A speedy route to sterically encumbered, benzene-fused derivatives of privileged, naturally occurring hexahydropyrrolo[1,2-b]isoquinoline

Article abstract of DOI:10.3762/bjoc.13.138

A series of 15 benzene-fused hexahydropyrrolo[1,2-b]isoquinolonic acids with substantial degree of steric encumbrance has been prepared via a novel variant of the Castagnoli-Cushman reaction of homophthalic anhydride (HPA) and various indolenines. The employment of a special kind of a cyclic imine component reaction allowed, for the first time, isolating a Mannich-type adduct between HPA and an imine component which has been postulated but never obtained in similar reactions.

Full text of DOI:10.3762/bjoc.13.138

A speedy route to sterically encumbered, benzene-fused
derivatives of privileged, naturally occurring
hexahydropyrrolo[1,2-b]isoquinoline
Olga Bakulina, Alexander Ivanov, Vitalii Suslonov, Dmitry Dar’in and Mikhail Krasavin*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1413–1424.
Institute of Chemistry, Saint Petersburg State University, 26
Universitetsky prospekt, Peterhof 198504, Russia
doi:10.3762/bjoc.13.138
Received: 19 May 2017
Accepted: 05 July 2017
Published: 18 July 2017
Email:
Mikhail Krasavin* - m.krasavin@spbu.ru
* Corresponding author
Associate Editor: T. J. J. Müller
§ ORCID Mikhail Krasavin: 0000-0002-0200-4772
© 2017 Bakulina et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Castagnoli–Cushman reaction; diastereoselectivity; homophthalic
anhydride; indolenines; lactam synthesis; multicomponent reactions
Abstract
A series of 15 benzene-fused hexahydropyrrolo[1,2-b]isoquinolonic acids with substantial degree of steric encumbrance has been
prepared via a novel variant of the Castagnoli–Cushman reaction of homophthalic anhydride (HPA) and various indolenines. The
employment of a special kind of a cyclic imine component reaction allowed, for the first time, isolating a Mannich-type adduct be-
tween HPA and an imine component which has been postulated but never obtained in similar reactions.
Introduction
The reaction of imines (prepared in a separate step or generated The use of cyclic imines (or surrogates thereof such as
in situ) with α-C–H dicarboxylic acid anhydrides (known as the isoquinoline [11]) in the CCR is quite scarce in the literature
Castagnoli–Cushman reaction or CCR [1]) offers a direct entry [12-14]. As an example, 1-pyrroline (in the form of its trimer 3)
into lactam frameworks 1 of various sizes (traditionally, δ- and has been reported by Smith and co-workers [15-17] to condense
γ- [2,3] and, more recently, ε-lactams [4,5]) containing a efficiently with HPA analogs to deliver hexahydropyrrolo[1,2-
carboxylic acid functionality. Employment of homophthalic an- b]isoquinolones 4. The hexahydropyrrolo[1,2-b]isoquinoline
hydride (HPA) in this reaction delivers medicinally important, core in general is ubiquitous to many natural products exempli-
most often trans-configured [6,7] tetrahydroisoquinolonic acids fied by tylophorine (5) [18], lycorine (6) [19] and its entire
2 (Figure 1) which have found utility as probe compounds or family of alkaloids, including zephyranthine (7) [20] and galan-
therapeutic agents in diverse areas such as neuroprotection [8], tine (8) [21]. Considering the plethora of biological activities
diabetes [9], and cancer [10].
displayed by the lycorine and tylophorine alkaloids (such as
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Beilstein J. Org. Chem. 2017, 13, 1413–1424.
dimensional features and potentially contain several quaternary
carbon centers (Figure 2). The first aspect has been recently
recognized [29] as a central principle in drug design ensuring
effective interaction of small molecules with protein targets and
lower off-target effects. The presence of quaternary carbons is
characteristic of the natural products domain and is also gaining
prominence in medicinal chemistry [30]. Herein, we disclose
the results obtained and observations made in the course of our
attempt to involve 9 in reactions with HPA. Notably, due to its
non-planar tetracyclic character, the hexahydropyrrolo[1,2-
b]isoquinolone fused with benzene scaffold (present in 10)
clearly appears related to (though topologically distinct from)
the natural and synthetic camptothecin-like topoisomerase in-
hibitors [31].
