Rearrangement of 2-azanorbornenes to tetrahydrocyclopenta[c]pyridines under the action of activated alkynes – A short pathway for construction of the altemicidin core

Article abstract of DOI:10.1016/j.tetlet.2017.10.015

A simple approach to a series of 2,4a,7,7a-tetrahydro-1H-cyclopenta[c]pyridines was proposed on the basis of the amino-Claisen rearrangement of readily accessible 2-azabicyclo[2.2.1]hept-5-enes under the action of dialkyl acetylenedicarboxylates, methyl propiolate or propiolamide. The rearrangement is highly diastereoselective and leads to the formation of only one isomer with cis-annulation of the five- and six-membered rings in satisfactory yields. Using the developed method, close analogs of the altemicidin and SB-203207 cores were synthesized.

Full text of DOI:10.1016/j.tetlet.2017.10.015

Accepted Manuscript
Rearrangement of 2-azanorbornenes to tetrahydrocyclopenta[c]pyridines under
the action of activated alkynes – a short pathway for construction of the alte-
micidin core.
Dinara K. Nasirova, Anastasia V. Malkova, Kirill B. Polyanskii, Kristina Yu.
Yankina, Prince N.-A. Amoyaw, Irina A. Kolesnik, Alexey V. Kletskov, Ivan
A. Godovikov, Eugeniya V. Nikitina, Fedor I. Zubkov
PII:
S0040-4039(17)31282-0
https://doi.org/10.1016/j.tetlet.2017.10.015
TETL 49377
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 August 2017
23 September 2017
5 October 2017
Please cite this article as: Nasirova, D.K., Malkova, A.V., Polyanskii, K.B., Yankina, K.Y., Amoyaw, P.N., Kolesnik,
I.A., Kletskov, A.V., Godovikov, I.A., Nikitina, E.V., Zubkov, F.I., Rearrangement of 2-azanorbornenes to
tetrahydrocyclopenta[c]pyridines under the action of activated alkynes – a short pathway for construction of the
altemicidin core., Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.015
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Graphical Abstract
Rearrangement of 2-azanorbornenes to
tetrahydrocyclopenta[c]pyridines under the
action of activated alkynes – a short pathway
for construction of the altemicidin core.
Leave this area blank for abstract info.
Dinara K. Nasirova, Anastasia V. Malkova, Kirill B. Polyanskii, Kristina Yu. Yankina, Prince N.-A.
Amoyaw, Irina A. Kolesnik, Alexey V. Kletskov, Ivan A. Godovikov, Eugeniya V. Nikitina, Fedor I.
Zubkov

1
Tetrahedron Letters
Rearrangement of 2-azanorbornenes to tetrahydrocyclopenta[c]pyridines under the
action of activated alkynes – a short pathway for construction of the altemicidin core.
Dinara K. Nasirovaa, Anastasia V. Malkovaa, Kirill B. Polyanskiia, Kristina Yu. Yankinaa, Prince N.-A.
Amoyawb, Irina A. Kolesnikc, Alexey V. Kletskovc, Ivan A. Godovikovd, Eugeniya V. Nikitinaa, Fedor I.
Zubkova,
a Department of Organic Chemistry, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow, 117198, Russian
Federation
bDivision of Liberal Arts and Sciences, State University of New York at Delhi, Delhi, New York, 13753, USA
c
Institute of Physical Organic Chemistry, National Academy of Sciences, 13 Surganov St., Minsk, 220072, Belarus
d A. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences, 28 Vavilova St., Moscow, 119991, Russian Federation
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple approach to a series of 2,4a,7,7a-tetrahydro-1H-cyclopenta[c]pyridines was proposed
on the basis of the amino-Claisen rearrangement of readily accessible 2-azabicyclo[2.2.1]hept-5-
enes under the action of dialkyl acetylenedicarboxylates, methyl propiolate or propiolamide.
The rearrangement is highly diastereoselective and leads to the formation of only one isomer
with cis-annulation of the five- and six-membered rings in satisfactory yields. Using the
developed method, close analogs of the altemicidin and SB-203207 cores were synthesized.
