Anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines via an endocyclic N-acyliminium ion cyclization: a joint experimental and theoretical study

Article abstract of DOI:10.1016/j.tet.2016.06.048

A simple and efficient strategy is reported for the synthesis of anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines via an endocyclic N-acyliminium ion cyclization. The cyclization of 18-aryl-21-(2-arylethyl)-22-hydroxy-16-oxa-17,21-diazahexacyclo[6.6.

Full text of DOI:10.1016/j.tet.2016.06.048

Accepted Manuscript
Anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines via an endocyclic N-
acyliminium ion cyclization: a joint experimental and theoretical study
Maria S. Ledovskaya, Alexander P. Molchanov, Rafael R. Kostikov, Taras L.
Panikorovsky, Vladislav V. Gurzhiy, Mikhail N. Ryazantsev, Vitali M. Boitsov,
Alexander V. Stepakov
PII:
S0040-4020(16)30570-1
10.1016/j.tet.2016.06.048
TET 27862
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 April 2016
Revised Date: 10 June 2016
Accepted Date: 20 June 2016
Please cite this article as: Ledovskaya MS, Molchanov AP, Kostikov RR, Panikorovsky TL, Gurzhiy VV,
Ryazantsev MN, Boitsov VM, Stepakov AV, Anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines via
an endocyclic N-acyliminium ion cyclization: a joint experimental and theoretical study, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.06.048.
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Anthracene-fused isoxazolopyrrolo[2,1-a]
isoquinolines via an endocyclic N-acyliminium
ion cyclization: a joint experimental and
theoretical study
a
a
a
a
Maria S. Ledovskaya, Alexander P. Molchanov, Rafael R. Kostikov, Taras L. Panikorovsky, Vladislav V.
a
a,b
b,c
a,d
Gurzhiy, Mikhail N. Ryazantsev, Vitali M. Boitsov, Alexander V. Stepakov
a
Saint-Petersburg State University, University emb. 7/9, St. Petersburg, 199034, Russian Federtion.
Saint-Petersburg National Research Academic University of the Russian Academy of Science, Khlopin str. 8/3,
St- Petersburg, 194021, Russian Federation.
Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6/8, St. Petersburg, 197022, Russia.
Voeikov Main Geophysical Observatory, ul. Karbysheva 7, St. Petersburg 194021, Russian Federation.
b
c
d
R'
R'
R1
O
Ar
N
H
N
H
O
R
O
R
N
N
BF3
.
OEt2
BF OEt
.
O
N
O
3
2
R2
N
1
1
R = OH
R = O
2
R'
R = O
R
R = OH
2
R'
single diastereomer
52-98% yields)
single diastereomer
(82-99% yields)
(

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines via an endocyclic N-
acyliminium ion cyclization: a joint experimental and theoretical study
a
a
a
a
Maria S. Ledovskaya, Alexander P. Molchanov, Rafael R. Kostikov, Taras L. Panikorovsky,
a
a,b
b,c
a,d,∗
Vladislav V. Gurzhiy, Mikhail N. Ryazantsev, Vitali M. Boitsov, Alexander V. Stepakov
a
Saint-Petersburg State University, University emb. 7/9, St. Petersburg, 199034, Russian Federtion.
Saint-Petersburg National Research Academic University of the Russian Academy of Science, Khlopin str. 8/3, St-Petersburg, 194021, Russian Federation.
Pavlov First Saint Petersburg State Medical University, L'va Tolstogo str. 6/8, St. Petersburg, 197022, Russia.
b
c
d
Voeikov Main Geophysical Observatory, ul. Karbysheva 7, St. Petersburg 194021, Russian Federation.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient strategy is reported for the synthesis of anthracene-fused isoxa-
zolopyrrolo[2,1-a]isoquinolines via an endocyclic N-acyliminium ion cyclization. The cyclization
of 18-aryl-21-(2-arylethyl)-22-hydroxy-16-oxa-17,21-
1
5,19 2,7 9,14 15,19
diazahexacyclo[6.6.5.3 .0 .0 .0 ]docosa-2,4,6,9,11,13,17-heptaen-20-ones proceeds with
high stereoselectivity, leading to 28-aryl-30-oxa-12,29-
Available online
2,14 2,14 3,12 4,9 16,21 22,27
diazaoctacyclo[13.6.6.3 .0 .0 .0 .0 .0 ]triaconta-4,6,8,16,18,20,22,24,26,28-decaen-
3-ones. The N-acyliminium cyclization of 18-aryl-21-(2-arylethyl)-20-hydroxy-16-oxa-17,21-
1
Keywords:
dihydroisoxazoles
hydroxylactams
N-acyliminium ion
intramolecular cyclization
quantum chemical investigation
15,19 2,7 9,14 15,19
diazahexacyclo[6.6.5.3 .0 .0 .0 ]docosa-2,4,6,9,11,13,17-heptaen-22-ones occurs only for
substrates with electron-rich aromatic groups in the arylalkyl fragment. In these cases, cyclization
also proceeds with a high stereoselectivity with the formation of anthracene-fused isoxa-
zolopyrrolo[2,1-a]isoquinolines as single diastereomers. To understand the mechanisms that allow
for cyclization of N-acyliminium ion a quantum chemical investigation was performed.
1
. Introduction
Various biological activities have been found for anthra-
1
7
18
cene based compounds, e.g., antioxidant, analgesic, anti-
Efficient creation of structural, functional and stereochemical
18
19
inflammatory, antibacterial and activity as calcium chan-
complexity from simple precursors is one of the most desired
aspects of new synthetic methodology development. Despite the
fact that some of natural and artificial biologically active com-
pounds have fairly simple structures, a variety of them consist of
several subunits. That dramatically complicates their synthesis
and requires the development of new efficient and effective syn-
thetic strategies. Present research focused at the compounds bear-
ing pyrrolo[2,1-a]isoquinoline, isoxazoline and anthracene subu-
nits.
20
21
nel blockers 5a and P-glycoprotein inhibitors 5b (Fig. 1).
Natural products containing
a pyrrolo[2,1-a]isoquinoline
framework display a variety of pharmacological effects including
1
cytotoxic [crispine B (1)], antitumor [crispine B (1) and crispine
1,2
A (2b)], antibacterial and antiviral activites [trolline (salsoline
3
A) (2a)], DPPH free radical scavenging activity and inhibitory
4
activity [oleracein E (2c)] (Fig. 1). Synthetic pyrroloisoquino-
lines are reported to exhibit wide variety of biological activities
5
6
7
such as antineoplastic, antitumor, antidepressant, antileuke-
5a
8
9
mic, antiviral and activity as α2-adrenoreceptor antagonists. It
is well documented that compounds containing isoxazoline units
are known for their various bioactive properties such as antibac-
terial (3), antituberculosis (4), antiplatelet, antiviral, anti-
convulsant, immunostimulatory and antihypertensive.
10
11
12
13
14
15
16
—
——
∗
Corresponding author. Tel: +7 812-428-4021; fax: +7-812-428-6939; e-mail: alstepakov@yandex.ru

2
Tetrahedron
ACCEPTED MANUSCRIPT
MeO
MeO
HO
HO
RO
RO
2
. Results and discussion
Cl
N
N
N
H
H
Synthesis: We have chosen an anthracene as the first subunit
crispine B (1)
trolline (salsoline A) (2a)
crispine A (2b: R = Me)
oleracein E (2c: R = H)
to be involved in the target compound and substituted malei-
mides – as the simple basis for further construction of isoxa-
zolopyrroloisoquinoline ring system (according to our previous
N
OH
O
O
N
HO
Me
H H
N
N
NH-Hex
25
Me
S
O
NH
N
study, Scheme 1). So the first key intermediates have to be pre-
O
pared are imides 16. They were easily prepared from anhydride
13. The latter in turn was synthesized in good overall yield start-
ing from anthracene and dimethyl acetylenedicarboxylate by a
slight modification of the original procedure of Diels and Alder
CO
2
H
EtO
2
C
antibacterial activity (3)
anti-tuberculosis activity (4)
-
Me
N
O
O
26
OMe
OMe
(Scheme 2). Treating 13 with amines 14a−c in toluene at 110
C gave the ring opened amides 15a−c which could be isolated,
NH
N
°
Cl
O
O
but more conveniently were cyclized immediately with acetic
L-type Ca2+ channel blocker (5a) potent P-glycoprotein inhibitor (5b)
anhydride and AcONa to yield the maleimides 16a−c (Table
R1
R2
26b
N
R2
R2
1).