Figure 1: The Castagnoli–Cushman reaction (CCR).
pro-apoptotic [22], antiviral [23], hypoxia-inducible factor-1 Results and Discussion
inhibitory [24]), the scaffold can be confidently regarded as The study commenced with the synthesis of set of 2-H as well
privileged [25]. Recently, we [26] and others [27] reported the as 2-substituted indolenines 9a–t using a previously published
use of indolenines as non-classical inputs for the Joullié–Ugi procedure (Figure 3) [26]. Acetonitrile was previously found
reaction and for subsequent preparation [28] of sterically [32] to be an effective solvent promoting the CCR of HPA with
encumbered, constrained peptidomimetic frameworks. acyclic amines at room temperature. As it also facilitated the
Diversely substituted indolenines 9 are easy to prepare via the isolation of the tetrahydroisoquinolonic acid product, it was
Fischer indole synthesis [26] and their use in the CCR can be chosen to study the CCR of 9a–t. The latter tend to precipitate
expected to result in hexahydropyrrolo[1,2-b]isoquinolone de- in a pure form (often as a single diastereomer) from the reac-
rivatives fused with benzene 10 that have pronounced three- tion mixture and can be conveniently isolated by filtration. This
Figure 2: Assembly of hexahydropyrrolo[1,2-b]isoquinoline core via the CCR and its occurrence in natural and synthetic bioactive compounds.
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Beilstein J. Org. Chem. 2017, 13, 1413–1424.
Figure 3: Indolenine substrates 9a–t investigated in this work. aPrepared for the first time (the rest are known compounds, see Experimental section).
bUnstable to isolation; was taken in the CCR step as a solution in chloroform.
prior observation also held true for the reaction between HPA 9l, 9n,o (Table 1, entries 1, 2, 4, 10, 12, 14 and 15) by simple
and most of indolenines 9.
filtration. We have also shown that in some of these cases
(Table 1, entries 1 and 2) an additional quantity of anti- and/or
As shown in Table 1, all of the 2-unsubstituted indolenines syn-configured CCR product could be recovered from the
9a–g and many 2-substituted one 9h–o furnished the expected filtrate in the form of respective methyl esters after O-methyla-
respective tetracyclic tetrahydroisoquinolonic acids 10 on treat- tion and chromatographic separation (see Experimental
ment with HPA (1.0 equiv) in acetonitrile (2 mL/mmol). section): syn-10a' (7%), anti-10a' (12%), syn-10b' (13%). In
Notably, when the CCR with HPA was repeated for 9h in other those cases when the carboxylic acid precipitate contained a
solvents (toluene, chloroform or DMF) at room temperature, significant proportion of the syn-configured CCR product
this resulted in a similar product yield and diastereomeric (Table 1, entries 3, 8, 11 and 13, anti/syn ratio ranging from
ratio. However, the isolation of 10h from the respective 3.3:1 to 6.5:1), the latter was removed by crystallization and the
reaction mixtures was distinctly cumbersome, which only respective pure anti-diastereomers (anti-10c, 10h, 10k and
confirmed acetonitrile to be the solvent of choice for these reac- 10m) were obtained and characterized. In certain instances
tions.
(Table 1, entries 5–7, and 9), isolation of pure diastereomeric
CCR adducts was achieved by total esterification of the
A number of observations emerged from examination of the carboxylic acid product mixture and chromatographic separa-
results in Table 1. In all cases (except entry 7 where carboxylic tion of the respective methyl esters (the 0.8:1 anti/syn-10e mix-
acid 10g did not precipitate from the reaction mixture and was ture stereoconverged to anti-10e' on esterification, vide infra).
isolated as respective methyl ester 10g'), the major diastereo-
mer was shown to possess the (RS,RS)-configuration (vide The trans-diastereoselectivity of the CCR is well documented in
infra) and is referred to as ‘anti‘ throughout this article (consid- the literature [33] and is, therefore, unsurprising. However, the
ering orientation of carboxylic group relative to C11a–C12 bond stereocontrol achieved in this reaction over 3 stereocenters
of the five-membered ring); the minor, (RS,SR)-configured dia- present in 10l (obtained in 81% yield as a single diastereomer)
stereomer is referred to as ‘syn’ (Figure 4). A good to excellent is certainly quite noteworthy and was confirmed by X-ray anal-
yield of pure anti-diastereomer was obtained with 9a,b, 9d, 9j, ysis (Figure 5).
