An efficient synthesis of substituted isoxazolopyrroloisoquinolines via diastereoselective N-acyliminium ion cyclization

Article abstract of DOI:10.1016/j.tet.2015.02.031

A simple and efficient strategy was developed for the synthesis of fused pyrrolo[2,1-a]isoquinoline ring systems. The 5- and 6-substituted isoxazolopyrroloisoquinolines were readily prepared via diastereoselective N-acyliminium ion cyclization of 5-(1-R(or 2-R)-substituted-2-phenylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]isoxazol-4-ones derived from the corresponding bicyclic dihydroisoxazoles.

Full text of DOI:10.1016/j.tet.2015.02.031

Tetrahedron xxx (2015) 1e7
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Tetrahedron
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An efficient synthesis of substituted isoxazolopyrroloisoquinolines
via diastereoselective N-acyliminium ion cyclization
Maria S. Ledovskaya a, Alexander P. Molchanova, Vitaly M. Boitsov b, Rafael R. Kostikov a,
,
Alexander V. Stepakova
*
a Chemistry Department, Saint-Petersburg State University, Universitetsky prosp. 26, St-Petersburg 198504, Russian Federation
b Saint-Petersburg Academic UniversitydNanotechnology Research and Education Centre RAS, Khlopin str. 8/3, St-Petersburg 194021,
Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient strategy was developed for the synthesis of fused pyrrolo[2,1-a]isoquinoline ring
systems. The 5- and 6-substituted isoxazolopyrroloisoquinolines were readily prepared via diaster-
eoselective N-acyliminium ion cyclization of 5-(1-R(or 2-R)-substituted-2-phenylethyl)-6-
hydroxytetrahydro-4H-pyrrolo[3,4-d]isoxazol-4-ones derived from the corresponding bicyclic
dihydroisoxazoles.
Received 13 December 2014
Received in revised form 25 January 2015
Accepted 6 February 2015
Available online xxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Dihydroisoxazoles
Hydroxylactams
N-Acyliminium ion
Intramolecular cyclization
Isoxazolopyrroloisoquinolines
MeO
MeO
HO
HO
RO
RO
1. Introduction
Cl
N
N
N
H
H
The pyrrolo[2,1-a]isoquinoline ring system is a major structural
fragment of Erythrina and lamellarin alkaloids.1 Natural products
that contains pyrroloisoquinoline framework (Scheme 1) display
a variety of pharmacological effects including cytotoxic [crispine B
(1) and lamellarin D (4a)],2 antitumour [crispine B (1), crispine A
(3a), lamellarin I (5a) and lamellarin K (5b)],2,3 antibacterial and
antiviral activities [trolline (salsoline A) (2)],4 DPPH free radical
scavenging activity and inhibitory activity [oleracein E (3b) and
crispine B (1)
trolline (salsoline A) (2)
crispine A (3a: R=Me)
oleracein E (3b: R=H)
OR1
R1O
MeO
O
O
N
N
MeO
MeO
O
O
lamellarin
a
-20-sulfate (4b)].5 Various biological activities have
been found for synthetic pyrroloisoquinolines, e.g., antineoplastic,6
antitumour activity,7 antidepressant,8 antileukaemic,6a antiviral9
R2O
R2O
OR3
OMe
OH
OMe
MeO
and activity as
a
2-adrenoreceptor antagonists10 and calcium
MeO
channel blockers.11 In addition, compounds with a pyrroloisoqui-
noline fragment have been described as having hypotensive, sym-
patholytic and psychotropic activity,12a as well as being useful in
the treatment of diseases such as psoriasis.12b
lamellarin D (4a: R1=R2=R3=H)
lamellarin α-20-sulfate (4b: R1=Me; R2=H; R3=SO3Na)
lamellarin I (5a: R1=R2=Me)
lamellarin K (5b: R1=R2=H)
Scheme 1. Representative natural active pyrroloisoquinolines 1e5.
Thereby development of simple, effective and efficient synthetic
methods for compounds containing such a structural fragment is
still an important and actual challenge of organic chemistry and
many approaches have been reported in the last years.13 In par-
ticular, the intramolecular reaction of cyclic N-acyliminium ions has
been successfully used for the preparation of pyrrolo[2,1-a]iso-
quinoline ring systems.14
* Corresponding author. Tel.: þ7 812 428 4021; fax: þ7 812 428 6939; e-mail
address: alstepakov@yandex.ru (A.V. Stepakov).
http://dx.doi.org/10.1016/j.tet.2015.02.031
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
M.S. Ledovskaya et al. / Tetrahedron xxx (2015) 1e7
2. Results and discussion
hydroximoyl chlorides 8b,c gave a chromatographically inseparable
1:1 mixtures of diastereomers 10d/11d and 10e/11e in total yields
64% and 56%, respectively (Table 1, entries and 5). Re-
crystallization of the mixture 10d/11d from methylene chloride/
methanol gave pure samples of isoxazoles 10d and 11d as single
diastereomers, while recrystallization of the 1:1 mixture of 10e/11e
led to pure isoxazole 10e and 3:1 mixture 11e and 10e, respectively.
The reactions of maleimide 9c with the nitrile oxides derived from
8b,c gave the desired isoxazoles 12a and 12b in excellent yields
(Table 1, entries 6 and 7).
For the next step in our study, we examined the reduction of the
imide function of racemic substrates 10aeewith NaBH4. The reduction
was carried out in methylene chloride/ethanol at ꢁ80 to ꢁ20 ꢀC for
2e5 days to provide the corresponding hydroxylactams 13aee as
single diastereomers in yields ranging from 40% to 99% (Table 2).
Previously, we described the first synthesis of iso-
xazolopyrroloisoquinolines 7 (Scheme 2) via intramolecular cycli-
zation of 5-(2-arylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]
isoxazol-4-ones 6 in the presence of boron trifluoride diethyl
etherate.15
4
N
R1
R
O
OH
N
H
H
.