H
O
N
R2
R1
O
1
. Dimethyl acetylenedicarboxylate
1
N
70-180 o
O
C
O
H
N
O
2. NaOH, MeOH/H
2
O, reflux
C
O
o
3
. Ac
2
O, AcONa, 80
Present study (6)
Present study (7)
O
12
13
Fig. 1 Natural active pyrrolo[2,1-
soxazole-containing bioactive compounds
bioactive compounds 5a
zolopyrrolo[2,1- ]isoquinolines
a
]isoquinolines
1
4
and 2a-c, dihydroi-
, anthracene based
3
and
Scheme 2 Synthesis of anhydride 13
.
,b
and the anthracene-fused isoxa-
and from this work.
a
6
7
Table 1 Synthesis of maleimide derivatives 16a
−
c
.
The interest in the compounds of these classes is not limited
only by their pharmacological action. They have found a wide
range of implementation and at the other fields. N-Substituted
Ar
O
O
N
Ar
N
Ar
H
2
N
H
O, AcONa, 80 o
C
14a-c
Ac
2
3
,4-(9’,10’-dihydroanthracene-9’,10’-diyl)succinimides
have
1
3
O
toluene, reflux
O
been used as model compounds to study the interaction of an
HO
aromatic π system with aliphatic H atoms and heteroatoms such
15a-c
1
6a-c
22
as oxygen, sulfur, and fluorine. Maleimide cycloadducts of
anthracene derivatives can evolve into the realization of valuable
molecular probes for imaging applications based on fluorescence
a
Entry
Ar
Product
Yield (%)
23
1
2
3
Ph (14a
3,4-(MeO)
1-naphthyl (14c
)
16a
16b
16c
72
75
53
photoactivation.
2
C
6
H
)
3
(
14b
)
Thereby the development of simple, efficient and effective
synthetic methods for compounds containing pyrrolo[2,1-
a]isoquinoline, isoxazole and anthracene structural fragments is
still an important and actual challenge of organic chemistry. In
the present work we report a simple and efficient approach to
synthesise anthracene-fused isoxazolopyrrolo[2,1-a]isoquinolines
via an endocyclic N-acyliminium ion cyclization as the key syn-
a
Isolated yield over two steps.
In the second part of this work we examined 1,3-dipolar cy-
cloaddition of maleimides 16a−c to nitrile oxides, generated from
the corresponding hydroximoyl chlorides 17a−c in the presence
of triethylamine (Table 2). Benzonitrile oxide (generated in situ
from the hydroximoyl chloride 17a in the presence of Et N) was
treated with 16a in benzene at 20 °C to give isoxazole 18a in
24
thetic step.
Previously, we described the first synthesis of isoxa-
zolopyrroloisoquinolines and spiro[isoxazolopyrroloiso-
quinolines] 11 via the diastereoselective intramolecular trapping
3
9
6
7% yield (Table 2, entry 1). A similar reaction occurred be-
25
tween imide 16a and nitrile oxide generated from 17b, giving
isoxazole 18b in 93% yield (Table 2, entry 2). The reactions of
maleimides 16b,c with nitrile oxides generated from hydroxi-
moyl chlorides 17a−c led to isoxazoles 18c−g in yields ranging
from 47% up to 98% (Table 2, entries 3-7). The structural as-
signment of the isolated isoxazoles 18a−g was made on the basis
of an N-acyliminium ion (Scheme 1).
R1
H
N
O
OH
H
H
O
Ph
.
BF
3 2
OEt
N
N
O
CH Cl2, RT
2
N
R2
H
1
R1
H
R2
of their spectroscopic data. The H NMR spectrum of 18a exhib-
O
(rac)-8
(rac)-9
ited two singlets at δ = 5.10 and 5.15 ppm which can be assigned
1
3
to the methine protons. The C NMR spectrum of 18a have sig-
nals at δ = 47.7 and 48.2 ppm belonging to the carbons of me-
thine groups. The quaternary carbon atoms of the isoxazole 18a
is observed at δ = 74.9 and 96.7 ppm.
N
OH
N
R
O
N
R
BF .
O
3
OEt
2
2
CH Cl2, RT
H
N
O
O
(
rac)-10
(rac)-11
Scheme 1 Previous works: synthesis of isoxazolopyrroloisoquinolines
and spiro[isoxazolopyrroloisoquinolines] 11 via diastereoselective
intramolecular trapping of an -acyliminium ion.
9
N

3
Table 2 1,3-Dipolar cycloaddition of nitrile oxides to maleimides
16a−c
ACCEPTED MAin
N
20
U
%
SCyie
R
ld
I
(
P
T
T
able 3, entry 9). The other regioisomeric prod-
a
uct 19f was not isolated in pure form. The use of NaBH led to
4
similar results. Thus, reduction of the amide 18a−g by NaBH or
R
O
Ar
4
O
N
NaEt BH occurred non-selectively to give regioisomeric hydrox-
3
Ar
O
R
N
N
Cl
OH
N
ylactams 19 and 20.
O
1
7a-c
O
Et
3
N
benzene, RT
Table 3 Reduction of compounds 18a
−g
with NaBH and NaEt BH
4
3
16a-c
18a-g
OH
Ar
Yield
N
O
R
Entry
Ar
R
4-MeC
Product
b
N
(
%)
O
1
2
3
4
5
6
Ph (16a
Ph (16a
3,4-(MeO)
3,4-(MeO)
3,4-(MeO)
)
)
6
H
4
4
(
17a
)
)
18a
18b
18c
18d
18e
18f
67
93
47
63
70
98
72
4-ClC
CO Et (17c
4-MeC
4-ClC
4-MeC
4-ClC
6
H
(
17b
)
(
17b
(
17b
O
Ar
2
2
2
C
C
C
6
6
6
H
H
H
)
)
3
3
(
(
(
16b)
2
16b
)
)
6
H
4
4
17a
)
17a
)
)
)
O
R
N
19a-f
N
16b
6
H
(
4
A or B
3
O
O
Ar
1-naphthyl (16c
1-naphthyl (16c
6
H
4
7
6
H
(
18g
N
O
R
a
N
H
Reaction conditions: 16 (1 equiv), 17 (1.5 equiv), Et
3
N (1.5 equiv), benzene,
b
18a-g
RT. Isolated yield.
OH
2
0a-f
For the next step in our study, the reduction of the imide func-
tion of substrates 18a−g were investigated. Recently we have
shown, that the reduction of some substituted pyrrolo[3,4-
d]isoxazol-4,6-diones and 1-oxa-2,7-diazaspiro[4.4]non-2-ene-
Yield of
Yield of
20 (%)
20a (42)
20a (31)
20b (30)
20b (35)
Entry
Ar
R
4-MeC
c
c
1
9
(%)
a
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
6
6
H
H
4
4
(
(
18a
18a
)
)
)
)
19a (29)
19a (36)
19b (41)
19b (51)
complex mixture
19c (43)
b
4-MeC
a
6
,8-diones with sodium borohydride in methylene chloride–
4-ClC
4-ClC
CO
4-MeC
4-ClC
4-MeC
4-ClC
6
H
H
4
(
(
18b
18b
)
(
18e
(
18g
b
6
4
ethanol at –80 to –20 °C proceeds regioselectively to yield corre-
sponding hydroxylactams. In all cases, only the carbonyl group at
the β-position with respect to the oxygen atom of the dihydroi-
soxazole ring was reduced. Presumably, this is related to the in-
a,b
3,4-(MeO)
3,4-(MeO)
3,4-(MeO)
1-naphthyl
1-naphthyl
2
C
C
C
6
6
6
H
H
H
3
3
3
2
Et (18c
b
2
2
6
H
4
4
18d
)
)
20c (24)
20d (63)
20e (31)
20f (20)
b
6
H
(
4
19d (30)
19e (45)
19f (−)
a
6
H
18f
)
b
d
9
6
H
4
(
)
2
7
ductive effect of the oxygen atom of the isoxazole ring. The
a
b
c
Reaction conditions: 18, NaBH
4 2 2
(2 equiv), CH Cl /EtOH, 5 to 20 °C.
Reaction conditions: 18, NaEt BH (3 equiv), THF, -78 to -20 °C.
Isolated yield. Was not isolated from the reaction mixture.
reduction of imide 18a with NaBH was carried out in methylene
3
4
d
chloride–ethanol at room temperature for 30 d, to provide the
regioisomeric hydroxylactams 19a and 20a in yields of 29% and
1
Next, the intramolecular Friedel-Crafts–type reactions of
4
2% respectively (Table 3, entry 1). А H NMR analysis of the
hydroxylactams 19a
ment of -acyliminium precursors 19a and 19b with an ex-
cess of BF3 OEt (6 equiv.) in CH Cl at room temperature
gave the
]isoquinolines 22a and 22b as single diastereomers in 93
−e were investigated (Table 4). Treat-
crude reaction mixtures showed that the hydroxylactams 19a and
0a formed as single diastereomers. The stereochemistry of 19a
N
2
⋅
2
2
2
was not determined. The hydroxylactam 20a is an epimer of 23a.