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Table 1: Indolo[1,2-b]isoquinolonic acids 10 obtained via the CCR of indolenines 9.
Entry
9
Product 10
Time
2 h
Isolated yield, %a
anti/syn
1
9a
56
>20:1b
10a
10b
10c
10d
10e
2
3
4
5
9b
9c
9d
9e
2 h
24 h
3 h
73
66
84
66
>20:1b
3.3:1c
>20:1
0.8:1d
48 h
6
9f
72 h
79
2:1d
10f
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Table 1: Indolo[1,2-b]isoquinolonic acids 10 obtained via the CCR of indolenines 9. (continued)
7
8
9g
9h
9i
16 h
16 h
48 h
48 h
87
86
72
73
1.4:1d
4.3:1c
3:1d
10g‘
10h
10i
9
10
9j
>20:1
10j
11
12
9k
48 h
57
81
6.5:1c
>20:1
10k
9l
48 h
10l
13
9m
72 h
79
6:1c
10m
14
9n
25 d
93
>20:1
10n
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Table 1: Indolo[1,2-b]isoquinolonic acids 10 obtained via the CCR of indolenines 9. (continued)
15
9o
50 d
52
11:1
10o
–
16
17
18
19
20
9p
9q
9r
7 d
7 d
7 d
7 d
7 d
0
0
0
0
0
–
–
–
–
–
–
–
9s
9t
–
–
aIsolated yield of the product precipitate from the reaction mixture. bAdditional quantity of the anti- and/or syn-diastereomer(s) isolated from the filtrate
as respective methyl esters 10' (see Experimental section). cPure anti-diastereomer obtained by crystallization. dIsolated and characterized as
respective methyl esters 10'.
Figure 4: Anti- and syn-diastereomers of 10 and 10'.
with literature reports [33]. However, the steric situation around
the five-membered ring of indolenines had a profound effect on
the reaction times and even the ability of certain indolenines to
act as competent partners in the CCR. 2-Substituted indolenines
9h–o required significantly longer times (from 16 h to 50 days)
to be converted to the respective CCR products, compared to
their 2-unsubstituted counterparts. Indolenines 9p–t failed to
undergo the reaction with HPA either at rt or at reflux tempera-
ture in acetonitrile or toluene. Attempts to trigger the reaction
with these substrates by excluding solvent altogether [34] or
applying microwave irradiation (up to 2 h at 200 °C in MeCN)
were also unsuccessful. Any appreciable conversion led to
predominant formation of HPA dimer 11 and product of its
Figure 5: Single-crystal X-ray structure of compound 10l.
decarboxylation 12 (Scheme 1). The formation of these two
products (observed by 1H NMR) was recently reported by
The tolerance of the reaction to the substitution pattern in the Knapp et al. [35] as a result from the treatment of HPA with a
aromatic portion of the indolenines appears rather broad, both in strong base (which was absent in our case). The failure to acti-
terms of the electronic character of substituents and steric vate sterically hindered indolenines toward the CCR using
effects – although substituents in position 7 of the indolenine forcing conditions justifies conducting the reaction at room tem-
significantly affect the conformational behavior of the respec- perature, which led to clean conversions and good product
tive CCR adducts 10d,e (vide infra). Notably, free phenolic yields despite the excruciatingly long reaction times (Table 1,
hydroxy function is well tolerated (9k → 10k) which is in line entries 14 and 15).
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Beilstein J. Org. Chem. 2017, 13, 1413–1424.
Scheme 1: Formation of unwanted products 11 and 12 in lieu of the CCR with 9p–t.