H
BF3 Et2O
R1
O
R1
R1
O
CH2Cl2, RT
N
N
H
H
R
O
6
7
Table 2
Scheme 2. Previous work: synthesis of pyrroloisoquinolines 7 by cyclization of hy-
droxylactams 6.
a
Reduction of compounds 10aee with NaBH4
O
OH
H
H
In this paper, we have studied the effects of substituents at
positions 1 and 2 of the N-(2-phenylethyl) fragment on stereo-
selective intramolecular cyclization of the corresponding hydrox-
ylactams. Our approach to 5- and 6-substituted isoxazolo
pyrroloisoquinolines began with the synthesis of dihydroisoxazoles
10 and 11, prepared by 1,3-dipolar cycloaddition of maleimides
9aec to nitrile oxides, generated from the corresponding hydrox-
imoyl chlorides 8aec in the presence of triethylamine. Benzonitrile
oxide (generated in situ from the corresponding hydroximoyl
chloride 8a in the presence of Et3N) was treated with 9a in benzene
at 20 ꢀC to give a chromatographically inseparable 1:1 mixture of
two diastereomers 10a and 11a in total yield of 50% (Table 1, entry
1). Recrystallization of 1:1 mixture from methylene chloride/
methanol resulted in a 6:1 mixture of 10a and 11a, respectively. A
similar reaction occurred between maleimide 9a and nitrile oxides
generated from 8b,c, giving chromatographically inseparable 1:1
mixture of diastereomers 10b/11b and 10c/11c in total yields 52%
and 59%, respectively (Table 1, entries 2 and 3). Recrystallization of
the 1:1 mixture of 10b/11b from methylene chloride/methanol
resulted in pure isoxazoles 10b and 11b, recrystallization of the 1:1
mixture of 10c/11c gave a 5:1 mixture 10c and 11c, respectively. The
reaction of maleimide 9b with nitrile oxides generated from
Ph
Ph
O
O
NaBH4
6
1
6a
3a
N 2
N
5
N
N
3
CH2Cl2/EtOH
80 to 20 oC
4
R2
R2
H
H
R1
O
R1
O
10a-e
13a-e
Entry
Substrate
R1
Ph
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
R2
Time (d)
Yield of 13b (%)
1
2
3
4
5
10ac
10b
10cd
10d
10e
Me
5
4
3
2
3
13a (40)e
13b (84)
13c (99)e
13d (42)f
13e (53)f
Me
Me
Ph
Ph
a
Reaction conditions: 10 (1 equiv), NaBH4 (1.1 equiv), CH2Cl2/EtOH, ꢁ80 to
ꢁ20 ꢀC.
b
Isolated yield.
c
d
e
f
Diastereomeric mixture (ratio 6:1) was used as the substrate.
Diastereomeric mixture (ratio 5:1) was used as the substrate.
The diastereomeric ratio is same as in the starting substrate.
The product was partially oxidized on air to the starting compound. Yield was
determined by 1H NMR.
Hydroxylactams 13aee were easily isolated by flash chroma-
tography on silica using a mixture of methanol/CH2Cl2 as the elu-
ent. In all cases, only the carbonyl group at the b-position with
respect to the oxygen atom of the dihydroisoxazole ring was re-
duced.16 Presumably, this is related to the inductive effect of the
oxygen atom. A 1H NMR study confirmed that the 6-hydroxy group
of hydroxylactams 13aee was orientated cis with respect to the
dihydroisoxazole ring: protons HeC(6a) and HeC(6) show coupling
constants of 5e6 Hz.15 The diastereomeric ratio in reaction prod-
ucts was not changed when diastereomeric mixtures were used as
starting substrates (Table 2, entries 1 and 3). It should be noted that
hydroxylactams 13d,e are oxidized on air to the starting com-
pounds 10d,e. The structure of 13a was established unequivocally
by X-ray diffraction analysis (Fig. 1). A similar reaction occurred on
Table 1
1,3-Dipolar cycloaddition of benzonitrile oxides to maleimides (9aec)a
R1
R3
O
R3
O
R3
N
O
H
H
Cl
OH
Ph
Ph
Ph
O
O
8a-c
Et3N
benzene, RT
+
N
N
N
N
N
R2
R2
R2
H
H
R1
O
R1
O
O
9a-c
10a-e, 12a,b
11a-e
Entry
R1
R2
R3
Productb
Overall
yieldc (%)
1
2
3
4
5
6
7
Ph (8a)
Me
Me
Me
Ph
Ph
H
H (9a)
H (9a)
H (9a)
H (9b)
H (9b)
Ph (9c)
Ph (9c)
10aþ11a (1:1)
10bþ11b (1:1)
10cþ11c (1:1)
10dþ11d (1:1)
10eþ11e (1:1)
12a
50d
52e
59f
64g
56h
84
4-MeC6H4 (8b)
4-ClC6H4 (8c)
4-MeC6H4 (8b)
4-ClC6H4 (8c)
4-MeC6H4 (8b)
4-ClC6H4 (8c)
C10
C11
O2
C9
C8
C12
O1
N1
C4
C13
C14
H
12b
99
C3
N2
C6
a
C7
C16
Reaction conditions: 8 (1 equiv), 9 (1 equiv), NEt3 (2 equiv), benzene, rt, 24 h.
Diastereomeric ratios were measured by 1H NMR analysis.
Isolated yield.
After several recrystallizations a 6:1 mixture of 10a and 11a was obtained.
Compounds 10b and 11b were isolated in pure forms by recrystallization.
After several recrystallizations a 5:1 mixture of 10c and 11c was obtained.
Compounds 10d and 11d were isolated in pure forms by recrystallization.
After several recrystallizations pure 10e and 3:1 mixture of 11e and 10e were
C1
C15
b
c
C2
C5
O3
C17
C18
d
e
f
C20
C19
g
h
obtained.
Fig. 1. ORTEP representation of compound 13a.
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M.S. Ledovskaya et al. / Tetrahedron xxx (2015) 1e7
3
Table 4
reduction of the compounds 11b,d,e and 12a,b with NaBH4, giving
hydroxylactams 14aec and 15a,b as single diastereomers (Table 3).
Next, the intramolecular FriedeleCrafts-type reactions of race-
mic hydroxylactams 13aee and 14aec were investigated (Table 4).