The compound 23a was prepared from 20a by treatment with
BF ⋅OEt (see scheme 3 and fig. 3). The reaction 18a with
anthracene-fused
isoxazolopyrrolo[2,1-
a
3
2
and 82% yield respectively (Table 4, entries 1 and 2). The
signals of the other possible diastereomers were not found in
NaEt BH in tetrahydrofuran at –80 to –20 °C for 3 d gave 19a in
3
3
6% yield along with regioisomeric adduct 20a in 31% yield
1
H NMR spectra of crude reaction mixtures. The
N-
(
Table 3, entry 2). The desired hydroxylactam 19b was obtained
acyliminium ion cyclization of hydroxylactams with meth-
oxy-substituted aromatic ring 19c,d with BF3
CH Cl at room temperature proceeded cleanly to provide
in 41% yield along with product 20b in 30% yield, when the re-
action of 18b was carried out with two molar equivalents of
⋅OEt2 in
NaBH in methylene chloride–ethanol at room temperature for 36
2
2
4
isoxazolopyrroloisoquinolines 22c,d in 92 and 91 % yields
respectively (Table 4, entries 3 and 4). Furthermore, the pol-
ycyclic compound 22e was formed in 99% yield in the case
d (Table 3, entry 3). The reaction 18b with NaEt BH in tetrahy-
3
drofuran at –80 to –20 °C for 4 d gave 19b in 51% yield along
with regioisomeric adduct 20b in 35% yield (Table 3, entry 4).
of the 1-naphthyl substituted
9e (Table 4, entry 5). From the analysis of H NMR spec-
trum of the crude reaction mixtures it was concluded that the
cyclization of hydroxylactams 19a produced only single
diastereomers. The relative stereochemistry of anthracene-
fused isoxazolopyrrolo[2,1- ]isoquinolines 22 was deter-
mined by single-crystal X-ray diffraction (for compound
2a) (Fig. ).
N-acyliminium ion precursor
Unfortunately, reaction of imide 18c with NaEt BH or NaBH as
3
4
1
1
hydride sources led to the formation of complex mixture (prod-
ucts of ester groups hydrolysis and opening of the imide ring)
that was difficult to separate (Table 3, entry 5). Sodium triethyl-
borohydride reduction of the imides 18d and 18e in tetrahydrofu-
ran gave mixture of hydroxylactams 19c, 20c and 19d, 20d re-
spectively, which were separated chromatographically (Table 3,
entries 6 and 7). Addition of a tetrahydrofuran solution of
−
e
a
2
2
NaEt BH (3 equiv.) to a pre-cooled (–78 °C) tetrahydrofuran
3
solution of 18e resulted (after warming to –20 °C for 3 d) in the
formation of regioisomeric hydroxylactams 19d and 20d in
yields of 30 and 63% respectively. The hydroxylactams deriva-
tives 19e and 20e with (naphthalen-1-yl)ethyl substituent at the
pyrrolidine ring were obtained in 45 and 31% yields respectively
by the reaction of 18f with the NaBH for 45 d (Table 3, entry
4
8
). The reduction of imide 18g with NaEt BH was then attempted
3
(
THF, –78 to –20 °C, 3 d). Separation of the crude mixture on
silica gel gave pure sample of lactam 20f as a single diastereomer

4
Tetrahedron
ACCEPTED MANUSCRIPT
Table 4 BF
Crafts–type cyclization of hydroxylactams 19a
3
⋅OEt
2
-catalyzed intramoleculardiastereoselective Friedel-
a
O
Ph
O
−e
Ph
O
R
N
O
R
N
N
H
.
N
OH
BF3 OEt2
Ar
OH
OH
Ar
CH2Cl2, RT
H
O
R
N
N
O
R
N
N
.
BF
3
OEt
2
O
O
CH Cl2, RT
2
20a,b
23a,b
3 2
Scheme 3 Reaction of compounds 20a,b with BF ⋅OEt .
2
1
19a-e
C34
C6
R'
C2
C1
C32
O2
C3
C33
R'
C31
C28
C25
C8
C7 C4 C5
N1
C30
C27 C26
C29
N2
C24
O3
O1
H
O
N
O
H
C9
N
O
N
O
C10 C23
N
C17
C22
C21
C16
C15
R
R
C11
C12
C18
C13
C19
C20
C14
2
2a-d
22e
Fig. 3 ORTEP representation of compound 23a
.
Yield of
22 (%)
Entry
Ar
R
R′
Time, d
b
1
2
3
4
5
Ph
Ph
4-MeC
4-ClC
4-MeC
4-ClC
4-MeC
6
H
4
(
19a
19b
19c
19d
19e
OEt
)
H
H
MeO
MeO
−
1
5
1
7
1
22a (93)
22b (82)
22c (92)
22d (91)
22e (99)
Table 5 BF3
Crafts–type cyclization of hydroxylactams 20c
⋅
OEt -catalyzed intramoleculardiastereoselective Friedel-
2
H
4
(
4
)
a
6
−f
3,4-(MeO)
3,4-(MeO)
1-naphthyl
2
C
C
6
6
H
H
3
3
6
H
(
)
2
6
H
4
(
)
O
Ar
O
Ar
6
H
4
(
)
a
b
O
R
N H
OH
N
Reaction conditions: 19 (1 equiv.), BF
Isolated yield.
3
⋅
2
(5 equiv.), CH
2
Cl
2
, RT.
N
O
R
N
.
BF3 OEt2
CH2Cl2, RT
2
0c-f
24
C3
C4
C2
C5
O
N
H
O
N
C1
C27
H
C6
O
O
R
O28 N29
C302
N
N
C303
C307
R
C26
C301
C25
R'
C7
N8
C30
C306
R'
H
C9
C304
C15
C10
O91
C18
C17
C16
C305
25a,b
2
5c,d
C19
C11
C12
C14
C13
C20
C24
C23
Yield of
C21
Entry
Ar
R
R′
Time, d
b
25 (%)
1
2
3
4
3,4-(MeO)
3,4-(MeO)
1-naphthyl
1-naphthyl
2
C
6
6
H
H
3
3
4-MeC
4-ClC
4-MeC
4-ClC
6
4
(
20c
20d
20e
20f
OEt
)
MeO
MeO
−
1
7
7
2
25a (99)
25b (82)
25c(85)
25d (52)
C22
2
C
6
H
4
(
)
6
H
4
(
)
Fig. 2. ORTEP representation of compound 22a
Interestingly, that N-acyliminium cyclization does not occur
6
H
4
(
⋅
)
−
a
b
Reaction conditions: 20 (1 equiv.), BF
3
2 2 2
(5 equiv.), CH Cl , RT.
Isolated yield.
for phenethyl-substituted N-acyliminium precursors 20a,b. For
example, the treatment of hydroxylactams 20a,b with an excess
of BF ⋅OEt in CH Cl at room temperature led to the formation
C25 C40
C15
3
2
2
2
C36
C27
C19 C23
C42
C32
C14
C28
of the corresponding epimers 23a,b in good yields (23a: 91%,
3b: 83%) (Scheme 3). We were able to obtain sufficiently good
C29
C31
2
C8
C44
C21
C45
crystals of 23a for an X-ray crystallographic study that confirmed
its structure (Fig. 3). At the same time, the N-acyliminium cy-
clization of hydroxylactams 20c and 20d with electron-rich di-
methoxy-functionalised aromatic group led to the polycyclic
compounds 25a and 25b as single diastereomers in 99 and 82%
yield respectively (Table 5, entries 1 and 2). Analogous cycliza-
tions were also achievable for the 1-naphthyl substituted hydrox-
ylactams 20e,f. The single diastereomers 25c,d were obtained by
the treatment of N-acyliminium ion precursors 20e,f with an ex-
cess of BF ⋅OEt (5 equiv.) in CH Cl at room temperature (Table
C39
C38
N22
C37
C20
C2
C18
C33
N5
C26
O4
C9
O1
C3
C7
C10
C6
C13
C17
C11
C34
C16
C12
C30
C35
Fig. 4 ORTEP representation of compound 25c
.
3
2
2
2
5
, entries 3 and 4). The structural elucidation and the attribution
of the relative stereochemistry of the products 25a−d were based
upon NMR analysis and were unequivocally confirmed by X-ray
diffraction of single crystals of 25c (Fig. 4).

