm-1
Ethyl
(
2S,3R,4S,5S)-3-{2-[(E)-2-carbethoxy-eth-1-enoxy]phenyl}-5-(2-fluorophenyl)-4-nitro-pyr
rolidine-2-carboxylate (2e)
ACS Paragon Plus Environment

Page 21 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
56 mg, 59% yield; 1H NMR (400 MHz, CDCl3) δ 7.80 (d,
J = 12.2 Hz, 1H), 7.43-7.36 (m,
8
9
2H), 7.35-7.29 (m, 2H), 7.23-7.18 (m, 2H), 7.14-7.06 (m, 2H), 5.71 (d,
J = 12.1 Hz, 1H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5.52 (ddd,
J = 6.3, 3.4, 1.4 Hz, 1H), 5.13 (dd, J = 12.6, 6.3 Hz, 1H), 4.32-4.19 (m, 5H),
4.07 (dd,
J
= 10.4, 8.6 Hz, 1H), 3.38 (dd,
J = 12.1, 11.1 Hz, 1H), 1.30 (t, J = 7.2 Hz, 3H),
1.24 (t,
J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.7, 166.5, 159.9, 157.0, 153.6,
130.8, 130.2, 129.9, 127.8, 126.7, 125.2, 124.5, 121.4, 117.3, 115.1, 104.2, 95.2, 65.8, 61.9,
61.8, 61.7, 60.3, 53.0, 14.2, 14.1; FTMS (ESI) calcd for C24H26FN2O7+ [M + H]+ 473.1719;
found, 473.1702; Enantiomeric excess was determined by HPLC with a Chiralcel AS-H
column (70:30 hexane:2-propanol, 1.0 mL/min, 254 nm); major enantiomer tr = 15.7 min,
minor enantiomer tr = 22.6 min; [α]D21 –109.2 (c 0.50, CHCl3, 97% ee); FTIR (neat) 2983,
1710, 1549, 1123, 756 cm-1
Ethyl
(
2S,3R,4S,5S)-3-{2-[(E)-2-carbethoxy-eth-1-enoxy]-5-methyl-phenyl}-4-nitro-5-phenyl-py
rrolidine-2-carboxylate (2f)
47 mg, 50% yield; 1H NMR (400 MHz, CDCl3) δ 7.76 (d,
J = 12.2 Hz, 1H), 7.39-7.30 (m,
5H), 7.18 (dd,
J = 8.2, 1.6 Hz, 1H), 7.10 (d, J = 1.6 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 5.61
(d,
J = 10.6 Hz, 1H), 5.34 (dd, J = 6.6, 3.9 Hz, 1H), 4.92 (dd, J = 11.0, 6.6 Hz, 1H),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 35
1
2
3
4
5
6
7
4.33-4.18 (m, 5H), 4.10 (t,
J = 8.7 Hz, 1H), 3.35 (t, J = 10.6 Hz, 1H), 2.35 (s, 3H), 1.29 (t, J
8
9
= 7.1 Hz, 3H), 1.24 (t,
J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 166.6, 158.0,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
151.5, 135.2, 134.2, 131.0, 130.3, 128.7 (2C), 127.8, 126.4, 117.7, 103.5, 96.5, 67.6, 65.8,
61.7, 60.3, 52.4, 20.7, 14.3, 14.1; FTMS (ESI) calcd for C25H29N2O7+ [M + H]+ 469.1969;
found, 469.1952; Enantiomeric excess was determined by HPLC with a Chiralcel AD-H
column (95:5 hexane:2-propanol, 1.0 mL/min, 254 nm); major enantiomer tr = 22.2 min,
minor enantiomer tr = 31.3 min; [α]D17 –71.5 (c 1.0, CHCl3, 95% ee); FTIIR (neat) 3734,
1709, 1548, 1126, 1028, 697 cm-1.