BF3$OEt2-catalyzed intramolecular diastereoselective FriedeleCrafts-type cycliza-
tion of hydroxylactams 13aee and 14aeca
To examine the effect of a substituent at the a-position to the ni-
trogen atom on the stereochemistry of the cyclization, we studied
the cyclization of hydroxylactams 13b and 14a. Treatment of N-
acyliminium precursor 13b with an excess of BF3$OEt2 (3 equiv) in
CH2Cl2 at room temperature for 16 h gave the tetracyclic product
16b as a single diastereomer in 99% yield (Table 4, entry 2). Simi-
larly, cyclization of diastereomeric hydroxylactam 14a afforded
exclusively to 17a in 94% yield (Table 4, entry 6). The signals of the
other possible diastereomers were not found in 1H NMR spectra of
crude reaction mixtures. The relative stereochemistry of the
formed stereocenter C(11b) of isoxazolopyrroloisoquinolines 16b
and 17a was confirmed by the 1H NMR spectra. The 1H NMR
spectrum of diastereomer 16b exhibited signals at
d
4.6 (d, J¼8 Hz),
Entry
Substrate
R1
R2
Product
Yieldb (%)
5.2 (d, J¼5 Hz) and 5.7 (dd, J¼8 and 5 Hz) belonging to the methine
protons at C(8a), C(11b) and C(11a), respectively. The value of the
spinespin coupling constant (5 Hz) for the protons HeC(11a) and
HeC(11b) clearly indicated their cis-location. The spinespin cou-
pling constant for HeC(11a) and HeC(11b) in the diastereomer 17a
was equal to 3 Hz.
1
2
3
4
5
6
7
8
13ac
13b
13cd
13d
13e
14a
14b
14ce
Ph
Me
Me
Me
Ph
Ph
Me
Ph
16a
16b
16c
16d
16e
17a
17b
17c
55f
99
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
75f
68g
92h
94
99
Table 3
Ph
99f
a
Reduction of compounds 11b,d,e and 12a,b with NaBH4
a
Reaction conditions: 13 or 14 (1 equiv), BF3$OEt2 (3 equiv), CH2Cl2, rt, 16 h.
Isolated yield.
b
c
d
e
f
Diastereomeric mixture (ratio 6:1) was used as the substrate.
Diastereomeric mixture (ratio 5:1) was used as the substrate.
Diastereomeric mixture (ratio 3:1) was used as the substrate.
The diastereomeric ratio is same as in the starting substrate.
The inseparable mixture of 16d and 10d was obtained. Yield was determined by
g
1H NMR.
h
The inseparable mixture of 16e and 10e was obtained. Yield was determined by
1H NMR.
Entry
Substrate
R1
R2
R3
Time (d)
Yieldb (%)
1
2
3
4
5
11b
11d
11ec
12a
12b
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
Me
Ph
Ph
H
H
H
H
Ph
Ph
8
4
7
14
20
14a (86)
14b (99)
14c (99)d
15a (66)
15b (75)
H
H
H
H
O
O
O
N
N
N
H
or
R2
H
N
N
N
a
R1
R1
R1
R2
Reaction conditions: 11 or 12 (1 equiv), NaBH4 (1.1 equiv), CH2Cl2/EtOH, ꢁ80 to
R2
H
ꢁ20 ꢀC.
O
O
O
b
c
A(1,3)
20b R2 = Me (or Ph)
Isolated yield.
20a R2 = Me (or Ph)
18, 19
Diastereomeric mixture (ratio 3:1) was used as the substrate.
The diastereomeric ratio is same as in the starting substrate.
d
For reactions of 13b and 14a, cyclizations to 16b and 17a pro-
ceeded via intermediates 18, 19 and 20 (Scheme 3): A(1,3) strain
between the equatorial C6-methyl and carbonyl groups in 20b de-
termined the preference for structures 20a in which the methyl
group occupied an axial position in relation to the newly formed
six-membered ring, thereby minimizing A(1,3) interaction with the
carbonyl group. The axial position of 6-Me group can be rational-
ized in accordance with Hart’s studies concerning the strong effect
O
N
R2
N
H
R1
H
O
16, 17
Scheme 3. The intermediates leading to compounds 16 and 17.
of substituents at a-position to nitrogen atom on the stereochem-
ical outcome of N-acyliminium ion cyclization to six-membered
rings.17 Our predictions were further confirmed by single-crystal
X-ray crystallography, which provided unequivocal proof of the
relative configuration of diastereomers 16b and 17a (Figs. 2 and 3).
Similarly, cyclization of hydroxylactams 13a,c proceeds stereo-
selectively with formation of tetracyclic products 16a,c (Table 4,
entries 1 and 3).
The N-acyliminium ion cyclization of hydroxylactam 13d with
BF3$OEt2 in CH2Cl2 at room temperature proceeded cleanly to
provide isoxazolopyrroloisoquinoline 16d in 68% yield (Table 4,
entry 4). It was concluded from an analysis of 1H NMR spectrum of
the crude reaction mixture that the cyclization produced only
C2A
C3A
O11A
N10A
C1A
C4A
C14A
C96A
C12A
C95A
C4AA
C13A
C91A
C9A
C5A
C6A
C15A
C1
C94A
C92A
N7A
C8AA
O81A
C61A
C93A
a
single diastereomer. The diastereospecific cyclization N-
Fig. 2. ORTEP representation of compound 16b.
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4
M.S. Ledovskaya et al. / Tetrahedron xxx (2015) 1e7
(76%) and 2.5:1 mixture of 22a and 23a in 21% overall yield. Simi-
C1
C2
O11
larly, cyclization of hydroxylactam 15b led to a mixtures of pyrro-
loisoquinolines 21b, 22b and 23b in 10:2.7:1.8 ratio, respectively.