5
Computational investigation of the reactio
A
n m
C
e
C
ch
E
an
P
i
T
sm
E
s:D MANtal
ly
U
S
o
C
bs
R
erv
I
ed compound is favorable both kinetically (the
PT
Since for all of the studied reactions N-acyliminium cyclization
products were observed (except hydroxylactames 20a,b), we
limited our investigation by dimethoxy-substituted hydroxylac-
tames 19c, 20c and 20a. We assumed that the key stage of the
process is the unimolecular π-nucleophile attack of an N-
acyliminium ion with the formation of corresponding σ-
complex. Indeed, for all investigated compounds the reaction
with BF ⋅OEt should result in formation of an N-acyliminium
barrier is only 4.0 kcal/mol) and thermodynamically (the ener-
gy difference is 1.7 kcal/mol).
a
b
3
2
ion (21 and 24). On other side, the release of the hydrogen
atom in the sigma-complex formed after the π-nucleophile
attack should be energetically favorable due to an aromatic
ring formation. Therefore, we focus on a search of the transi-
tion states that describe the cyclization process with a subse-
quent calculations of the reaction path starting from each found
transition state and moving in both possible directions: to the
product and to the reactant. Results of these calculations are
summarized in the schemes 4-6. For all reactions, we found
two types of transition states that differ in relative arrangement
of hydrogens on the reactive carbon atoms: cis- and trans-ts
Fig. 5 Cis- (a) and trans- (b) σ-complex after π-nucleophile attack on the
N-acyliminium ion 21 from isoxazoline moiety.
a
b
(
Fig. 5 and 6). For all investigated compounds trans-σ-
complexes (Fig. 5b and 6b) are substantially lower in energy
than cis-σ-complex (Fig. 5a and 6a) and reactions proceed via
transition states of this kind. According to the calculations, the
barriers for the cyclization of N-acyliminium cations 21 and 24
(Schemes 4-6) that leads to cis-σ-complexes are higher by 6.7-
1
9.1 kcal/mol then the barriers for the reactions to form trans-
Fig. 5 Cis- (a) and trans- (b) σ-complex after π-nucleophile attack on the
N-acyliminium ion 24 from isoxazoline moiety.
σ-complexes (Table S1).
Possible pathways for cyclization of generated from 19c N-
acyliminium cation 21 are shown in the scheme 4. The for-
mation of the sigma-complex A trans that leads to experimen-
OMe
HO
OMe
OMe
O
N
N
MeO
O
OMe
Ar
OMe
H
H
+
H
H
N O
Ar
O
N
N
19c
N
∆
G, (kkal/mol)
MeO
O
O
Ar
MeO
ts 21 - B cis (27.3)
-OH
O
MeO
OMe
OMe
OMe
H
B cis
A cis
H
N
N
O
N
N
O
N
N
OMe
O
MeO
O
O
Ar
OMe
Ar
Ar
OMe
ts 21 - A cis (13.3)
H
H
+
B cis (12.1)
2
1
H
H
ts 21 - B trans (7.7)
ts 21 - A trans (4.8)
O
N
N
N O
Ar
22c
N
2
1 (4.2)
O
Ar = 4-Tol
A cis (4.6)
Ar
O
2
1 (2.8)
B trans (1.3)
A trans (-0.9)
21 (0.8)
21 (0.0)
B trans
A trans
Scheme 4 Calculated reaction mechanism for the formation of 22с.
agreement with experiment. This product is formed via a tran-
sition state with the 5.9 kcal/mol barrier and the stabilization
energy is 2.7 kcal/mol.
No cyclization products were observed at the same condition
for 20a (Scheme 6). Our calculations are in full agreement with
this finding. All cyclization reactions are forbidden thermody-
The free energy barrier for the cyclization of N-acyliminium
cation 21 into sigma-complex B trans are higher by 1.0
kcal/mol than those for cyclization into A trans. The routes that
lead to other products are forbidden thermodynamically or both
thermodynamically and kinetically.
For the investigated reaction routes shown in scheme 5 for
N-acyliminium cation 24, the only favorable path is the path
that proceeds through the sigma-complex B trans to 25a in full
namically or both thermodynamically and kinetically.

6
Tetrahedron
ACCEPTED MANUSCRIPATr HO
OMe
OMe
OMe
N
MeO
N
OMe
O
O
OMe
Ar
N
H
H
H
H
Ar
N
N
MeO
N
O
O
20c
O
O
MeO
OMe
MeO
-
OH
OMe
OMe
∆
G, (kkal/mol)
H
Ar
H
Ar
N
B cis
A cis
MeO
Ar
N
N
Ar
N
N
ts 24 - B cis (21.5)
N
OMe
O
O
O
O
OMe
O
O
OMe
H
H
ts 24 - A cis (12.6)
ts 24 - B trans (8.4)
Ar
H
H
25a
N
N
24
N
O
O
N
O
ts 24 - A trans (7.7)
A trans (5.9)
B cis (4.5)
A cis (3.6)
Ar = 4-Tol
O
24 (3.3)
2
2
4 (2.6)
4 (2.5)
B trans
B trans (-0.2)
24 (0.0)
A trans
Scheme 5 Calculated reaction mechanism for the formation of 25а.
OH
N
Ar
N
Ph
O
O
Ar
H
H
H
N
H
Ar
N
N
O
N
20a
OH
O
O
O
-
Ar
N
H
H
B cis
A cis
Ar
Ar
N
N
Ph
N
N
∆G, (kkal/mol)
N
O
O
O
O
ts 24 - B cis (28.3)
ts 24 - A cis (22.2)
O
O
H
H
Ar
H
N
Ar
H
N
N
N
O
24
O
O
O
A cis (16.5)
B cis (16.4)
A trans (14.0)
B trans (13.5)
ts 24 - A trans (14.3)
ts 24 - B trans (13.9)
OH
B trans
Ar
N
A trans
Ph
N
O
O
2
4 (2.9)
4 (0.0)
2
2
4 (2.8)
4 (2.2)
Ar = 4-Tol
2
23a
Scheme 6 Calculated reaction mechanism for the compound 20а.
4
4
. Experimental section
.1. General remarks
From the obtained results it is evident that the N-
acyliminium cyclization for substrates 19a 20c ) occurs
by direct attack the -acyliminium ion intermediate 21 24
by the -aromatic system linked to the nitrogen atom of the
pyrrolidinone ring producing the anthracene-fused isoxa-
zolopyrrolo[2,1- ]isoquinolines 22 25).
−
e
(
−f
N
(
)
IR spectra were obtained on a Bruker Tensor 27 spectrometer.
π
Melting points were determined on a Boetius instrument and are
uncorrected. NMR spectra were recorded on a Bruker Avance III
spectrometer ( H, 400 MHz; C, 100 MHz). Chemical shifts δ
are reported in ppm relative to residual CHCl ( H, δ = 7.26) and
CDCl ( C, δ = 77.16) as internal standard. High-resolution mass
spectra (HRMS) were recorded on a Bruker micrOTOF 10223
spectrometer using electrospray ionization (ESI). The X-ray dif-
fraction 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 5−40 mesh
eluted with dichloromethane/methanol. Crystallographic data for
compounds 22a, 23a, and 25c have been deposited at the Cam-
bridge Crystallographic Data Centre (Deposition No. CCDC-
a
(
1
13
1
3
13
3
. Conclusion
In conclusion, we have shown simple and efficient approach to
3
the synthesis of anthracene-fused isoxazolopyrrolo[2,1-
.
a]isoquinolines in good yield by BF OEt -mediated N-
3
2
acyliminium ion cyclisation. The cyclization of 18-aryl-21-(2-
arylethyl)-22-hydroxy-16-oxa-17,21-diazahexacyclo-
1
5,19 2,7 9,14 15,19
[
6.6.5.3 .0 .0 .0 ]docosa-2,4,6,9,11,13,17-heptaen-20-
ones proceeds with high stereoselectivity, leading to 28-aryl-30-
2,14 2,14 3,12 4,9 16,21 22,27
oxa-12,29-diazaoctacyclo[13.6.6.3 .0 .0 .0 .0 .0 ]-
triaconta-4,6,8,16,18,20,22,24,26,28-decaen-13-ones. The N-
acyliminium cyclization of 18-aryl-21-(2-arylethyl)-20-hydroxy-
1
403120, CCDC-1402997, and CCDC-1403317, respectively)
and can be obtained free of charge via
15,19 2,7 9,14 15,19
1
2
6-oxa-17,21-diazahexacyclo[6.6.5.3 .0 .0 .0 ]docosa-
,4,6,9,11,13,17-heptaen-22-ones occurs only for substrates with
www.ccdc.cam.ac.uk/data_request/cif. Preparation and character-
ization of compounds 22a−e and 25a−d are disclosed below,
while compounds 13, 16a−c, 18a−g, 19a−e, 20a−f and 23a,b
described in the Supplementary data.
electron-rich aromatic groups in arylalkyl fragment. In these cas-
es, cyclization also proceeds with a high stereoselectivity with
the formation of
anthracene-fused isoxazolopyrrolo[2,1-
a]isoquinolines as single diastereomers. A quantum chemical
investigation was performed to understand the mechanisms that
allow for cyclization of the N-acyliminium ion.