Ethyl
(
2S,3R,4S,5S)-5-(4-bromophenyl)-3-{2-[(E)-2-carbethoxy-eth-1-enoxy]-5-methyl-phenyl}-
4-nitro-pyrrolidine-2-carboxylate (2g)
63mg, 58% yield; 1H NMR (400 MHz, CDCl3) δ 7.75 (d,
J
= 12.2 Hz, 1H), 7.49 (d, J = 8.5
Hz, 2H), 7.23 (d,
J = 8.5 Hz, 1H), 7.18 (dd, J = 8.3, 1.8 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H),
7.00 (d,
J = 8.3 Hz, 1H), 5.60 (d, J = 12.2 Hz, 1H), 5.32 (dd, J = 6.7, 4.0 Hz, 1H), 4.86 (t, J
= 7.9 Hz, 1H), 4.32-4.17 (m, 5H), 4.09 (t,
J = 7.9 Hz, 1H), 3.35 (t, J = 7.9 Hz, 1H), 2.35 (s,
3H), 1.29 (t,
J = 7.1 Hz, 3H), 1.23 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.9,
166.6, 157.9, 151.5, 135.3, 133.4, 131.9, 131.0, 130.4, 128.1, 127.5, 122.8, 117.8, 103.5,
ACS Paragon Plus Environment

Page 23 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
+
96.1, 66.8, 65.5, 61.8, 60.4, 52.2, 20.7, 14.3, 14.1; FTMS (ESI) calcd for C25H28BrN2O7
8
9
[M + H]+ 547.1074; found, 547.1057; calcd for C25H28Br81N2O7+ [M + H]+ 549.1054; found,
549.1038; Enantiomeric excess was determined by HPLC with a Chiralcel OD-H column
(90:10 hexane:2-propanol, 1.0 mL/min, 254 nm); minor enantiomer tr = 19.9 min, major
enantiomer tr = 23.7 min; [α]D17 –73.5 (c 0.13, CHCl3, 98% ee); FTIIR (neat) 3734, 1709,
1548, 1126, 1028, 697 cm-1; m.p. 60-62°C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl
(
1S,3S,3aS,4R,9bR)-4-carbethoxy-3a-nitro-3-phenyl-2,3,4,9b-tetrahydro-1H-chromeno[3
,4-c]pyrrole-1-carboxylate (1a)
1
66mg, 81% yield (90% purity); H NMR (400 MHz, CDCl3) δ 7.49 (d,
J = 7.6 Hz, 1H),
7.42-7.29 (m, 5H), 7.23 (d,
J = 7.0 Hz, 1H), 7.12 (td, J = 7.6, 0.9 Hz, 1H), 6.95 (dd, J = 8.1,
0.9 Hz, 1H), 5.14 (dd,
J = 9.9, 2.5 Hz, 1H), 4.84 (d, J = 10.7 Hz, 1H), 4.54-4.42 (m, 2H),
4.38 (d,
J
= 3.4 Hz, 1H), 4.16-4.07 (m, 2H), 4.04-4.02 (m, 1H), 3.17 (dd,
J
= 10.7, 8.0 Hz,
1H), 2.59 (dd,
J = 15.7, 9.9 Hz), 2.42 (dd, J = 15.7, 2.5 Hz, 1H), 1.46 (t, J = 7.2 Hz, 3H),
1.20 (t,
J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 169.2, 148.8, 133.4, 129.6,
129.1 (2C), 129.0, 126.5, 124.2, 123.5, 118.4, 96.8, 69.8, 69.2, 68.7, 62.1, 61.0, 46.0, 34.2,
–
14.3, 14.1; FTMS (ESI) calcd for C24H25N2O7 [M – H]– 453.1667; found, 453.1685;
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 35
1
2
3
4
5
6
7
8
9
Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column (70:30
hexane:2-propanol, 1.0 mL/min, 254 nm); minor enantiomer tr = 15.4 min, major
enantiomer tr = 20.4 min; [α] D 23 = +9.5 (c 0.1, CHCl3, 99% ee); FTIR (neat) 3774, 3663,
1710, 1550, 1223, 1124, 756, 699 cm-1; m.p. 52-55°C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl
(
1S,3S,3aS,4R,9bR)-3-(4-chlorophenyl)-4-carbethoxy-3a-nitro-2,3,4,9b-tetrahydro-1H-ch
romeno[3,4-
c]pyrrole-1-carboxylate (1b)
1
82mg, 93% yield (98% purity); H NMR (400 MHz, CDCl3) δ 7.49 (d,
J = 7.6 Hz, 1H),
7.41-7.38 (m, 2H), 7.30-7.26 (m, 2H), 7.25-7.22 (m, 1H), 7.12 (td,
J = 7.6, 1.1 Hz, 1H),
6.94 (dd,
J = 8.2, 1.1 Hz, 1H), 5.10 (dd, J = 9.9, 2.7 Hz, 1H), 4.82 (d, J = 10.5 Hz, 2H),
4.51-4.42 (m, 2H), 4.39 (d,
J = 3.6 Hz, 1H), 4.12-4.08 (m, 2H), 4.02 (dd, J = 7.4, 3.6 Hz,
1H), 3.02 (dd,
J
= 10.5, 7.5 Hz, 1H), 2.58 (dd,
J = 15.7, 9.9 Hz), 2.40 (dd, J = 15.7, 2.7 Hz,
1H), 1.46 (t,
J = 7.2 Hz, 3H), 1.20 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7,
169.1, 148.7, 135.5, 132.2, 129.3, 129.1, 128.7, 128.0, 124.0, 123.6, 118.5, 96.6, 69.7, 68.3,
+
68.2, 62.2, 61.1, 45.6, 34.2, 14.3, 14.1; FTMS (ESI) calcd for C24H26ClN2O7 [M + H]+
+
489.1423; found, 489.1419; calcd for C24H26Cl37N2O7 [M + H]+ 491.1394; found,
491.1378; Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column
ACS Paragon Plus Environment

Page 25 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(95:5 hexane:2-propanol, 1.0 mL/min, 254 nm); major enantiomer tr = 23.8 min, minor
enantiomer tr = 34.4 min; [α] D 23 = +19.3 (c 0.1, CHCl3, 94% ee); FTIR (neat) 3847, 2981,
1710, 1549, 1225, 1125, 836, 760 cm-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl
(
1S,3S,3aS,4R,9bR)-3-(4-bromophenyl)-4-carbethoxy-3a-nitro-2,3,4,9b-tetrahydro-1H-c
hromeno[3,4-
c]pyrrole-1-carboxylate (1c)
86mg, 90% yield (92% purity); 1H NMR (400 MHz, CDCl3) δ 7.54 (d,
J
= 8.5 Hz, 2H), 7.48
(d,
J = 7.5 Hz, 1H), 7.25-7.21 (m, 3H), 7.12 (td, J = 7.5, 1.1 Hz, 1H), 6.94 (dd, J = 8.2, 1.1
Hz, 1H), 5.10 (td,
J = 10.1, 2.6 Hz, 1H), 4.81 (d, J = 10.3 Hz, 1H), 4.53-4.42 (m, 2H), 4.39
(d,
J = 3.6 Hz, 1H), 4.17-4.08 (m, 2H), 4.01 (dd, J = 7.5, 3.6 Hz, 1H), 3.01 (dd, J = 10.3,
7.5 Hz, 1H), 2.58 (dd,
J = 15.7, 10.1 Hz), 2.40 (dd, J = 15.7, 2.6 Hz, 1H), 1.46 (t, J = 7.2
Hz, 3H), 1.21 (t,
J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.7, 169.1, 148.7, 132.7,
132.2, 129.1, 128.3, 124.0, 123.7, 123.6, 118.5, 96.6, 69.7, 68.3 (2C), 62.2, 61.1, 45.6, 34.2,
+
14.3, 14.1; FTMS (ESI) calcd for C24H26BrN2O7 [M + H]+ 533.0918; found, 533.0920;
calcd for C24H26Br81N2O7+ [M + H]+ 535.0897; found, 535.0899; Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H column (95:5 hexane:2-propanol, 1.0
mL/min, 254 nm); major enantiomer tr = 35.7 min, minor enantiomer tr = 52.1 min; [α] D