In order to ensure a correct stereochemical assignment of all be rationalized by a different conformer population in the solu-
major (anti) and minor (syn) products obtained in the reactions tion compared to solid state. This hypothesis was preliminary
discussed herein, we obtained single-crystal X-ray structures of confirmed by the results of variable-temperature NMR experi-
sixteen CCR adducts synthesized in this work and correlated ments summarized in Supporting Information File 1 (Figures
this structural information with the NMR behavior of these S1–S6). Another potentially useful criterion for stereochemis-
compounds. The range of the coupling constant J(H11-H11a) try assignment of compounds 10 derived from 2-methylin-
values appears a straightforward criterion for relative stereo- dolenines 10h–k, 10m,n is the range of 13C chemical shifts ob-
chemistry assignment in compounds 10 derived from served for the angular methyl group in their syn- and anti-dia-
2H-indolenines. As summarized in Figure 6 (see also Table S1 stereomers (Supporting Information File 1, Figure 7, Table S2).
in Supporting Information File 1), anti-diastereomers display These findings were also verified by the available X-ray infor-
this coupling constant around 13 Hz, while it is in the 3-4 Hz mation on these compounds. Finally, the relative stereochemis-
range for syn-isomers.
try of compound 10o (for which neither X-ray structures nor
reliable NMR criteria were available) was assigned on the basis
of the through-space interactions observable in its NOESY
spectrum and the value of a 3JCH coupling constant (Support-
ing Information File 1, Figure 8, Figures S7–9).
Figure 6: Typical J(H11-H11a)-values and corresponding dihedral
angles for syn- and anti-diastereomers of compounds 10 derived from
2H-indolenines.
Figure 7: The difference in the 13C NMR chemical shifts of the angular
methyl group between syn- and anti-diastereomers of 11a-Me in com-
pounds 10h–k, 10m,n.
According to the X-ray analysis, the dihedral angle values
in the C11H–C11aH fragment lie within the 165–170° and
55–58° range for anti- and syn-diastereomers, respectively
(Supporting Information File 1, Table S1). Thus, for most of the
2H-indolenine-derived compounds (except for 10d,e), there
appears to be a good correlation between the relative stereo-
chemistry of 10, J(H11-H11a) values observed in the 1H NMR
spectra of their solutions and said dihedral angle in crystals.
Surprisingly, compounds 10d,e (derived from more sterically
congested 7-substituted indolenines 9d,e) display the
J(H11-H11a) values of 3.0 Hz for both diastereomers, which is
inconsistent with the regular values of corresponding dihedral
angles (166.3° and 169.7° for anti-10d and anti-10e, respective-
ly; 57.5° for syn-10e) measurable in the X-ray structures of
these compounds. We reasoned that such a phenomenon could
Figure 8: Criteria for stereochemistry assignment of anti-10o.
Besides the anomalous NMR behavior discussed above, com-
pound 10e displayed a number of unusual tendencies which
may shed some light on the diastereomeric integrity of CCR
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Beilstein J. Org. Chem. 2017, 13, 1413–1424.
adducts in general as well as on the mechanism of their forma- that exposure of 9e to an equimolar amount of HPA in aceto-
tion. Compound 10e initially formed as a 0.8:1 mixture of anti/ nitrile at low temperature (5 °C) and higher dilution (two-fold
syn diastereomers (Table 1). However, it was promptly noted compared to that used throughout this study) over 2 days led to
that this mixture converges to thermodynamically more stable a predominant formation of the respective Mannich adduct 13e
anti-10e (the isomerization occurs on heating to 80 °C or, more which crystallized out as a single diastereomer from the reac-
slowly, even at room temperature). Esterification of anti/syn- tion mixture along with syn/anti-10e mixture and was separated
10e in the presence of potassium carbonate led to the formation from the latter mechanically under a microscope. Adduct 13e
of anti-10e' as a sole product, presumably, via a base-promoted (which has been postulated in the literature as a principal inter-
enolization and subsequent isomerization of the syn-10e (10e', mediate in the CCR [1,28] but never isolated) was character-
Scheme 2).
ized by means of 1H and 13C NMR spectroscopy as well as
X-ray crystallography. The isolation, for the first time, of the
Enolization is thought to be a key event in the formation of the Mannich-type adduct 13 between HPA and an imine clearly
CCR products which can occur via two alternative mechanisms: attests to the viability of mechanistic pathway (b) shown in
(a) N-acylation of the imine component followed by intramolec- Scheme 3.
ular Mannich reaction or (b) Mannich-type addition of the HPA
enolate to a protonated imine component followed by intramo- When left at room temperature for 12 h as a solution in CDCl3,
lecular aminolysis of the cyclic anhydride moiety in Mannich single diastereomer 13e fully converted itself into a ca. 1:1 anti/
adduct 13 (Scheme 3) [1].
syn-10e (Scheme 4).