Available online
Keywords:
Amino-Claisen rearrangement
2-Azanorbornene
DMAD
2017 Elsevier Ltd. All rights reserved.
2-Azabicyclo[2.2.1]hept-5-ene
Cyclopenta[c]pyridine
Altemicidin
Partially hydrogenated cyclopenta[c]pyridine is the main
structural element of a number of alkaloids and a common motif
in the plant kingdom. Nearly 30 years ago the first natural
products possessing the cyclopenta[c]pyridine structure were
isolated and documented.1-4 For example, nepetalactam1 was
isolated from the oil of Nepeta cataria (catnip), lindenialine2 was
obtained from the leaves of Lindenia austro-caledonica Brongn,
and dinklageine3 was found in the leaves of Strychnos dinklagei
Gilg. (Fig. 1). However, until recently, the previously mentioned
alkaloids or their heterocyclic cores have not attracted significant
attention.
In 2000, the SmithKline Beecham group published the
structure of SB-203207, which was isolated from a Streptomyces
species, and established that it inhibits isoleucyl tRNA synthetase
with an IC50 value below 2 nM.5 This discovery has highlighted
the potent biological activities of the cyclopenta[c]pyridine
skeleton, establishing it as a challenging structural goal for target
oriented synthesis. Currently, many approaches to altemicidin
derivatives have been proposed,6 including the enantioselective
synthesis of SB-203207.7
Figure 1. Selected naturally occurring cyclopenta[c]pyridines.
N-Substituted 2-azabicyclo[2.2.1]heptenes, which are easily
obtained by a three-component aza-Diels-Alder reaction between
the corresponding primary alkylamines, formaldehyde and
cyclopentadiene,8 are building-blocks commonly used in the
stereoselective synthesis and in the synthesis of natural products.9
Herein, we report a short synthetic route for the synthesis of
partly hydrogenated cyclopenta[c]pyridines with structures
similar to the natural alkaloids (Fig. 1).
———
 Corresponding author. Tel.: +7-495-955-0729; fax: +7-495-952-2644; e-mail: fzubkov@sci.pfu.edu.ru

2
Tetrahedron
These building-blocks are attractive not only because of their
of a new σ-bond completes the amino-Claisen rearrangement. For
obvious structural reasons, the cyclization in cation B proceeds
diastereospecifically and leads to the formation of a single
diastereoisomer of compound 2 with cis-annulation of the five-
and six-membered rings. However, strong evidence for the
proposed mechanism cannot be provided at this time and an
alternative synchronous process can also be envisioned.
ready availability, but also due to the fact that they are available
in optically pure form.10
Through extensive literature review, we found only one
example of the sigmatropic rearrangement of the 2-
azabicyclo[2.2.1]hept-5-ene core (1a) to a cyclopenta[c]pyridine
under the action of methyl propiolate (MP).11 The reaction was
carried out in acetonitrile at reflux and the target product of the
rearrangement 2a (R1 = Me) was isolated in 19% yield (Scheme
1).11a
Reactions involving the addition of dimethyl, diethyl or di-t-
butyl acetylenedicarboxylates to 2-azabicyclo[2.2.1]heptenes (1)
also proceeded in a similar fashion, affording adducts 3a-m in
moderate yields under the same reaction conditions (Scheme 3,
Table 1).
Scheme 1. Amino-Claisen rearrangement of 2-azanorbornenes under
the action of MP.
Scheme 3. Amino-Claisen rearrangement of 2-azanorbornenes 1
under the action of acetylenedicarboxylic acid esters.
Taking into account the close similarity of compound 2a (R1 =
Me) and the structures of the natural compounds (Fig. 1), we
attempted to optimize the conditions for its preparation. Thus, we
discovered that increasing the reaction temperature above room
temperature, in order to speed up the reaction between the
activated alkyne and 2-azanorbornene 1a, led to significant
polymerization, thereby resulting in a dramatic reduction in the
yield of the desired product 2a. Protic solvents (MeOH,
CF3CH2OH) render impossible or inhibit the rate of reaction
between MP and 1a, and the best yields were achieved in CHCl3
at r.t. Although other solvents (MeCN, CH2Cl2, PhH, THF) were
also found to be suitable, the reaction proceeds slowly and
affords only moderate yields of 2a. It is possible the most polar
CHCl3 facilitates the formation of zwitterion B (Scheme 2). The
optimized parameters were then used for the synthesis of
compounds 2a-e.