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 35
1
2
3
4
5
6
7
23 = +0.8 (c 0.1, CHCl3, 98% ee); FTIR (neat) 2981, 1733, 1540, 1190, 1010, 735 cm-1.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl (1S,3S,3aS,4R,9bR)-
4-carbethoxy-3-(3-methoxyphenyl)-3a-nitro-2,3,4,9b-tetrahydro-1H-chromeno[3,4-c]pyr
role-1-carboxylate (1d)
1
52mg, 59% yield (>99% purity); H NMR (400 MHz, CDCl3) δ 7.48 (d,
J = 7.6 Hz, 1H),
7.33 (t,
J = 8.0 Hz, 1H), 7.24-7.22 (m, 1H), 7.11 (td, J = 8.0, 1.1 Hz, 1H), 7.00-6.86 (m,
4H), 5.17 (dd,
J
= 10.0, 2.6 Hz, 1H), 4.80 (d,
J
J
= 11.0 Hz, 1H), 4.51-4.42 (m, 2H), 4.38 (d,
J
= 3.6 Hz, 1H), 4.16-4.08 (m, 2H), 4.02 (dd,
= 7.5, 3.6 Hz, 1H), 3.83 (s, 3H), 3.12 (dd,
J
J
= 11.0, 7.6 Hz, 1H), 2.59 (dd,
J = 15.7, 10.0 Hz), 2.44 (dd, J = 15.7, 2.6 Hz, 1H), 1.46 (t,
= 7.1 Hz, 3H), 1.20 (t,
J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.8, 169.2, 159.9,
148.8, 135.0, 130.1, 129.1, 129.0, 124.2, 123.5, 118.6, 118.4, 114.8, 112.4, 96.7, 69.8, 69.1,
68.6, 62.1, 61.0, 55.3, 46.0, 34.3, 14.3, 14.1; FTMS (ESI) calcd for C25H27N2O8– [M – H]–
483.1773; found, 483.1787; Enantiomeric excess was determined by HPLC with a
Chiralcel AD-H column (95:5 hexane:2-propanol, 1.0 mL/min, 254 nm); major
enantiomer tr = 29.2 min, minor enantiomer tr = 36.4 min; [α] D 23 = +10.3 (c 0.1, CHCl3,
93% ee); FTIR (neat) 2980, 1735, 1541, 1236, 1191, 1091, 893, 736 cm-1; m.p. 45-45°C.
ACS Paragon Plus Environment

Page 27 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
Ethyl (1S,3S,3aS,4R,9bR)-
8
9
4-carbethoxy-3-(2-fluorophenyl)-3a-nitro-2,3,4,9b-tetrahydro-1H-chromeno[3,4-c]pyrrol
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
e-1-carboxylate (1e)
1
67mg, 79% yield (99% purity); H NMR (400 MHz, CDCl3) δ 7.47 (d,
J = 7.7 Hz, 1H),
7.41-7.35 (m, 2H), 7.24-7.08 (m, 4H), 6.96 (dd,
4.52-4.37 (m, 3H), 4.20-4.09 (m, 2H), 4.02 (dd,
J = 8.2, 0.9 Hz, 1H), 5.18-5.13 (m, 2H),
J
= 7.7, 4.5 Hz, 1H), 3.24 (t,
J = 9.3 Hz,
1H), 2.66-2.45 (m, 2H), 1.45 (t,
J = 7.1 Hz, 3H), 1.21 (t, J
= 7.1 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 171.7, 169.3, 149.3, 130.9, 129.0, 127.6, 124.8, 123.4 (C), 121.4, 118.4,
115.9, 97.1, 70.4, 68.4, 62.9, 62.2, 61.1, 45.9, 34.6, 14.3, 14.1; FTMS (ESI) calcd for
C24H26FN2O7– [M + H]+ 473.1724; found, 473.1713; Enantiomeric excess was determined
by HPLC with a Chiralcel AD-H column (95:5 hexane:2-propanol, 0.7 mL/min, 254 nm);
major enantiomer tr = 30.5 min, minor enantiomer tr = 34.3 min; [α] D 23 = +9.0 (c 0.1,
CHCl3, 95% ee); FTIR (neat) 2982, 1735, 1542, 1192, 1028 cm-1; m.p. 62-66°C.
