One-pot tandem cyclization of enantiopure asymmetric cis-2,5-disubstituted pyrrolidines: Facile access to chiral 10-heteroazatriquinanes

Article abstract of DOI:10.3762/bjoc.9.32

A series of chiral 10-heteroazatriquinanes were synthesized from enantiopure asymmetric cis-2,5-disubstituted pyrrolidines through a one-pot tandem cyclization procedure. The structures and configurations of these new chiral 10-heteroazatriquinanes are confirmed by X-ray single-crystal diffraction analysis.

Full text of DOI:10.3762/bjoc.9.32

One-pot tandem cyclization of enantiopure
asymmetric cis-2,5-disubstituted pyrrolidines:
Facile access to chiral 10-heteroazatriquinanes
Ping-An Wang*1, Sheng-Yong Zhang1 and Henri B. Kagan2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 265–269.
1Department of Medicinal Chemistry, School of Pharmacy, The Fourth
Military Medical University, Changle Xilu 17, Xi-An, 710032, P. R.
China and 2Institut de Chimie Moléculaire et des Matériaux d’Orsay
(ICMMO-UMR 8182, CNRS), Laboratoire de Catalyse Moléculaire,
Université Paris-Sud, 15 rue Georges Clemenceau, 91405 Orsay
Cedex, France
doi:10.3762/bjoc.9.32
Received: 12 October 2012
Accepted: 16 January 2013
Published: 07 February 2013
Associate Editor: B. Stoltz
Email:
Ping-An Wang* - ping_an1718@yahoo.com.cn
© 2013 Wang et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
cis-2,5-disubstituted pyrrolidine; 10-heteroazatriquinane; tandem
cyclization; X-ray single-crystal diffraction analysis
Abstract
A series of chiral 10-heteroazatriquinanes were synthesized from enantiopure asymmetric cis-2,5-disubstituted pyrrolidines through
a one-pot tandem cyclization procedure. The structures and configurations of these new chiral 10-heteroazatriquinanes are
confirmed by X-ray single-crystal diffraction analysis.
Introduction
The azatriquinane derivatives are an important substance class proton affinity [7]. Recently, Mascal [8] and colleagues have
in organic chemistry containing nitrogen and three fused five- developed a series of 10-azatriquinanes as a C3v-symmetric
membered rings [1-3]. Due to the unique rigid bowl-shaped platform for tripodal metal complexes and calixiform scaffolds
structure with one noninversible electron lone pair at the bottom (Figure 1).
of the central nitrogen (“centro-N”) atom, 10-azatriquinane
analogues are used as efficient chelation reagents of metal Previously, we established a facile access to enantiopure asym-
cations [4,5]. Mascal and colleagues [6] described the first syn- metric cis-2,5-disustituted pyrrolidines 4 from commercially
thesis of 10-azatriquinane (1) from dimethyl 3,3'-(1H-pyrrole- available starting materials diethyl meso-2,5-dibromoadipate
2,5-diyl)dipropanoic acid in five steps, and the reactivity of 1 and (S)-(−)-1-phenylethylamine (Figure 2) [9]. The prepara-
was also investigated. 10-azatriquinane (1) is very active tions of compounds 5a, 5b, 6a and 6b were also reported in [9],
because of its high basicity. The X-ray structure of 1·HBF4 but our previously published structures for compounds 5a and
revealed that the centro-N is pyramidalized. 10-azatriquinacene 5b were not completely correct, because the B–N dative bonds
(2), an unsaturated analogue of 1, was attractive due to its high were missing. The aim of the following procedures was to
265

Beilstein J. Org. Chem. 2013, 9, 265–269.
Figure 1: The structures of azatriquinanes and azatriquinacene.
obtain several novel bifunctional N-hetereocyclic carbenes
(NHCs) [10-14] from compounds 4 through three steps,
including reduction, debenzylation and cyclization (Scheme 1),
but this failed. However, we have found a novel one-pot tandem
cyclization of these enantiopure asymmetric cis-2,5-disubsti-
tuted pyrrolidines to produce chiral trisubstituted 10-heteroaza-
triquinane derivatives. To the best of our knowledge, there is
Scheme 2: The reduction of amides 4 by LiAlH4 and BH3·THF.
very little research on the synthesis of 10-heteroazatriquinanes, heating under reflux for 18 h under an inert atmosphere, and no
and the chiral 10-heteroazatriquinanes are unknown up to now. desired diamino-alcohols were obtained after workup. However,
4a reacted smoothly with BH3 to give white crystals after
Results and Discussion
chromatographic purification (Scheme 2). The X-ray single-
For the reduction of highly hindered amides 4, the system of crystal diffraction analysis established that the reduction pro-
LiAlH4 in anhydrous THF was found to be useless even upon duct 5a (Figure 3) was formed with a rigid 10-heteroaza-
Figure 2: The synthesis of 4 (previous work).
Scheme 1: The designed synthetic route to a hydroxy NHC from 4b.
266