The spatial structures of cyclopenta[c]pyridines 2 and 3 were
established based on their NMR spectroscopic data. The most
noticeable signals in the 1H NMR spectra are a doublet of
doublets at δ 2.6-2.8 ppm belonging to the ABX system of the
NCH2CH group (2J ~11-12, 3J ~5-6 and 10-11 Hz) and two
multiplets of the CH=CH fragment at δ ~5.6 and 5.9 ppm. The
13C NMR spectra are characterized by signals for the carbon
atoms of the double bonds at δ ~97 (C-4), 125, 136, and 146 ppm
(see ESI).
Table 1. Substituents R1, R2 and isolated yields of
cyclopenta[c]pyridines 3.
Compound 3
R1
R2
Yield 3 (%)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
69
56
64
60
33
55
58
41
65
67
63
48
42
a
b
c
d
e
f
Allyl
A plausible reaction mechanism for the rearrangement is
shown in Scheme 2.
Bn
CH2C6H4-4-Cl
CH2Furyl
Cyclohexyl
n-C12H25
Cyclopropyl
i-Pr
g
h
i
Me
j
Et
Bn
k
l
Et
CH2C6H4-4-Cl
Me
t-Bu
m
The cis-annulation of the rings in compounds 3 was proven by
single crystal X-ray analysis using di-tert-butyl ester 3m as a
representative example. The spatial structures of compounds 2
and 4 were assigned by analogy.
Scheme 2. Proposed mechanism for the diastereoselective amino-
Claisen rearrangement of 2-azabicyclo[2.2.1]heptenes (1).
The first step involves the initial addition of methyl propiolate
to bicycle 1 to form zwitterion A, the relative configuration of
which does not affect the spatial structure of the final product 2,
formed via the resonance-stabilized bipolar ion B. The formation

3
Scheme 5. Selective reduction of cyclopenta[c]pyridines 3a,c.
In conclusion, during the course of this investigation the
reaction between 2-azanorbornenes and activated alkynes was
carried out. The obtained results revealed that the reaction
proceeds via the stereoselective amino-Claisen rearrangement.
This simple protocol may be useful in the synthesis of natural-
like products possessing a cyclopenta[c]pyridine core.
Figure 2. Crystal structure for compound 3m. Displacement
ellipsoids are shown at the 50% probability level. Almost all H
atoms of the molecule were deleted for clarity, H-4a, H-5, H-6 and
H-7a atoms are shown as small spheres of arbitrary radii.
Acknowledgments
This publication was supported by the Ministry of Education
and Science of the Russian Federation (the Agreement number
02.a03.21.0008).
The single crystal X-ray structure of di-tert-butyl ester 3m (R1
= Me, R2 = t-Bu) is shown in Figure 2. Compound 3m comprises
of the fused bicyclic system containing five-membered
(cyclopentene) and six-membered (piperidine) rings. The five-
membered ring possess a flat envelope conformation, and the six-
membered ring adopts a distorted flat boat conformation. The
nitrogen atom is almost planar (sum of the bond angles are
356.9°). The dihedral angle between H-4a and H-7a is 31.5(6)°.
References and notes
1. Eisenbraun, E. J.; Sullins, D. W.; Browne, C. E.; Shooler, J. N. J. Org.
Chem. 1988, 53, 3968.
2. Saad, H. E. A.; Anton, R.; Quirion, J. C.; Chauviere, G.; Pusset, J.
Tetrahedron Lett. 1988, 29, 615.
3. Skaltsounis, A. L.; Michel, S.; Tillequin, F.; Koch, M. Tetrahedron Lett.
1984, 25, 2783.