Computational methodology: A number of minima and sad-
dle points were located on the potential energy surface to obtain
equilibrium structures and transition states. The type of all sta-

7
tionary points found was confirmed by harmonic frequencies
4.2.3. 6,7-Dimethoxy-28-(p-tolyl)-30-oxa-12,29-diazaoctacyclo-
2,14 2,14 3,12 4,9 16,21 22,27
ACCEPTED MANUSCRIPT
calculations. The accessibility of products and reactants from a
given transition state were confirmed by IRC calculations. Gibbs
free energies were calculated at 273 K using energies and har-
monic frequencies calculated at the previous step. Calculations
were done at the M06-2X/6-31g* level of theory. Gaussian 09
quantum chemistry software package was used for all calcula-
[13.6.6.3 .0 .0 .0 .0 .0 ]triaconta-
4,6,8,16,18,20,22,24,26,28-decaen-13-one (22c). 40 mg (92%)
yield [m. p. 240 ºC (dec.), methanol] as colorless solid. H NMR
(400.1 MHz, CDCl ): δ 2.39 (s, 3H, Me), 2.47 (dd, 1H, CH , J =
1
3
2
15.9, 2.4 Hz), 2.65−2.69 (m, 1H, CH ), 2.73−2.82 (m, 1H, CH ),
2
2
3.83 (s, 3H, OMe), 4.06 (s, 3H, OMe), 4.12 (dd, 1H, CH , J =
12.3, 4.1 Hz), 4.60 (s, 1H, CH), 4.89 (s, 1H, CH), 5.16 (s, 1H,
2
28
tions.
CH), 6.52 (s, 1H), 6.78 (d, 1H, J = 7.3 Hz), 6.97−7.01 (m, 2H),
7
.17−7.23 (m, 5H), 7.47−7.54 (m, 3H), 7.98 (d, 2H, J = 8.1 Hz);
C NMR (100.6 MHz, CDCl ): δ 21.5 (Me), 28.0 (CH ), 38.3
4
.2. General procedure for the preparation of substi-
13
3
2
tuted isoxazolopyrroloisoquinolines (22a and 25a d)
−
e
− .
(CH ), 47.6 (CH), 54.4 (CH), 55.9 (OMe), 56.5 (OMe), 63.6
2
(
CH), 78.4 (С), 96.9 (С), 110.6 (CH ), 111.9 (CH ), 123.1
Ar
Ar
To vigorously stirred solution of corresponding hydrox-
ylactam (19 or 20) in anhyd. dichloromethane under argon
atmosphere was added 5 equiv. of boron trifluoride diethyl
etherate. The reaction mixture was stirred in a capped vial
(C ), 124.7 (CH ), 125.2 (C ), 125.7 (CH ), 125.8 (CH ),
Ar Ar Ar Ar Ar
1
26.3 (C ), 126.5 (CH ), 126.6 (CH ), 127.0 (CH ), 127.2
Ar Ar Ar Ar
(CH ), 127.7 (CH ), 128.3 (2CH ), 129.1 (2CH ), 138.3 (C ),
Ar Ar Ar Ar Ar
1
1
1
1
38.5 (C ), 138.8 (C ), 139.4 (C ), 140.1 (C ), 147.6 (C ),
Ar
Ar
Ar
Ar
Ar
for 1−7 d at room temperature (see tables 4 and 5). After
-
1
48.4 (C ), 154.5 (C=N), 166.5 (CO). IR (KBr, cm ): 2923,
Ar
completion of the reaction, water was added carefully to the
reaction mixture (10 mL). The aqueous layer was extracted
with CH Cl (3 x 5 mL), the organic layers were combined,
685, 1520, 1466, 1436, 1359, 1332, 1291, 1259, 1230, 1148,
113, 1010, 938, 908; HRMS (ESI): calcd for C H N O
4
3
6
31
2
2
2
+
[
M+H] 555.2278, found 555.2273.
dried over MgSO , and evaporated to dryness. The residue
4
was then purified by preparative thin-layer chromatography
4
.2.4.
6,7-Dimethoxy-28-(4-chlorophenyl)-30-oxa-12,29-
2,14 2,14 3,12 4,9 16,21 22,27
(
using a mixture of CH Cl /MeOH as eluent), or crystallized
2 2
diazaoctacyclo[13.6.6.3 .0 .0 .0 .0 .0 ]triaconta-
,6,8,16,18,20,22,24,26,28-decaen-13-one (22d). 16 mg (91 %)
from methanol (or ethanol).
4
1
yield (m. p. 117−120 ºС, methanol) as yellow solid. H NMR
(400.1 MHz, CDCl ): δ 2.49 (dd, 1H, CH , J = 15.5, 3.0 Hz),
2
4
[
4
.2.1.
13.6.6.3 .0 .0 .0 .0 .0 ]triaconta-
,6,8,16,18,20,22,24,26,28-decaen-13-one (22a). 13 mg (93 %)
28-(p-Tolyl)-30-oxa-12,29-diazaoctacyclo-
2
,14 2,14 3,12 4,9 16,21 22,27
3
2
.66−2.70 (m, 1H, CH ), 2.74−2.82 (m, 1H, CH ), 3.84 (s, 3H,
2
2
1
OMe), 4.06 (s, 3H, OMe), 4.12 (dd, 1H, CH , J = 12.4, 5.0 Hz),
2
yield (m. p. 235−238 ºС, methanol) as a colorless solid. H NMR
4
1
7
8
.61 (s, 1H, CH), 4.89 (s, 1H, CH), 5.09 (s, 1H, CH), 6.53 (s,
H), 6.75 (d, 1H, J = 7.3 Hz), 6.95 (s, 1H), 6.98−7.02 (m, 1H),
.18−7.26 (m, 3H), 7.36 (d, 2H, J = 8.7 Hz), 7.47−7.54 (m, 3H),
(
400.1 MHz, CDCl ): δ 2.39 (s, 3H, Me), 2.59 (dd, 1H, CH , J =
3
2
1
4
1
5.7, 3.2 Hz), 2.67−2.74 (m, 1H, CH ), 2.79−2.87 (m, 1H, CH ),
2 2
.15 (dd, 1H, CH , J = 12.6, 5.3 Hz), 4.66 (s, 1H, CH), 4.95 (s,
2
13
.05 (d, 2H, J = 8.7 Hz); C NMR (100.6 MHz, CDCl ): δ 27.9
3
H, CH), 5.16 (s, 1H, CH), 6.76 (d, 1H, J = 7.3 Hz), 6.96−7.00
(CH ), 38.3 (CH ), 47.4 (CH), 54.3 (CH), 55.9 (OMe), 56.5
2 2
(
(
(
(
m, 1H), 7.06 (d, 1H, J = 7.6 Hz), 7.18−7.25 (m, 6H), 7.33−7.37
13
(OMe), 63.6 (CH), 78.0 (С), 97.3 (С), 110.6 (CHAr), 111.9
m, 1H), 7.44−7.57 (m, 4H), 7.96 (d, 2H, J = 8.2 Hz); C NMR
100.6 MHz, CDCl ): δ 21.5 (Me), 28.4 (CH ), 38.2 (CH ), 47.5
(CH ), 122.9 (C ), 124.6 (CH ), 125.7 (CH ), 125.9 (CH ),
Ar Ar Ar Ar Ar
3
2
2
1
26.2 (C ), 126.59 (CH ), 126.64 (CH ), 126.7 (C ), 127.1
Ar Ar Ar Ar
CH), 54.2 (CH), 63.7 (CH), 78.3 (С), 96.9 (С), 124.7 (CHAr),
25.2 (C ), 125.7 (CH ), 125.8 (CH ), 126.3 (CH ), 126.5
(
(
(
(
CH ), 127.3 (CH ), 127.8 (CH ), 128.7 (2CH ), 129.7
2CH ), 136.1 (C ), 138.2 (C ), 138.3 (C ), 138.6 (C ), 139.1
C ), 147.7 (C ), 148.5 (C ), 153.9 (C=N), 166.3 (CO); IR
KBr, cm ): 2934, 2853, 2249, 1694, 1615, 1518, 1459, 1358,
Ar Ar Ar Ar
1
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
(
CH ), 126.6 (CH ), 127.0 (CH ), 127.17 (CH ), 127.23
Ar Ar Ar Ar
Ar
Ar
Ar
(
CH ), 127.3 (CH ), 127.7 (CH ), 128.3 (2CH ), 129.1
-1
Ar
Ar
Ar
Ar
(
2CH ), 129.5 (CH ), 131.0 (C ), 133.7 (C ), 138.3 (C ),
Ar Ar Ar Ar Ar
1
330, 1289, 1258, 1228, 1147, 1112, 1014, 908; HRMS (ESI):
1
1
1
38.6 (C ), 138.8 (C ), 139.3 (C ), 140.1 (C ), 154.5 (C=N),
35
+
Ar
Ar
Ar
Ar
-
1
calcd for C35
H
28 ClN
2
O
4
[M+H] 575.1732, found 575.1739.