The relative configurations of products 21, 22 and 23 were de-
termined by 1H NMR spectra. 1H NMR spectra of compounds 21a,b
showed a signals at 4.5 (d, J¼10 Hz), 5.0 (br s) and 5.5 ppm (dd, J¼10
and 3 Hz) belonging to the methine protons at C(8a), C(11b) and
C(11a), respectively. The value of the spinespin coupling constant
(3 Hz) for the protons HeC(11a) and HeC(11b) clearly indicated
their trans-location. The 1H NMR spectrum of compound 21b dis-
played a singlet at 5.14 ppm for HeC(11b), which showed an H,H-
NOESY correlation with a doublet of doublets at 3.16 ppm
(H2eC(6) of the isoquinoline ring), additionally a cross peak be-
tween H2eC(6) and phenyl group was observed. Also a NOESY
correlation was found between signals of H1eC(6) and HeC(5) (see
Supplementary data). The structure of compound 21b was de-
termined by X-ray diffraction study of a single crystal and sup-
ported the relative configuration deduced from NMR spectroscopy
(Fig. 5). From X-ray diffraction analysis data, it was determined that
in compound 21b the phenyl group in position-5 occupied the
equatorial position. The 1H NMR spectra of compounds 22 and 23
had signals at 4.6 (d, J¼8 Hz), 5.4 (d, J¼5 Hz) and 5.8 ppm (dd, J¼8
and 5 Hz) belonging to the methine protons at C(8a), C(11b) and
C(11a), respectively. The value of the spinespin coupling constant
(5 Hz) for the protons HeC(11a) and HeC(11b) indicated their cis-
location. The relative configuration of products 22 and 23 was de-
termined on the basis of the 2D NOESY 1H NMR spectra of com-
pounds 22b and 23b. In the NOESY spectrum of 23b, we observed
a cross peak between H1eC(6) and HeC(11b), H1eC(6) and phenyl
group, and also between H2eC(6) and HeC(5) (see Supplementary
data). Additionally, the absence of NOESY cross peak of H1eC(6) of
the isoquinoline ring and Ph-C(5) group was indicative for the
assigned relative stereochemistry of compound 22b.
N10
C11A
C10
C12
C3
C91
C96
C8A
C8
C9
C95
C4
C4A
C92
N7
C93
C94
C941
C5
O81
C6
C61
Fig. 3. ORTEP representation of compound 17a.
acyliminium precursor 13d must occur so that the phenyl group
occupies an axial position in relation to the newly formed six-
membered ring, thereby minimizing A(1,3) interaction with the
carbonyl group (vide supra). As observed in the cyclization of 13e,
only a single diastereomer 16e was produced in 92% yield (Table 4,
entry 5). The cyclization of diastereomeric hydroxylactams 14b,c
was carried out under similar conditions. The reactions proceeded
smoothly to give the corresponding derivatives 17b,c in high yields
(Table 4, entries 7 and 8). The fused tetracyclic structure and rela-
tive stereochemistry of the product 17b were confirmed by single-
crystal X-ray diffraction (Fig. 4).
C2
C1
C3
O13
C16
C14
N12
C4
C15
N8
C5
C10
C11
C111
C116
C112
C113
C6
C9
O9
C7
C72
C115
C71
C76
C114
C117
C73
C74
C75
C38
C37
C39
O3
Fig. 4. ORTEP representation of compound 17b.
N3
C36
C34
C35
To examine the effect of a substituent at b-position to the ni-
C32
C40
trogen atom on the stereoselectivity of cyclization, we studied the
cyclization of racemic hydroxylactams 15a,b (Table 5). Cyclization
of hydroxylactam 15a with BF3$OEt2 gave a mixture of three di-
astereomeric pyrroloisoquinolines 21a, 22a and 23a in 10:2.8:1
ratio, respectively. Separation of the crude mixture by preparative
thin-layer chromatography on silica led to pure diastereomer 21a
C30
C41
C42
C31
C26
C33
C29
C28
N4
C43
C44
O4
C50A
C49A
C45A
Cl2
C27
C46A
C48A
C47A
Fig. 5. ORTEP representation of compound 21b.
Table 5
BF3$OEt2-catalyzed intramolecular diastereoselective FriedeleCrafts-type cycliza-
3. Conclusion
tion of hydroxylactams 15a,ba
In summary, we have developed a simple and efficient route to
5- and 6-substituted isoxazolopyrroloisoquinolines by BF3$OEt2-
induced intramolecular cyclizations of 5-(1-R(or 2-R)-2-
phenylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]isoxazolones.
The presence of a methyl or phenyl group in a neighbouring posi-
tion relative to the nitrogen atom strongly influences the overall
stereoselectivity of the cyclization. The cyclization of 5-(1-Me(Ph)-
2-phenylethyl)-6-hydroxytetrahydro-4H-pyrrolo[3,4-d]iso-
xazolones into 6-Me(Ph)-tetrahydroisoxazolo[50,40:3,4]pyrrolo-
[2,1-a]isoquinolinones proceeds so that the 6-Me or 6-Ph group
always occupies an axial position in relation to the newly formed
six-membered ring, thereby minimizing A(1,3) interaction with the
carbonyl group. The cyclization of 5-(2,2-diphenylethyl)-6-
hydroxytetrahydro-4H-pyrrolo-[3,4-d]isoxazolones proceeds with
lower stereoselectivity, leading to mixture of three diastereomeric
5-phenyl-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]iso-
OH
N
Ph
Ph
Ph
H
H
H
H
H
Ph
H
O
O
O
H
H2
BF3 Et2O
N
N
N
H2
N
N
CH2Cl2, RT, 16 h
H1
H1
H
R1
O
H
R1
O
H
R1
O
15a,b
21a,b
22a,b
Ph
H
H
H
O
H
H2
N
N
H1
R1
O
23a,b
Entry
Substrate
R1
Products (yield, %)b
21a (76), 22aþ23a (21)
21b (43), 22b (7), 23b (7)
1
2
15a
15b
4-MeC6H4
4-ClC6H4
a
quinolinones with predominant formation of products with the
equatorial location 5-Ph group.
Reaction conditions: 15 (1 equiv), BF3,OEt2 (3 equiv), CH2Cl2, RT, 16 h.
Isolated yield.
b
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M.S. Ledovskaya et al. / Tetrahedron xxx (2015) 1e7
5
4. Experimental section
4.1. General remarks
8(6H)-one (16c). Compound 16c (45 mg, 75%) was obtained using
general procedure from hydroxylactam 13c (5:1 diastereomeric
mixture was used as the substrate) (63 mg) and BF3$OEt2 (66
The diastereomeric ratio in 16c is same as in the starting substrate.
White solid, mp 168e170 ꢀC. 1H NMR (400.1 MHz, CDCl3)
7.91 (d,
mL).
IR spectra were obtained on a Bruker Tensor 27 spectrometer.