4. Pombo-Villar, E.; Boelsterli, J.; Cid, M. M.; France, J.; Fuchs, B.;
Walkinshaw, M.; Weber, H. P. Helv. Chim. Acta 1993, 76, 1203.
5. (a) Stefanska, A. L.; Cassels, R.; Ready, S. J.; Warr, S. R. J. Antibiot.
2000, 53, 357. (b) Houge-Frydrych, C. S. V.; Gilpin, M. L.; Skett, P. W.;
Tyler, J. W. J. Antibiot. 2000, 53, 364.
6. (a) Takahashi, A.; Naganawa, H.; Ikeda, D.; Okami, Y. Tetrahedron
1991, 47, 3621. (b) Kende, A. S.; Lui, K.; Brands, K. M. J. J. Am. Chem.
Soc. 1995, 117, 10597. (c) Banwell, M. G.; Crasto, C. F.; Easton, C. J.;
Forrest, A. K.; Karoli, T.; March, D. R.; Mensah, L.; Nairn, M. R.;
O'Hanlon, P. J.; Oldham, M. D.; Yue, W. Bioorg. Med. Chem. Lett. 2000,
10, 2263.
In order to synthesize structures more closely related to
altemicidin and SB-203207, we demonstrated that propiolamide
(PA)12 can also be involved in the rearrangement (Scheme 4).
7. Hirooka, Y.; Ikeuchi, K.; Kawamoto, Y.; Akao, Y.; Furuta, T.; Asakawa,
T.; Inai, M.; Wakimoto, T.; Fukuyama, T.; Kan, T. Org. Lett. 2014, 16,
1646.
8. (a) Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768. (b)
Grieco, P. A.; Larsen, S. D. Org. Synth. 1990, 68, 206. (c) Demuynck, A.
L. W.; Levecque, P.; Kidane, A.; Gammon, D. W.; Sickle, E.; Jacobs, P.
A.; De Vos, D. E.; Sels, B. F. Adv. Synth. Catal. 2010, 352, 3419. (d)
Memeo, M. G.; Mantione, D.; Bovio, B.; Quadrelli, P. Synthesis 2011,
13, 2165. (e) Gorbunova, M.; Anikina, L. Eur. J. Med. Chem. 2013, 63,
655.
9. (a) Alonso, D. A.; Bertilsson, S. K.; Johnsson, S. Y.; Nordin, S. J. M.;
Soedergren, M. J.; Andersson, P. G. J. Org. Chem. 1999, 64, 2276. (b)
Malpass, J. R.; White, R. J. Org. Chem. 2004, 69, 5328. (c)
Venkatraman, S.; Njoroge, F. G.; Wu, W.; Girijavallabhan, V.; Prongay,
A. J.; Butkiewicz, N.; Pichardo, J. Bioorg. Med. Chem. Lett. 2006, 16,
1628. (d) Bunnelle, W. H.; Daanen, J. F.; Ryther, K. B.; Schrimpf, M. R.;
Dart, M. J.; Gelain, A.; Meyer, M. D.; Frost, J. M.; Anderson, D. J.;
Buckley, M.; Curzon, P.; Cao, Y.-J.; Puttfarcken, P.; Searle, X.; Ji, A.;
Putman, C. B.; Surowy, C.; Toma, L.; Barlocco, D. J. Med. Chem. 2007,
50, 3627. (e) Mazurov, A. A.; Miao, L.; Bhatti, B. S.; Strachan, J.-P.;
Akireddy, S.; Murthy, S.; Kombo, D.; Xiao, Y.-D.; Hammond, P.;
Zhang, J.; Hauser, T. A.; Jordan, K. G.; Miller, C. H.; Speake, J. D.;
Gatto, G. J.; Yohannes, D. J. Med. Chem. 2012, 55, 9181. (f) Potter, R.
A.; Bowser, A. M.; Yang, Y.; Madalengoitia, J. S.; Ziller, J. W. J. Org.
Chem. 2013, 78, 11772.
Scheme 4. Amino-Claisen rearrangement of 2-azanorbornenes (1)
under the action of propiolamide.