Investigation of the CCR leading to the formation of 10e under- Conversion of diastereomerically pure 13e into a mixture of
taken in this work led to a serendipitous important observation diastereomers can be rationalized by a faster formation of
Scheme 2: Syn/anti isomerization of compound 10e.
Scheme 3: Alternative mechanistic pathways for the CCR.
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Beilstein J. Org. Chem. 2017, 13, 1413–1424.
Scheme 4: Formation and fate of Mannich adduct 13e.
kinetic product syn-10e preceded by enolization, in competition cally encumbered tetracyclic lactams 14 lacking the carboxylic
with direct albeit slow conversion 13e → anti-10e (Scheme 5).
acid group as we showed for exemplary compound 10h. The
4.3:1 anti/syn mixture of diastereomers of 10h rapidly and
We mentioned that tetracyclic compounds 10 carry resem- cleanly lost the carboxylic function at 200 °C and gave
blance to natural as well as synthetic camptothecin-like topo- 83% yield of racemic compound 14h (Scheme 6).
isomerase inhibitors (vide supra). Compounds 10 are endowed
with HPA-derived carboxylic acid functionality which may Conclusion
facilitate or prevent compounds’ binding to DNA or DNA-topo- We have described a novel variant of the Castagnoli–Cushman
isomerase complex. Depending on the medicinal chemistry reaction employing indolenines as cyclic imine components in
context, compounds 10 can be decarboxylated to deliver steri- the reaction with homophthalic anhydride (HPA). The com-
Scheme 5: Mechanistic rationale for the 13e→ syn/anti-10e conversion.
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Beilstein J. Org. Chem. 2017, 13, 1413–1424.
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic
Data Centre via http://www.ccdc.cam.ac.uk.
Indolenines 9. Indolenines 9a,b [26], 9d–g [26], 9h [36], 9i
[37], 9j [38], 9k [39], 9p [40] are known compounds and were
prepared from the arylhydrazine hydrochlorides and respective
aldehydes or ketones according to the literature protocols.
Scheme 6: Decarboxylation of anti/syn-10h.
pounds obtained contain a benzene-fused, privileged, naturally General procedure 1. Synthesis of indolenines 9c,l,n,o,q–t.
occurring hexahydropyrrolo[1,2-b]isoquinoline core and are To a screw-cap vial containing suspension of corresponding
distinctly encumbered from steric perspective. The novel com- arylhydrazine hydrochloride in glacial AcOH (15 mL) the car-
pounds have been characterized by NMR spectroscopy, high- bonyl compound (1.1 equiv) was added in one portion. The
resolution mass spectrometry and X-ray crystallography and reaction mixture was stirred at 55–60 °C for 4 h (or at reflux for
certain regularities in the NMR behavior have been established, 2–16 h) and concentrated in vacuo at 40 °C. The residue was
leading a set of rules for stereochemical assignment based on diluted with DCM (50 mL) and filtered through Celite. The re-
the NMR data. A Mannich-type adduct between HPA and an sulting solution was passed through a short pad of silica,
imine (previously only postulated as a crucial intermediate en washed with sat. NaHCO3 and water. The organic layer was
route to CCR products) has been isolated for the first time and dried over Na2SO4 and concentrated under reduced pressure to
fully characterized. Certain insights into the role of enolization give pure indolenines 9c,l,s. Indolenines 9n,o,q,r,t were sub-
equilibria in the formation and diastereomeric integrity of the jected to extra column chromatography.