Melting points were determined on a Boetius instrument and are
uncorrected. NMR spectra were recorded on a Bruker Avance III
d
J¼8 Hz, 2H, ArH), 7.44e7.18 (m, 6H, ArH), 5.71 (dd, J1¼8 Hz, J2¼5 Hz,
1H, CH), 5.25 (d, J¼5 Hz, 1H, CH), 4.77e4.65 (m, 1H, CH), 4.56 (d,
J¼8 Hz, 1H, CH), 3.11 (dd, J1¼16 Hz, J2¼6 Hz, 1H from CH2), 2.61 (d,
J¼16 Hz, 1H from CH2), 1.26 (d, J¼8 Hz, 3H, CH3). 13C NMR
spectrometer (1H, 400 MHz; 13C, 100 MHz). Chemical shifts
d
are
reported in parts per million (ppm) relative to residual CHCl3 (1H,
¼7.26) and CDCl3 ¼77.16) as internal standard. High-
13C,
d
(
d
(100.6 MHz, CDCl3) d 165.8, 154.4, 136.5, 132.6, 130.3, 129.7, 129.4,
resolution mass spectra (HRMS) were recorded on a Bruker
micrOTOF 10223 spectrometer using electrospray ionization (ESI).
The X-ray diffraction data were performed by means of a Bruker
APEX-II CCD diffractometer with Mo-K X-ray radiation. Reactions
were monitored by TLC analysis using Silufol UV-254 plates. Thin-
layer chromatography was performed on silica gel 5e40 mesh
eluted with dichloromethane/methanol. Preparation and charac-
terization of compounds 16aee, 17aec, 21a,b, 22a,b, 23a,b are
disclosed below, while compounds 10aee, 11b,d,e, 12a,b, 13aee,
14aec, 15a,b are described in Supplementary data.
128.9 (2C), 127.7, 127.1, 126.7, 126.4, 125.9, 81.8, 57.8, 56.8, 42.9, 34.3,
17.2. IR (KBr) nmax 3365, 3296, 3218, 3091, 3068, 3042, 2970, 2955,
2923, 2852, 1683, 1587, 1493, 1454, 1414, 1346, 1307, 1271, 1200,
1121, 1092, 1042, 1013. HRMS (ESI) calcd for C20H1735ClN2O2
[MþH]þ 353.1051, found 353.1047.
4.2.4. (6RS,8aSR,11aRS,11bRS)-9-(4-Methylphenyl)-6-phenyl-
5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-
8(6H)-one (16d). Product 16d was prepared from hydroxylactam
13d (the mixture of 13d with the starting isoxazole 10d was used as
the substrate). The inseparable mixture of 16d and 10d was ob-
tained. Yield 68% was determined by 1H NMR. 1H NMR (400.1 MHz,
4.2. General procedure for the preparation of substituted
isoxazolopyrroloisoquinolines (16, 17, 21e23)
CDCl3)
d
7.91 (d, J1¼8 Hz, 2H, ArH), 7.37e7.03 (m, 11H, ArH), 5.74 (d,
J¼6 Hz, 1H, CH), 5.64 (dd, J1¼8 Hz, J2¼5 Hz, 1H, CH), 4.93 (d, J¼5 Hz,
1H, CH), 4.62 (d, J1¼8 Hz, 1H, CH), 3.90 (dd, J1¼14 Hz, J2¼12 Hz, 1H
from CH2), 3.42e3.29 (m, 1H from CH2), 2.41 (s, 3H, CH3). HRMS
(ESI) calcd for C26H23N2O2 [MþH]þ 395.1754, found 395.1751.
To vigorously stirred solution of corresponding hydroxylactams
(13e15) in anhyd dichloromethane (5 mL) under argon was added
3 equiv of boron trifluoride diethyl etherate. The reaction mixture was
stirred ina capped vial for 16 h at room temperature. Aftercompletion
of the reaction, water was added carefully to the reaction mixture
(10 mL). The aqueous layer was extracted with CH2Cl2 (3ꢂ5 mL), the
organic layers were combined, dried over MgSO4 and evaporated to
dryness. The residue was then purified by chromatography on silica
gel column using a mixture of CH2Cl2/MeOH as eluent.
4.2.5. (6RS,8aSR,11aRS,11bRS)-9-(4-Chlorophenyl)-6-phenyl-
5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-
8(6H)-one (16e). Product 16e was prepared from hydroxylactam
13e (the mixture of 13e with the starting isoxazole 10e was used as
the substrate). The inseparable mixture of 16e and 10e was ob-
tained. Yield 92% was determined by 1H NMR. 1H NMR (400.1 MHz,
4.2.1. (6SR,8aSR,11aRS,11bRS)-6-Methyl-9-phenyl-5,8a,11a,11b-tetra-
hydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-8(6H)-one
(16a). Compound 16a (55 mg, 55%) was obtained using general
CDCl3)
d
7.74 (d, J¼8 Hz, 2H, ArH), 7.44e7.00 (m, 11H, ArH), 5.74 (d,
J¼5 Hz, 1H, CH), 5.67 (dd, J1¼8 Hz, J2¼5 Hz, 1H, CH), 4.94 (d, J¼5 Hz,
1H, CH), 4.59 (d, J¼8 Hz, 1H, CH), 3.79 (dd, J1¼10 Hz, J2¼8 Hz, 1H
from CH2), 3.42e3.30 (m, 1H from CH2). 13C NMR (100.6 MHz,
procedure from hydroxylactam 13a (106 mg) and BF3$OEt2 (140
mL).