66.5 (CO); IR (KBr, cm ): 3031, 2918, 2859, 2129, 1688, 1458,
434, 1334, 1294, 920; HRMS (ESI): calcd for C H N O
2
34
27
2
+
4.2.5.
32-(p-Tolyl)-34-oxa-16,33-diazanonacyclo-
[
M+H] 495.2067, found 495.2071.
2,18 2,18 3,16 4,13 7,12 20,25 26,31
[
4
17.6.6.3 .0 .0 .0 .0 .0 .0 ]tetratriaconta-
,6,7,9,11,12,20,22,24,26,28,30,32-tridecaen-17-one (22e). 28
4
.2.2.
28-(4-Chlorophenyl)-30-oxa-12,29-diazaoctacyclo-
1
2
,14 2,14 3,12 4,9 16,21 22,27
mg (99 %) yield (m. p. > 260 ºС, methanol) as colorless solid. H
NMR (400.1 MHz, CDCl ): δ 2.39 (s, 3H, Me), 2.77−2.84 (m,
1H, CH ), 2.97−3.06 (m, 1H, CH ), 3.14 (dd, 1H, CH , J = 16.3,
4
5
6
[
4
13.6.6.3 .0 .0 .0 .0 .0 ]triaconta-
,6,8,16,18,20,22,24,26,28-decaen-13-one (22b). 28 mg (82 %)
3
1
2
2
2
yield [m. p. 177 ºС (dec.), methanol] as light yellow solid. H
NMR (400.1 MHz, CDCl ): δ 2.60 (dd, 1H, CH , J = 15.7, 3.2
.5 Hz), 4.36 (dd, 1H, CH , J = 13.1, 5.9 Hz), 4.84 (s, 1H, CH),
.05 (s, 1H, CH), 5.21 (s, 1H, CH), 6.79 (d, 1H, J = 7.2 Hz),
.97-7.01 (m, 1H), 7.18−7.28 (m, 5H), 7.49−7.58 (m, 5H), 7.68
2
3
2
Hz), 2.71−2.75 (m, 1H, CH ), 2.80−2.88 (m, 1H, CH ), 4.15 (dd,
2
2
1
5
7
7
H, CH , J = 12.5, 5.0 Hz), 4.67 (s, 1H, CH), 4.96 (s, 1H, CH),
2
(
d, 1H, J = 8.5 Hz), 7.82−7.88 (m, 3H), 7.97 (d, 2H, J = 8.3 Hz).
.09 (s, 1H, CH), 6.74 (d, 1H, J = 7.3 Hz), 6.97−7.01 (m, 1H),
.07 (d, 1H, J = 7.6 Hz), 7.17−7.26 (m, 4H), 7.34−7.35 (m, 3H),
1
3
C NMR (100.6 MHz, CDCl ): δ 21.5 (Me), 24.7 (CH ), 37.8
3
2
13
(CH
1
2
), 47.5 (CH), 54.4 (CH), 64.0 (CH), 78.5 (С), 97.3 (С),
.37−7.56 (m, 4H), 8.03 (d, 2H, J = 8.9 Hz). C NMR (100.6
22.9 (CH ), 124.7 (CH ), 124.9 (CH ), 125.2 (C ), 125.7
Ar
Ar
Ar
Ar
MHz, CDCl ): 28.3 (CH ), 38.2 (CH ), 47.3 (CH), 54.1 (CH),
3
2
2
(
(
(
(
(
(
CH ), 125.9 (2CH ), 126.4 (CH ), 126.5 (CH ), 126.56
CH ), 126.60 (CH ), 127.0 (CH ), 127.3 (CH ), 127.8
CH ), 128.3 (2CH ), 128.6 (CH ), 128.8 (C ), 129.1
2CH ), 129.2 (C ), 132.1 (C ), 132.6 (C ), 138.3 (C ), 138.6
C ), 138.8 (C ), 139.4 (C ), 140.1 (C ), 154.5 (C=N), 166.5
CO). IR (KBr, cm ): 2920, 1698, 1514, 1444, 1367, 1292, 1189,
Ar Ar Ar Ar
6
3.7 (CH), 78.0 (С), 97.4 (С), 124.6 (CH ), 125.7 (CH ), 125.8
Ar Ar
Ar
Ar
Ar
Ar
(
CH ), 126.3 (CH ), 126.6 (CH ), 126.7 (CH + C ), 127.1
Ar Ar Ar Ar Ar
Ar
Ar
Ar
Ar
(
CH ), 127.3 (2CH ), 127.4 (CH ), 127.8 (CH ), 128.7
Ar Ar Ar Ar
Ar
Ar
Ar
Ar
Ar
(
2CH ), 129.6 (CH ), 129.7 (2CH ), 130.8 (C ), 133.6 (C ),
Ar Ar Ar Ar Ar
Ar
Ar
Ar
Ar
1
1
36.1 (C ), 138.2 (C ), 138.4 (C ), 138.6 (C ), 139.0 (C ),
-1
Ar
Ar
Ar
Ar
Ar
53.9 3 (C=N), 166.3 (CO); HRMS (ESI): calcd for
+
5
+
1118, 929; HRMS (ESI): calcd for C38
45.2224, found 545.2252.
H N O [M+H]
29 2 2
C H ClN O [M+H] 515.1521, found 515.1550.
3
3
24
2
2
5

8
Tetrahedron
4
.2.6. 6,7-Dimethoxy-30-(p-tolyl)-28-oxa-12,29-diazaoctacyclo-
4,6,7,9,11,12,20,22,24,26,28,30,33-tridecaen-17-one (25d). 8 mg
ACCEPTED MANUSCRIPT
2
,14 2,14 3,12 4,9 16,21 22,27
[
4
13.6.6.3 .0 .0 .0 .0 .0 ]triaconta-
,6,8,16,18,20,22,24,26,29-decaen-13-one (25a). 9 mg (99 %)
(52 %) yield (m. p. 115−116 ºС, isolated by PTLC) as colorless
1
solid. H (400.1 MHz, CDCl ): δ 1.60 (1H, CH , overlapped with
3 2
1
yield (m. p. > 265 ºС, ethanol) as colorless solid. H NMR (400.1
H O), 2.77−2.85 (m, 2H, CH ), 4.27 (dd, 1H, CH , J = 12.1, 5.4
2 2 2
MHz, CDCl ): δ 2.30 (s, 3H, Me), 2.40−2.44 (m, 1H, CH ),
Hz), 4.93 (s, 1H, CH), 5.09 (s, 1H, CH), 5.19 (d, 1H, CH , J =
3
2
Ar
2
.51−2.55 (m, 1H, CH ), 2.75−2.79 (m, 1H, CH ), 3.63 (s, 3H,
7.3 Hz), 5.28 (s, 1H, CH), 6.17−6.21 (m, 1H), 6.90-6.94 (m, 1H),
2
2
1
3
OMe), 3.79 (s, 3H, OMe), 4.23 (dd, 1H, CH , J = 12.6, 4.3 Hz),
4
7.11−7.23 (m, 6H), 7.51−7.75 (m, 7H), 7.90−7.95 (m, 2H).