Ethyl (1S,3S,3aS,4R,9bR)-
4-carbethoxy-8-methyl-3a-nitro-3-phenyl-2,3,4,9b-tetrahydro-1H-chromeno[3,4-
e-1-carboxylate (1f)
c]pyrrol
75mg, 89% yield (98% purity); 1H NMR (400 MHz, CDCl3) δ 7.43-7.31 (m, 6H), 7.03 (dd,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 35
1
2
3
4
5
6
7
8
9
J
= 8.4, 2.0 Hz, 1H), 6.83 (d,
J
= 8.4Hz, 1H), 5.11 (dd,
J
= 10.1, 2.6 Hz, 1H), 4.84 (d,
J
J
J
=
=
=
11.1 Hz, 1H), 4.54-4.41 (m, 2H), 4.33 (d,
J = 3.6 Hz, 1H), 4.16-4.07 (m, 2H), 4.03 (dd,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7.6, 3.6 Hz, 1H), 3.13 (dd,
J
= 11.1, 7.6 Hz, 1H), 2.58 (dd,
J
= 15.6, 10.1 Hz), 2.40 (dd,
15.7, 2.6 Hz, 1H), 2,34 (s, 3H), 1.47 (t,
J
= 7.1 Hz, 3H), 1.20 (t, J
= 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 171.9, 169.3, 146.5, 133.5, 133.0, 129.8, 129.6, 129.2, 129.0, 126.5,
123.8, 118.1, 97.0, 69.7, 69.2, 68.7, 62.1, 61.0, 46.1, 34.2, 20.8, 14.3, 14.1; FTMS (ESI)
+
calcd for C25H28KN2O7 [M + K]+ 507.1534; found, 507.1508; Enantiomeric excess was
determined by HPLC with a Chiralcel AD-H column (95:5 hexane:2-propanol, 1.0
mL/min, 254 nm); major enantiomer tr = 14.4 min, minor enantiomer tr = 18.5 min;
[α]D17 +2.1 (c 0.67, CHCl3, 95% ee); FTIR (neat) 3734, 3032, 2938, 2828, 1735, 1540, 1180,
1029, 698 cm-1; m.p. 52-54°C.
Ethyl (1S,3S,3aS,4R,9bR)-3-(4-bromophenyl)-
4-carbethoxy-8-methyl-3a-nitro-2,3,4,9b-tetrahydro-1H-chromeno[3,4-c]pyrrole-1-carbo
xylate (1g)
1
80mg, 81% yield (>99% purity); H NMR (400 MHz, CDCl3) δ 7.54 (d,
J = 8.4 Hz, 2H),
7.25 (d,
J = 1.8 Hz, 1H), 7.21 (d, J = 8.4Hz, 1H), 7.03 (dd, J = 8.2, 1.8 Hz, 1H), 6.82 (d, J =
8.2 Hz, 1H), 5.07 (dd,
J = 10.0, 2.5 Hz, 1H), 4.80 (d, J = 10.4 Hz, 1H), 4.53-4.39 (m, 2H),
ACS Paragon Plus Environment

Page 29 of 35
The Journal of Organic Chemistry
1
2
3
4
5
6
7
4.35 (d,
J = 3.5 Hz, 1H), 4.16-4.08 (m, 2H), 4.01 (dd, J = 7.5, 3.5 Hz, 1H), 2.99 (dd, J =
8
9
10.4, 7.5 Hz, 1H), 2.57 (dd,
J
= 15.6, 10.0 Hz), 2.37 (dd,
J = 15.6, 2.5 Hz, 1H), 2,34 (s, 3H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.46 (t,
J = 7.1 Hz, 3H), 1.20 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.8,
169.1, 146.4, 133.1, 132.8, 132.2, 129.9, 129.2, 128.3, 123.6, 118.2, 96.7, 69.7, 68.3, 68.2,
62.1, 61.1, 45.6, 34.1, 20.8, 14.3, 14.1; FTMS (ESI) calcd for C25H28BrN2O7 [M + H]+
+
+
547.1074; found, 547.1063; calcd for C25H28Br81N2O7 [M + H]+ 549.1054; found,
549.1042; Enantiomeric excess was determined by HPLC with a Chiralcel AD-H column
(95:5 hexane:2-propanol, 1.0 mL/min, 254 nm); major enantiomer tr = 22.2 min, minor
enantiomer tr = 31.3 min; [α]D17 +10.5 (c 0.51, CHCl3, 97% ee); FTIR (neat) 2981, 1735,
1541, 1212, 1010, 753 cm-1.
Supporting Information
Optimization of [3+2] cycloaddition, and copies of H and 13C spectra. This material is
1
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* tarai@faculty.chiba-u.jp
ACS Paragon Plus Environment