White solid, mp 191e193 ꢀC.1H NMR (300.1 MHz, CDCl3)
d
7.99e7.97
CDCl3) d 166.3, 154.3, 138.5, 137.0, 136.5, 133.2, 129.4, 129.1 (2C),
(m, 2H, ArH), 7.43e7.15 (m, 7H, ArH), 5.70 (dd, J1¼8 Hz, J2¼5 Hz, 1H,
CH), 5.25 (d, J¼4 Hz,1H, CH), 4.75e4.68 (m, 1H, CH), 4.60 (d, J¼8 Hz,
1H, CH), 3.16 (dd, J1¼16 Hz, J2¼6 Hz, 1H from CH2), 2.61 (d, J¼16 Hz,
1H from CH2), 1.28 (d, J¼7 Hz, 3H, CH3). 13C NMR (74.5 MHz, CDCl3)
128.9 (2C), 128.8 (2C), 128.7 (2C), 127.9, 127.8, 127.3, 126.7, 126.1,
81.6, 57.8, 56.8, 49.6, 39.1. HRMS (ESI) calcd for C25H2035ClN2O2
[MþH]þ 415.1208, found 415.1205.
d
166.3, 155.7, 133.1, 130.8, 130.7, 130.1, 129.0 (2C), 128.5 (3C), 128.0,
4.2.6. (6SR,8aRS,11aSR,11bRS)-6-Methyl-9-(4-methylphenyl)-
5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-
8(6H)-one (17a). Compound 17a (45 mg, 94%) was obtained using
general procedure from hydroxylactam 14a (50 mg) and BF3$OEt2
127.0,126.3, 82.1, 58.1, 57.3, 43.2, 34.7, 17.6. IR (KBr) nmax 3059, 2892,
2853,1696,1481,1452,1428,1337,1316,1230,1192. HRMS (ESI) calcd
for C20H18N2NaO2 [MþNa]þ 341.1266, found 341.1255.
(46
CDCl3)
m
L). Colourless crystals, mp 156e158 ꢀC. 1H NMR (400.1 MHz,
4.2.2. (6SR,8aSR,11aRS,11bRS)-6-Methyl-9-(p-tolyl)-5,8a,11a,11b-tet-
rahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-8(6H)-one
(16b). Compound 16b (51 mg, 99%) was obtained using general
d
8.01 (d, J¼8 Hz, 2H, ArH), 7.48 (d, J¼8 Hz, 1H, ArH)
7.38e7.26 (m, 4H, ArH), 7.17 (d, J¼8 Hz, 1H, ArH), 5.52 (dd, J1¼10 Hz,
J2¼3 Hz, 1H, CH), 4.93 (s, 1H, CH), 4.68e4.64 (m, 1H, CH), 4.59 (d,
J¼10 Hz, 1H, CH), 3.19 (dd, J1¼16 Hz, J2¼6 Hz, 1H from CH2), 2.61 (d,
J¼16 Hz, 1H from CH2), 2.41 (s, 3H, CH3), 1.21 (d, J1¼8 Hz, 3H, CH3).
procedure from hydroxylactam 13b (54 mg) and BF3$OEt2 (57
Colourless crystals, mp 218e220 ꢀC (dec). 1H NMR (400.1 MHz,
CDCl3)
mL).
d
7.88 (d, J¼8 Hz, 2H, ArH), 7.34e7.23 (m, 5H, ArH), 7.17 (d,
13C NMR (100.6 MHz, CDCl3)
d 166.4, 154.0, 140.9, 133.5, 132.4, 130.1,
J¼4 Hz,1H, ArH), 5.69 (dd, J1¼8 Hz, J2¼5 Hz,1H, CH), 5.24 (d, J¼5 Hz,
1H, CH), 4.74e4.71 (m, 1H, CH), 4.58 (d, J¼8 Hz, 1H, CH), 3.12 (dd,
J1¼16 Hz, J2¼6 Hz, 1H from CH2), 2.61 (d, J¼16 Hz, 1H from CH2),
2.39 (s, 3H, CH3), 1.24 (d, J¼8 Hz, 3H, CH3). 13C NMR (100.6 MHz,
129.4 (2C), 128.2 (2C), 127.9, 127.2, 125.0,124.9, 87.0, 61.3, 58.0, 43.0,
33.9, 21.5, 17.2. IR (KBr) nmax 3066, 2969, 2916, 2849, 1691, 1608,
1513,1497,1453,1421,1359,1336,1309,1244,1220,1188,1121,1088,
982. HRMS (ESI) calcd for C21H21N2O2 [MþH]þ 333.1597, found
333.1599.
CDCl3) d 166.0, 155.2, 140.7, 132.7, 130.3,129.7, 129.3 (2C), 128.1 (2C),
127.5, 126.6, 125.9, 125.3, 81.4, 57.7, 57.1, 42.8, 34.3, 21.5, 17.2. IR
(KBr) nmax 3060, 2970, 2918, 2848, 1693, 1605, 1514, 1498, 1451,
1427,1362,1334,1308,1243,1222,1186,1120,1088, 984. HRMS (ESI)
calcd for C21H21N2O2 [MþH]þ 333.1597, found 333.1598.
4.2.7. (6RS,8aRS,11aSR,11bRS)-9-(4-Methylphenyl)-6-phenyl-
5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-
8(6H)-one (17b). Compound 17b (51 mg, 99%) was obtained using
general procedure from hydroxylactam 14b (54 mg) and BF3$OEt2
4.2.3. (6SR,8aSR,11aRS,11bRS)-9-(4-Chlorophenyl)-6-methyl-
5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-
(57
CDCl3)
m
L). Colourless crystals, mp 148e150 ꢀC. 1H NMR (400.1 MHz,
d
8.01 (d, J1¼8 Hz, 2H, ArH), 7.39e7.13 (m, 11H, ArH), 5.66
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6
M.S. Ledovskaya et al. / Tetrahedron xxx (2015) 1e7
(dd, J1¼6 Hz, J2¼2 Hz, 1H, CH), 5.55 (dd, J1¼10 Hz, J2¼3 Hz, 1H, CH),
4.67 (br s, 1H, CH), 4.65 (d, J¼10 Hz, 1H, CH), 3.43 (dd, J1¼16 Hz,
J2¼6 Hz, 1H from CH2), 2.61 (dd, J1¼16 Hz, J2¼2 Hz, 1H from CH2),
129.9, 129.7 (2C), 129.4 (2C), 129.0 (2C), 128.1 (2C), 127.4, 127.3,
126.8, 125.9, 125.2, 81.7, 61.0, 57.0, 45.0, 44.9, 21.5.