Amides 4a and 4b were isolated in moderate yields. In the
case of R1 = Me, a compound resembling the A ring of SB-
203207 (Fig. 1) was generated in one step.
We also attempted to perform further modifications of the
unsubstituted double bond in cyclopenta[c]pyridines 2-4, in order
to develop routes to access the target natural products.
Unfortunately, the Prilezhaev oxidation of compounds 2a, 3a,
and 4a with m-CPBA did not occur over a broad temperature
range (0–70 °C), and instead of the desired epoxides a
multicomponent mixture formed. However, the reduction of
cyclopenta[c]pyridines (3) proceeded chemospecifically at the
least substituted and more electronically enriched double bond of
the five-membered ring, leading to derivatives 5, possessing the
core of nepetalactam and lindenialine, in good yields (Scheme 5).
10. (a) Gayet, A.; Andersson, P. G. Synth. Catal. 2005, 347, 1242. (b)
Pombo-Villar, E.; Boelsterli, J.; Cid, M. M.; France, J.; Fuchs, B.;
Walkinshaw, M.; Weber, H. P. Helv. Chim. Acta. 1993, 76, 1203.
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12. Hay, L. A.; Koenig, T. M.; Ginah, F. O.; Copp, J. D.; Mitchell, D. J. Org.
Chem. 1998, 63, 5050.

4
Tetrahedron
g/cm3. 20411 total reflections were measured (4.488° ≤ 2Θ ≤ 61.008°),
13. General procedure for the preparation of substituted tetrahydro-
cyclopenta[c]pyridines (2-4). 2-Azanorbornene 1 (2 mmol) was
dissolved in dry CHCl3 (15 mL) at ambient temperature, then the
substituted acetylene (2.2 mmol) was added to the solution and the
homogenous mixture stirred at r.t (24 h for MP and PA; 72 h for dialkyl
acetylene dicarboxylates; TLC monitoring). Evaporation of the solvent
under reduced pressure gave a crude brown oil which was purified by
silica gel column chromatography (hexane-EtOAc with increasing
polarity as eluent) to provide products 2-4 as colorless oils or white
powders. In the case of the reaction with MP, the obtained products 2a-e
were unstable at r.t in air (quickly became dark), but relatively stable
under a N2 atmosphere at –16 °C.
5622 unique reflections (Rint = 0.0851, Rsigma = 0.0829) which were used
in all calculations. The final R1 was 0.0652 (I > 2σ (I)) and wR2 was
0.1619 (all data). Crystallographic data (excluding structure factors) for
the structure of 3m reported herein have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
no. CCDC 1556691. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1 EZ, UK
(fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk or
www.ccdc.cam.ac.uk).
Supplementary Material
General procedure for the preparation of
Supplementary data (characterization data, copies of 1H and
13C NMR spectra for compounds 2-5, and X-ray data for
compound 3m associated with this article can be found in the
online version, at ESI.
hexahydrocyclopenta[c]pyridines (5). A moderate hydrogen flow (one
bubble per second) was passed through a solution of compound 3 (2
mmol) and 5% Pd/C (70 mg) in EtOH (10 mL) for 1 h at r.t. The reaction
mixture was purged with argon and filtered through a thin layer of celite.
The filtrate was concentrated under reduced pressure and purified by
silica gel column chromatography to give cyclopenta[c]pyridines 5a,b.
14. The colorless crystal of 3m (C19H29NO4, M = 335.43) is orthorhombic,
space group Pna21, a = 9.903(2) Å, b = 17.692(4) Å, c = 10.573(3) Å, V
= 1852.3(7) Å3, Z = 4, T = 120 K, μ (MoKα) = 0.083 mm-1, dcalc = 1.203
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Highlights
 Amino-Claisen rearrangement of
azabicyclo[2.2.1]heptenes under the action
of alkynes
 Diastereoselective pathway to altemicidin
and dinklageine core analogs
 Effective synthesis of 2,4a,7,7a-
tetrahydrocyclopenta[c]pyridines under mild
conditions
 Short pathway for construction of the
altemicidin core