C
2
.48 (s, 1H, CH), 5.13 (s, 1H, CH), 5.14 (s, 1H, CH), 6.17 (s,
NMR (100.6 MHz, CDCl ): δ 24.9 (CH ), 37.7 (CH ), 47.3 (CH),
3
2
2
1
H), 6.40 (s, 1H), 6.93 (br.s, 4H), 7.18−7.25 (m, 4H), 7.49−7.52
48.9 (CH), 63.2 (CH), 71.5 (С), 100.6 (С), 123.1 (CH ), 124.0
Ar
13
(m, 3H), 7.57−7.59 (m, 1H). C NMR (100.6 MHz, CDCl ): δ
(CH ), 124.1 (CH ), 125.3 (CH ), 125.52 (CH ), 125.54
3
Ar
Ar
Ar
Ar
2
1.2 (Me), 29.7 (CH ), 38.5 (CH ), 47.5 (CH), 50.8 (CH), 55.2
(CH ), 126.4 (CH ), 126.67 (CH ), 126.70 (CH ), 126.9
2
2
Ar Ar Ar Ar
(OMe), 56.0 (OMe), 63.8 (CH), 74.1 (С), 99.2 (С), 110.5 (CHAr),
(CH ), 126.99 (CH ), 127.04 (C ), 127.3 (CH ), 127.35
Ar Ar Ar Ar
1
11.8 (CH ), 122.2 (C ), 124.8 (CH ), 125.9 (CH ), 126.4
(CH ), 127.43 (C ), 128.5 (CH ), 129.4 (2CH ), 130.1
Ar
Ar
Ar
Ar
Ar Ar Ar Ar
(
CH ), 126.8 (CH ), 127.19 (CH + C ), 127.22 (2CH ),
(2CH ), 131.9 (C ), 132.3 (C ), 133.9 (C ), 136.8 (C ), 137.6
Ar Ar Ar Ar Ar
Ar
Ar
Ar
Ar
Ar
1
27.27 (CH ), 127.30 (CH ), 127.8 (CH ), 127.9 (C ), 128.6
(C ), 138.9 (C ), 139.3 (C ), 139.4 (C ), 157.8 (C=N), 167.4
Ar Ar Ar Ar
-1
Ar
Ar
Ar
Ar
(
(
(
2CH ), 138.0 (C ), 138.7 (C ), 138.9 (C ), 139.6 (C ), 140.1
C ), 146.8 (C ), 148.4 (C ), 156.3 (C=N), 167.3 (CO). IR
KBr, cm ): 2921, 2851, 1706, 1615, 1520, 1459, 1292, 1258,
229, 1144, 1110, 1016, 902; HRMS (ESI): calcd for
(CO). IR (KBr, cm ): 2922, 1771, 1703, 1607, 1514, 1467, 1427,
1395, 1326, 1227, 1092, 1015, 954, 933, 900; HRMS (ESI):
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
-
1
35
+
calcd for C H ClN O [M+H] 565.1677, found 565.1689.
37 26 2 2
1
+
C H N O Na [M+Na] 577.2098, found 577.2109.
3
6
30
2
4
Acknowledgements
4
.2.7.
diazaoctacyclo[13.6.6.3 .0 .0 .0 .0 .0 ]triaconta-
,6,8,16,18,20,22,24,26,29-decaen-13-one (25b). 32 mg (82 %)
30-(4-Chlorophenyl)-6,7-dimethoxy-28-oxa-12,29-
We gratefully acknowledge the financial support from the Rus-
sian Science Foundation (Project No 14-13-00126). This research
made use of resources from the X-ray Diffraction Centre, Centre
for Magnetic Resonance, Educational Resourse Center of Chem-
istry and the Centre for Chemical Analysis and Materials of
Saint-Petersburg State University.
2,14 2,14 3,12 4,9 16,21 22,27
4
1
yield [m. p. 240 ºС (dec.), methanol] as beige solid. H (400.1
MHz, CDCl ): 2.40−2.44 (m, 1H, CH ), 2.51−2.55 (m, 1H, CH ),
2
4
1
2
3
2
2
.70− 2.78 (m, 1H, CH ), 3.67 (s, 3H, OMe), 3.79 (s, 3H, OMe),
2
.22 (dd, 1H, CH , J = 12.4, 4.2 Hz), 4.49 (s, 1H, CH), 5.13 (s,
2
H, CH), 5.14 (s, 1H, CH), 6.42 (s, 1H), 6.22 (s, 1H), 6.99 (d,
H, CH, J = 8.2 Hz), 7.13 (d, 2H, CH, J = 8.2 Hz), 7.18− 7.25
Supplementary Material
13
(m, 4H), 7.49− 7.57 (m, 4H). C NMR (100.6 MHz, CDCl ): δ
3
2
9.2 (CH ), 38.5 (CH ), 47.4 (CH), 50.7 (CH), 55.7 (OMe), 56.2
Supplementary data (experimental procedures, characteriza-
tion data, and copies of NMR spectra) associated with this article
can be found in the online version, at doi:
2
2
(OMe), 63.7 (CH), 74.2 (С), 99.7 (С), 111.1 (CH ), 112.4
Ar
(CH ), 122.2 (C ), 124.6 (CH ), 125.9 (CH ), 126.4 (CH ),
Ar
Ar
Ar
Ar
Ar
1
26.9 (CH ), 127.3 (CH ), 127.41 (CH ), 127.43 (CH ), 127.5
Ar Ar Ar Ar
(
C ), 128.0 (CH ), 128.2 (2CH ), 128.7 (2CH ), 129.4 (C ),
Ar Ar Ar Ar Ar
1
35.1 (C ), 137.8 (C ), 138.5 (C ), 139.5 (C ), 139.9 (C ),
Ar Ar Ar Ar Ar
-
References and notes
1
47.1 (C ), 148.8 (C ), 155.5 (C=N), 167.1 (CO). IR (KBr, cm
Ar Ar
1
)
: 2941, 2851, 2252, 1708, 1612, 1518, 1466, 1435, 1355, 1291,
1
.
Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795.
1
257, 1228, 1144, 1110, 1012, 905; HRMS (ESI): calcd for
2. Xie, W.-D.; Li, P.-L.; Jia, Z.-J. Pharmazie 2005, 60, 233.
35
+
3
.
Wang, R. F.; Yang, X. W.; Ma, C. M.; Cai, S. Q.; Li, J. N.; Shoyama,
Y. Heterocycles 2004, 63, 1443.
C H ClN O [M+H] 575.1732, found 575.1732.
3
5
28
2
4
4
5
.
.
Yang, Z.; Liu, C.; Xiang, L; Zheng, Y. Phytother. Res. 2009, 23, 1032.
(a) Anderson, W. K.; Heider, A. R.; Natarajan, R.; Yucht, J. A. J. Med.
Chem. 1988, 31, 2097; (b) Pla, D.; Marchal, A.; Olsen, C. A.;
Francesch, A.; Cuevas, C.; Albericio, F.; Álvarez, M. J. Med. Chem.
2006, 49, 3257.
4
[
4
.2.8.
17.6.6.3 .0 .0 .0 .0 .0 .0 ]tetratriaconta-
,6,7,9,11,12,20,22,24,26,28,30,33-tridecaen-17-one (25c). 19
34-(p-Tolyl)-32-oxa-16,33-diazanonacyclo-
2
,18 2,18 3,16 4,13 7,12 20,25 26,31
mg (85 %) yield [m. p. 258 ºС (dec.), methanol] as colorless sol-
id. H (400.1 MHz, CDCl ): δ 1.52−1.59 (m, 1H, CH ), 2.51 (s,
3
1
6. (a) Anderson, W. K.; McPherson, Jr., H. L.; New, J. S.; Rick, A. C. J.
Med. Chem. 1984, 27, 1321; (b) Cironi, P.; Albericio, F.; Álvarez, M. In
Progress in Heterocyclic Chemistry; G. W. Gribble and J. A. Joule,
Eds.; Pergamon: Oxford (UK), 2004; Vol. 16, pp 1–26; (c) Tardy, C.;
Facompré, M.; Laine, W.; Baldeyrou, B.; García-Grávalos, D.; Fran-
cesch, A.; Mateo, C.; Pastor, A.; Jiménez, J. A.; Manzanares, I.; Cue-
vas, C.; Bailly, C. Bioorg. Med. Chem. 2004, 12, 1697.
3
2
H, Me), 2.75−2.83 (m, 2H, CH ), 4.23−4.28 (m, 1H, CH ), 4.98
2
2
(s, 1H, CH), 5.09 (s, 1H, CH), 5.19 (d, 1H, CH , J = 7.3 Hz),
Ar
5
7
7
.30 (s, 1H, CH), 6.16−6.20 (m, 1H), 6.89−6.93 (m, 1H),
.12−7.19 (m, 2H), 7.27−7.36 (m, 2H), 7.41 (d, 2H, J = 7.9 Hz),
13
.49−7.62 (m, 4H), 7.68−7.71 (m, 3H), 7.88−7.97 (m, 2H).
C
7
.
(a) Maryanoff, B. E.; McComsey, D. F.; Gardocki, J. F.; Shank, R. P.;
Costanzo, M. J.; Nortey, S. O.; Schneider, C. R.; Setler, P. E. J. Med.
Chem. 1987, 30, 1433; (b) Maryanoff, B. E.; McComsey, D. F.; Dukor,
R. K.; Nafie, L. A.; Freedman, T. B.; Cao, X.; Day, V. W. Bioorg. Med.
Chem. 2003, 11, 2463.
NMR (100.6 MHz, CDCl ): δ 21.5 (Me), 24.9 (CH ), 37.6 (CH ),
4
3
2
2
7.3 (CH), 49.0 (CH), 63.2 (CH), 71.8 (С), 100.2 (С), 123.1
(CH ), 124.26 (CH ), 124.30 (CH ), 125.3 (CH ), 125.4
Ar
Ar
Ar
Ar
(CH ), 125.5 (CH ), 125.9 (C ), 126.3 (CH ), 126.6 (2CH ),
Ar Ar Ar Ar Ar
8
.