2.42 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3)
d
166.8, 153.9, 140.9,
4.2.10. (5SR,8aRS,11aSR,11bRS)-9-(4-Chlorophenyl)-5-phenyl-
5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-
8(6H)-one (21b), (5SR,8aRS,11aSR,11bSR)-9-(4-chlorophenyl)-5-
phenyl-5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]iso-
quinolin-8(6H)-one (22b), (5RS,8aRS,11aSR,11bSR)-9-(4-
chlorophenyl)-5-phenyl-5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]
pyrrolo[2,1-a]isoquinolin-8(6H)-one (23b). Following the general
138.0, 134.1, 133.0, 129.4 (2C), 129.2, 128.8 (2C), 128.0 (2C), 127.7,
127.3, 127.2, 126.9 (2C), 125.1, 124.9, 86.6, 61.3, 57.8, 49.8, 31.3, 21.5.
IR (KBr) nmax 2995, 2921, 1703, 1512, 1471, 1437, 1338, 1311, 1081.
HRMS (ESI) calcd for
395.1752.
C
26H23N2O2 [MþH]þ 395.1754, found
4.2.8. (6RS,8aRS,11aSR,11bRS)-9-(4-Chlorophenyl)-6-phenyl-
5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-
8(6H)-one (17c). Compound 17c (43 mg, 97%) was obtained using
general procedure from hydroxylactam 14c (3:1 diastereomeric
mixture was used as the substrate) and BF3,OEt2. The di-
astereomeric ratio in 17c is same as in the starting substrate. White
procedure hydroxylactame 15b (76 mg) and BF3,OEt2 (60 mL) were
reacted in CH2Cl2. PTLC (CH2Cl2/MeOH 40:1) gave 21b (31 mg, 43%),
22b (5 mg, 7%) and 23b (5 mg, 7%).
4.2.10.1. Compound (21b). Colourless crystals, mp 164e167 ꢀC
1H NMR (400.1 MHz, CDCl3)
d
8.09 (d, J¼8 Hz, 2H, ArH), 7.52 (d,
solid, mp 159e163 ꢀC. 1H NMR (400.1 MHz, CDCl3)
d
8.10 (d, J¼8 Hz,
J¼8 Hz, 1H, ArH), 7.44 (d, J¼8 Hz, 2H, ArH), 7.38e7.31 (m, 4H, ArH),
7.22e7.18 (m, 3H, ArH), 6.86 (d, J¼8 Hz, 1H, CH), 5.54 (dd, J1¼10 Hz,
J2¼3 Hz, 1H, CH), 5.14 (br s, 1H, CH), 4.62 (d, J¼10 Hz, 1H, CH), 4.45
(dd, J1¼13 Hz, J2¼6 Hz, 1H from CH2), 4.23 (dd, J1¼11 Hz, J2¼6 Hz,
1H, CH), 3.16 (dd, J1¼13 Hz, J2¼11 Hz, 1H from CH2). 13C NMR
2H, ArH), 7.48e7.13 (m, 11H, ArH), 5.66 (d, J¼6 Hz, 1H, CH), 5.58 (dd,
J1¼10 Hz, J2¼3 Hz, 1H, CH), 4.67 (s, 1H, CH), 4.63 (d, J¼10 Hz, 1H,
CH), 3.44 (dd, J1¼17 Hz, J2¼6 Hz, 1H from CH2), 3.32 (d, J¼17 Hz, 1H
from CH2). 13C NMR (100.6 MHz, CDCl3)
d 166.6, 153.1, 137.8, 136.7,
133.8, 132.9, 129.5 (2C), 129.3, 129.0 (2C), 128.8 (2C), 128.2, 127.9,
127.3, 126.9 (2C), 126.3, 124.9, 87.0, 61.4, 57.6, 49.9, 31.2. IR (KBr)
nmax 3067, 2926, 1698, 1588, 1494, 1457, 1430, 1404, 1363, 1303,
1231, 1101, 1044. HRMS (ESI) calcd for C25H2035ClN2O2 [MþH]þ
415.1208, found 415.1211.
(100.6 MHz, CDCl3) d 166.2, 153.1, 141.2, 137.7, 136.8, 134.2, 130.0,
129.5 (2C), 129.1 (2C), 129.0 (2C), 128.9 (2C), 127.9, 127.5, 127.5,
126.3, 125.0, 87.7, 64.9, 57.7, 45.1, 44.4. IR (KBr) nmax 3156, 3066,
3027, 2976, 2959, 2917, 2861, 1698, 1591, 1492, 1451, 1431, 1362,
1341, 1311, 1219, 1112, 1087, 968. HRMS (ESI): calcd for
C
25H1935ClN2NaO2 [MþNa]þ 437.1027, found 437.1032.
4.2.9. (5SR,8aRS,11aSR,11bRS)-9-(4-Methylphenyl)-5-phenyl-
5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]isoquinolin-
8(6H)-one (21a), (5SR,8aRS,11aSR,11bSR)-9-(4-methylphenyl)-5-
phenyl-5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]pyrrolo[2,1-a]iso-
quinolin-8(6H)-one (22a), (5RS,8aRS,11aSR,11bSR)-9-(4-
methylphenyl)-5-phenyl-5,8a,11a,11b-tetrahydroisoxazolo[50,40:3,4]
pyrrolo[2,1-a]isoquinolin-8(6H)-one (23a). Following the general
4.2.10.2. Compound (22b). Colourless crystals, mp 228e230 ꢀC
(dec). 1H NMR (400.1 MHz, CDCl3)
d
7.85 (d, J¼9 Hz, 2H, ArH), 7.52
(m, 2H, ArH), 7.35 (d, J¼9 Hz, 2H, ArH), 7.31e7.27 (m, 2H, ArH),
7.15e7.00 (m, 4H, ArH), 6.96 (d, J¼8 Hz, 1H, CH), 5.81 (dd, J1¼8 Hz,
J2¼5 Hz, 1H, CH), 5.36 (d, J¼5 Hz, 1H, CH), 4.55 (d, J¼8 Hz, 1H, CH),
4.28e4.25 (m, 1H from CH2 and CH), 3.55e3.48 (dd, J1¼13 Hz,
procedure hydroxylactam 15a (35 mg) and BF3$OEt2 (29
mL) were
J2¼3 Hz, 1H from CH2). 13C NMR (100.6 MHz, CDCl3)
d 166.1, 154.4,
reacted in CH2Cl2. PTLC (CH2Cl2/MeOH 40:1) gave 21a (25 mg, 76%)
and the mixture of 22aþ23a (7 mg, 21%).