CCR adducts has been obtained. The synthetic methodology de-
scribed herein significantly expands the scope and tests the General procedure 2. Synthesis of compounds 10. A mixture
limits of the sterically permitted Castagnoli–Cushman reaction. of homophthalic anhydride (1 equiv) and the corresponding
indolenine 9a–t (1 equiv) was placed in a sealed screw-cap vial,
Experimental
dissolved in dry acetonitrile (2 mL per 1 mmol) and stirred at
General information. NMR spectroscopic data were recorded room temperature for the time indicated in Table 1. The reac-
with a 400 MHz (400.13 MHz for 1H and 100.61 MHz for 13C) tion mixture was cooled to −14 °C, the resulting precipitate was
and a 500 MHz (500.03 MHz for 1H and 125.7 MHz for 13C) filtered and washed with a minimum amount of cold aceto-
spectrometers in DMSO-d6 or in CDCl3 and were referenced to nitrile to give pure compound 10.
residual solvent proton signals (δH = 7.26 and 2.50 ppm, re-
spectively) and solvent carbon signals (δC = 77.2 and 39.5 ppm, General procedure 3. Synthesis of methyl esters 10'. The
respectively). Coupling constants, J are reported in Hz. Melting Castagnoli–Cushman product 10 was dissolved in dry acetone
points were determined with an automated heat block instru- (10 mL per 1 mmol). Methyl iodide (2.5 equiv) and K2CO3
ment and are uncorrected. Mass spectra were recorded with a (2.5 equiv) were added to the solution and the resulting suspen-
HRMS-ESI-qTOF spectrometer (electrospray ionization mode). sion was stirred for 24 h at room temperature. The volatiles
X-ray single crystal analyses were performed with monochro- were removed in vacuo. The residue was dissolved in DCM,
mated Mo Kα or Cu Kα radiation, respectively. Column chro- washed with water, brine, dried over Na2SO4 and concentrated
matography was performed on silica gel 60 (230–400 mesh). to give crude methyl ester 10', which was purified by column
For TLC analysis UV254 silica gel coated plates were used. chromatography on silica gel.
MeCN was distilled from P2O5 and stored over molecular
sieves 4 Å. Homophthalic anhydride was acquired from a com-
Supporting Information
mercial source, stored at 5 °C and used as received. All
indolenines 9 were stored in sealed vials at 5 °C in the dark.
Supporting Information File 1
Detailed experimental procedures, analytical data and
CCDC 1503093 (13e), 1503094 (anti-10c), 1503095 (anti-10d),
1503096 (anti-10g'), 1503097 (anti-10e), 1503098 (anti-10a'),
1503099 (anti-10f), 1503100 (syn-10a'), 1503101 (syn-10f),
1503102 (anti-10e'), 1503103 (anti-10n), 1503104 (anti-10i),
1503105 (syn-10e), 1503106 (anti-10l), 1470399 (anti-10b),
1470389 (anti-10h), 1461790 (anti-10j) contain the supplemen-
copies of 1H and 13C NMR spectra for all new compounds;
crystallographic data for compounds 10 and 13e; results of
correlational and variable temperature NMR experiments.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-138-S1.pdf]
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Beilstein J. Org. Chem. 2017, 13, 1413–1424.
21.Schramm, A.; Saxena, P.; Chlebek, J.; Cahlikova, L.; Baburin, I.;
Hering, S.; Hamburger, M. Planta Med. 2014, 80, 740.
doi:10.1055/s-0034-1368590
Acknowledgements
This research was supported by the Russian Scientific Fund
(project grant 14-50-00069). NMR, mass spectrometry and
X-ray studies were performed at the Research Centre for Mag-
netic Resonance, the Centre for Chemical Analysis and Materi-
als Research of Saint Petersburg State University Research Park
and the Centre for X-ray Diffraction Methods. The authors are
grateful to Dr. Sergey Miltsov for providing 2,3,3-trimethylin-
dolenines employed in this study.
22.Wang, C.; Wang, Q.; Li, X.; Jin, X.; Xu, P.; Xu, N.; Xu, A.; Xu, Y.;
Zheng, S.; Zheng, J.; Liu, C.; Huang, P.
Biochem. Biophys. Res. Commun. 2017, 483, 197.
doi:10.1016/j.bbrc.2016.12.168
23.Guo, Y.; Wang, Y.; Cao, L.; Wang, P.; Qing, J.; Zheng, Q.; Shang, L.;
Yin, Z.; Sun, Y. Antimicrob. Agents Chemother. 2016, 60, 913.
doi:10.1128/AAC.02274-15
24.Chen, C.-Y.; Zhu, G.-Y.; Wang, J.-R.; Jiang, Z.-H. RSC Adv. 2016, 6,
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