An, T.-Y.; Huang, R.-Q.; Yang, Z.; Zhang, D.-K.; Li, G.-R.; Yao, Y.-
C.; Gao. J. Phytochemistry 2001, 58, 1267.
1
26.7 (CH ), 126.9 (CH ), 127.1 (CH ), 127.2 (CH ), 127.4
Ar Ar Ar Ar
(C ), 128.4 (CH ), 128.8 (2CH ), 129.7 (2CH ), 131.9 (C ),
Ar Ar Ar Ar Ar
9. Chung, S.-H.; Yook, J.; Min, B. J.; Lee, J. Y.; Lee, Y. S.; Jin, C. Arch.
Pharmacol. Res. 2000, 23, 353.
10. Kang, Y. K.; Shin, K. J.; Yoo, K. H.; Seo, K. J.; Lee, C.; Park, S. Y.;
Kim, D. J.; Park, S. W. Bioorg. Med. Chem. Lett. 2000, 10, 95.
11. Rakesh, Sun, D.; Lee, R. B.; Tangallapally, R. P.; Lee, R. E. Eur. J.
Med. Chem. 2009, 44, 460.
1
1
32.2 (C ), 133.7 (C ), 137.9 (C ), 139.2 (C ), 139.49 (C ),
Ar Ar Ar Ar Ar
39.52 (C ), 140.8 (C ), 158.6 (C=N), 167.6 (CO). IR (KBr,
Ar
Ar
-
1
cm ): 2923, 2853, 1705, 1512, 1458, 1293, 1118, 902; HRMS
+
(ESI): calcd for C H N O [M+H] 545.2224, found 545.2239.
38 29 2 2
1
2. Xue, C.; Roderick, J.; Mousa, S.; Olson, R. E.; De Grado, W. F. Bioorg.
Med. Chem. Lett. 1998, 8, 3499.
4
.2.9.
34-(4-Chlorophenyl)-32-oxa-16,33-diazanonacyc-
,18 2,18 3,16 4,13 7,12 20,25 26,31
2
lo[17.6.6.3 .0 .0 .0 .0 .0 .0 ]tetratriaconta-
13. Diana, G. D.; McKinlay, M. A.; Brisson, C. J.; Zalay, E. S.; Mirallas, J.
V.; Salvador, U. J. J. Med. Chem. 1985, 28, 748.

9
1
1
1
4. Lepage, F.; Tombert, F.; Cuvier, G.; Marivain, A.; Gillardin, J. M. Eur.
ACCEPTED MANUSCRIPT
J. Med. Chem. 1992, 27, 581.
5. Ryng, S.; Macho, Z.; Wieczorek, Z.; Zimecki, M.; Mokrosz, M. Eur. J.
Med. Chem. 1998, 33, 831.
6. Dallanoce, C.; Meroni, G.; De Amici, M.; Hoffman, C.; Klotz, K.-N.;
De Micheli, C. Bioorg. Med. Chem. 2006, 14, 4393.
1
7. Suyavaran, A.; Ramamurthy, C.; Mareeswaran, R.; Shanthi, Y. V.;
Selvakumar, J.; Mangalaraj, S.; Kumar, M. S.; Ramanathan, C. R.;
Thirunavukkarasu, C. Bioorg. Med. Chem. 2015
8. Abu-Hashem, A.; Gouda, M. A. Arch. Pharm. Chem. Life Sci. 2011
44, 543.
9. Khalil, A. M.; Berghot, M. A.; Gouda, M. A. Eur. J. Med. Chem.
010 45, 1552.
, 23, 488.
1
1
2
,
3
2
,
0. Bova, S.; Saponara, S.; Rampa, A.; Gobbi, S.; Cima, L.; Fusi, F.;
Sgaragli, G.; Cavalli, M.; de los Rios, C.; Striessnig, J.; Bisi, A. J.
Med. Chem. 2009
1. Bisi, A.; Gobbi, S.; Rampa, A.; Belluti, F.; Piazzi, L.; Valenti, P.;
Gyemant, N.; Molnár, J. J. Med. Chem. 2006 49, 3049.
, 52, 1259.
2
,
2
2
2. Raimondi, L.; Benaglia, M.; Cozzi, F. Eur. J. Org. Chem. 2014, 4993.
3. Sanhes, D.; Raluy, E.; Rétory, S.; Saffon, N.; Teuma, E.; Gómez, M.
Dalton Trans. 2010
4. Synthesis of pyrrolo[2,1-
acyliminium ion cyclisation: (
Tetrahedron 2000 56, 3817; (
M. D. Chem. Rev. 2004 104, 3341; (
Micouin, L. Chem. Rev. 2004 104, 2311; (
S.; Blake, A. J. Org. Biomol. Chem. 2009
Meldal, M. J. Comb. Chem. 2005
Gaskell, S. N.; Saha, B.; Martin, W. P.; Page, P. C. B.; Edgar, M. Tet-
rahedron 2010 66, 9538; ( ) Othman, R. B.; Affani, R.; Tranchant,
M.-J.; Antoniotti, S.; Dalla, V.; Duñach, E. Angew. Chem. Int. Ed.
010 49, 776; ( ) Marson, C. M. Arkivoc 2001 (i), 1; ( ) Allin, S. M.;
Gaskell, S. N.; Towler, J. M. R.; Page, P. C. B.; Saha, B.; McKenzie,
M. J.; Martin, W. P. J. Org. Chem. 2007 72, 8972 ) Lee, Y. S.;
Kang, D. W.; Lee, S. J.; Park, H. J. Org. Chem. 1995 60, 7149; (
Kałuża, Z.; Mostowicz, D. Tetrahedron: Asymmetry 2003, 14, 225;
) Marson, C. M.; Pink, J. H.; Smith, C. Tetrahedron 2003 59
0019; ( ) Allin, S. M.; James, S. L.; Martin, W. P.; Smith, T. A. D.
Tetrahedron Lett 2001 42, 3943; ( ) Speckamp, W. N.; Hiemstra, H.
Tetrahedron 1985 41, 4367; ( ) Maryanoff, B. E.; Zhang, H.-C.; Co-
hen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004 104,
) Unsworth, W. P.; Kitsiou, C.; Taylor, R. J. K. Org. Lett
15, 258; ( ) Chambers, S. J.; Coulthard, G.; Unsworth, W. P.;
22, 6496.
) Stepakov, A. V.; Ledovskaya, M. S.; Boitsov, V. M.; Molchanov,
A. P.; Kostikov, R. R.; Gurzhiy, V. V.; Starova, G. L. Tetrahedron
Lett 2012 53, 5414; ( ) Ledovskaya, M. S.; Molchanov, A. P.;
Boitsov, V. M.; Kostikov, R. R.; Stepakov, A. V. Tetrahedron 2015
, 1952; (
Kostikov, R. R. Tetrahedron 2015
6. ( ) Diels, O.; Alder, K. Liebigs Ann. Chem. 1931
,
39, 9719.
]isoquinolines via an endocyclic
) Speckamp, W. N.; Moolenaar, M. J.
) Chrzanowska, M.; Rozwadowska,
) Royer, J.; Bonin, M.;
2
a
N-
a
,
b
,
c
,
d
7
) Zhang, F.; Simpkins, N.
, 1963; ( ) Nielsen, T. E.;
) Allin, S. M.; Towler, J.;
,
e
,
7
, 599; (
f
,
g
2
,
h
,
i
,
; (j
,
k)
(l
,
,
1
m
.
,
n
,
o
,
1
431; (
p
.
2013
,
q
O'Brien, P.; Taylor, R. J. K. Chem. Eur. J. 2016
,
2
5. (a
.
,
b
,
7
1
c
) Ledovskaya, M. S.; Stepakov, A. V.; Molchanov, A. P.;
71, 7562.
,
2
2
a
,
486, 191; (
b
) Smet,
M.; Corens, D.; Van Meervelt, L.; Dehaen, W. Molecules 2000
79.
) Stepakov, A. V.; Galkin, I. A.; Larina, A. G.; Molchanov, A. P.;
Kostikov, R. R. Russ. J. Org. Chem. 2009 45, 1776; ( ) Konopiková,
M.; Fišera, L.; Prónayová, N.; Ertl, P. Justus Liebigs Ann. Chem
993, 1047.
, 5,
1
7. (a
,
b
.
1
2
8. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakaji-
ma, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery Jr.,
J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M. J.; Heyd, J.; Brothers,
E. N.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; To-
masi, J.; Cossi M., Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.;
Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels,
A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox,
D. J. Gaussian, Inc., Wallingford, CT, USA, 2009.