143.0, 136.3, 136.2, 131.0, 130.9, 129.3 (2C), 128.8 (2C), 128.3 (2C),
128.2 (2C), 127.9, 127.4, 126.8, 126.5, 126.3, 81.5, 61.2, 57.0, 44.8,
44.4. IR (KBr) nmax 3089, 3063, 3031, 2984, 2927, 2874, 1699, 1591,
1493, 1453, 1430, 1338, 1303, 1233, 1181, 1093, 1048, 1012. HRMS
4.2.9.1. Compound 21a. White solid, mp 177e179 ꢀC. 1H NMR
(400.1 MHz, CDCl3)
d
8.02 (d, J¼8 Hz, 2H, ArH), 7.53 (d, J¼8 Hz, 1H,
(ESI) calcd for
437.1026.
C
25H1935ClN2NaO2 [MþNa]þ 437.1027, found
ArH), 7.39e7.26 (m, 6H, ArH), 7.21e7.29 (m, 3H, ArH), 6.85 (d,
J¼8 Hz, 1H, ArH), 5.51 (dd, J1¼10 Hz, J2¼3 Hz, 1H, CH), 5.13 (br s, 1H,
CH), 4.64 (d, J¼10 Hz, 1H, CH), 4.45 (dd, J1¼13 Hz, J2¼6 Hz, 1H from
CH2), 4.23 (dd, J1¼11 Hz, J2¼6 Hz, 1H, CH), 3.14 (dd, J1¼13 Hz,
J2¼11 Hz, 1H from CH2), 2.41 (s, 3H, CH3). 13C NMR (100.6 MHz,
4.2.10.3. Compound (23b). Colourless crystals, mp 258e260 ꢀC
(dec). 1H NMR (400.1 MHz, CDCl3)
7.95 (d, J¼8 Hz, 2H, ArH),
d
7.41e7.15 (m, 11H, ArH), 5.77 (dd, J1¼8 Hz, J2¼5 Hz, 1H, CH), 5.44 (d,
J¼5 Hz,1H, CH), 4.62 (d, J¼8 Hz,1H, CH), 4.47 (dd, J1¼13 Hz, J2¼6 Hz,
1H from CH2), 4.14 (dd, J1¼11 Hz, J2¼6 Hz, 1H from CH2), 3.23 (dd,
J1¼13 Hz, J2¼11 Hz, 1H from CH2). IR (KBr) nmax 3063, 3029, 2965,
2921, 2852, 1683, 1596, 1493, 1453, 1428, 1403, 1346, 1301, 1269,
1215, 1166, 1092, 1014, 916. HRMS (ESI) calcd for C25H1935ClN2NaO2
[MþNa]þ 437.1027, found 437.1036.
CDCl3)
d 166.4, 153.9, 141.3, 141.0, 137.7, 134.4, 129.9, 129.4 (2C),
129.1 (2C), 128.9 (2C), 128.2 (2C), 127.8, 127.5, 127.4, 125.0, 124.9,
87.4, 64.8, 57.7, 45.1, 44.4, 21.6. IR (KBr) nmax 3171, 3061, 2966, 2921,
2857, 1695, 1597, 1492, 1451, 1438, 1356, 1220, 1123, 1093. HRMS
(ESI) calcd for C26H23N2O2 [MþH]þ 395.1754, found 395.1750.
4.2.9.2. Compound 22a. 1H NMR (400.1 MHz, CDCl3)
d 7.8 (d,
J¼8 Hz, 2H, ArH), 7.54e6.98 (m, 11H, ArH), 5.79 (dd, J1¼8 Hz,
J2¼5 Hz, 1H, CH), 5.34 (d, J¼5 Hz, 1H, CH), 4.58 (d, J¼8 Hz, 1H, CH),
4.28e4.25 (m, 1H from CH2 and CH), 3.52 (dd, J1¼13 Hz, J2¼4 Hz, 1H
Acknowledgements
We gratefully acknowledge the financial support from the
Russian Science Foundation (Project No 14-13-00126). This re-
search made use of resources from the X-ray Diffraction Centre,
Centre for Magnetic Resonance, and the Centre for Chemical
Analysis and Materials of Saint-Petersburg State University.
from CH2), 2.36 (s, 3H, CH3). 13C NMR (100.6 MHz, CDCl3)
d 166.3,
155.2, 143.1, 140.5, 136.3, 131.2, 130.8, 129.2 (2C), 128.4 (2C), 128.2
(2C), 128.0 (2C), 127.8, 127.3, 126.7, 126.2, 125.1, 81.2, 61.1, 57.2, 44.7,
44.4, 21.5.
4.2.9.3. Compound 23a. 1H NMR (400.1 MHz, CDCl3)
d
7.89 (d,
Supplementary data
J¼8 Hz, 2H, ArH), 7.45e6.82 (m, 11H, ArH), 5.73 (dd, J1¼8 Hz,
J2¼5 Hz, 1H, CH), 5.50 (d, J¼5 Hz, 1H, CH), 4.64 (d, J¼9 Hz, 1H, CH),
4.49e4.43 (m, 1H, CH), 4.14 (dd, J1¼12 Hz, J2¼4 Hz, 1H from CH2),
3.22 (dd, J1¼12 Hz, J2¼12 Hz, 1H from CH2), 2.40 (s, 3H, CH3). 13C
Crystallographic data for compounds 13a (CCDC-1010495), 16b
(CCDC-1010821), 17a (CCDC-1010800), 17b (CCDC-974521) and 21b
(CCDC-1010677) have been deposited at the Cambridge Crystallo-
graphic Data Centre and can be obtained free of charge via
NMR (100.6 MHz, CDCl3)
d 166.3, 155.2, 141.1, 140.8, 138.3, 130.8,
Please cite this article in press as: Ledovskaya, M. S.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.02.031

M.S. Ledovskaya et al. / Tetrahedron xxx (2015) 1e7
7
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characterization data, and copies of NMR spectra. Supplementary
data associated with this article can be found in the online version,
at http://dx.doi.org/10.1016/j.tet.2015.02.031. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.
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€
12. (a) Niewohner, M. T.; Bauser, M.; Erguden, J.-K.; Flubacher, D.; Naab, P.; Repp, T.-
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