Beilstein J. Org. Chem. 2013, 9, 265–269.
obtained in good yield (87%), and the configurations of
5b were assigned to be S, 3R, 6S, 9R (chiral B atom) and 10S
(chiral N atom), respectively. Compounds 5a and 5b are
diastereomers.
In the presence of a catalytic amount of Pd(OH)2/C, under
1.0 atm of hydrogen, the above 10-heteroazaquinane deriva-
tives 5 were converted into enantiopure asymmetric cis-2,5-
disubstituted pyrrolidines 6 in good yields with a diamino-
alcohol skeleton. In this process, both N-debenzylation and a
ring-opening reaction occurred. Diamino-alcohols 6a and 6b are
enantiomers, and they can serve as precursors for the synthesis
of hydroxy N-heterocyclic carbenes. Following the reported
procedure for the preparation of N-heterocyclic carbenes
[19,20], the enantiopure pyrrolidine 6b and NH4BF4 in
HC(OCH3)3 is heated to 80 °C for 2 h, the light yellow crystals
were obtained in good yield after workup (Scheme 3). The same
result was obtained by heating the mixture of 6b, NH4BF4 and
HC(OCH3)3 in anhydrous toluene under reflux.
Figure 3: X-ray crystal structure of compound 5a.
quinane skeleton through an intramolecular Lewis acid–base To our delight, a single crystal was grown from CH2Cl2, suit-
pair interaction [15-18]. Three five-membered rings are fused to able for X-ray diffraction analysis. It was found that the ring-
give a very stable bowl-shaped tricyclic system with five stereo- closing reaction took place during the heating process following
genic centers, especially for one chiral nitrogen center and one N-methylation to provide the rigid 1-oxo-3-aza-10-azaquinane
chiral boron center. The configurations of the stereogenic skeleton 7b as its ammonium salt. Compound 7b contains four
centers in 5a are deduced from the configuration of the chiral stereogenic centers, and their configurations are assigned to be
auxiliary (S)-(−)-1-phenylethylamine to be S, 3S, 6R, 9S (chiral 2R, 5S, 8R and 10R (chiral N atom) based on its starting ma-
B atom) and 10R (chiral N atom), respectively. This novel terial 4b (Figure 4). Actually, HC(OCH3)3 as an efficient
tandem reduction/cyclization was made possible by the cis-con- reagent for C-, N-, and O-methylation has been reported [21-
figuration of the starting 2,5-disubstituted pyrrolidine 4a. 24], but the mechanism of these methylations is elusive. The
Following the same procedure, 10-heteroazaquinane 5b was other chiral ammonium salt 7a was obtained under the same
Scheme 3: One-pot tandem cyclization of 6 in the presence of HC(OCH3)3.
267

Beilstein J. Org. Chem. 2013, 9, 265–269.
conditions as those for the preparation of 7b. The chiral ammo-
nium salts 7a and 7b were derived from the enantiomers 6a
and 6b, therefore, 7a and 7b are also enantiomers. The
configurations of 7a are assigned to be 2S, 5R, 8S and 10S
(chiral N atom).
Figure 5: The structural comparison of chiral ammonium salts such as
7 with the chiral PTCs of Denmark et al.
Supporting Information
Supporting Information File 1
Full experimental details, analytical data and
crystallographic information.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-32-S1.pdf]
Acknowledgements
Figure 4: X-ray crystal structure of compound 7b.
We would like to thank the National Science Foundation of
China (No. 20802092) and the Young Scholar Foundation of
the Fourth Military Medical University (FMMU, China) for
financial support of this work. P. A. Wang also thanks the
Centre National de la Recherche Scientifique (CNRS, France)
for a postdoctoral fellowship to work in the Laboratoire de
Catalyse Moléculaire in the ICMMO, Université Paris-Sud.
As shown in Figure 4, this 10-heteroazatriquinane 7b possesses
a rigid bowl-like molecular scaffold with a quaternary nitrogen
site (N2) at the bottom of the cavity. Recently, Denmark and
colleagues [25,26] have synthesized a series of chiral phase-
transfer catalysts (chiral PTCs) based on a 2-azatriquinane
skeleton (Figure 5), and they have investigated their catalytic
activities in asymmetric alkylation reactions for producing
enantiomerically enriched amino acids. The synthesis of these
quaternary ammonium ions follows a diversity-oriented ap-
proach wherein the tandem inter-[4 + 2]/intra-[3 + 2] cyclo-
addition of nitroalkenes serves as the key transformation. The
chiral ammonium salts 7 have a structure similar to the chiral
PTCs of Denmark et al. The substituents in the chiral ammoni-
um salts 7 are easily tunable, which could open a route to
various chiral PTCs for organic synthesis.
References
1. Mascal, M.; Lera, M.; Blake, A. J. J. Org. Chem. 2000, 65, 7253–7255.
doi:10.1021/jo005571o
2. Mascal, M.; Hafezi, N.; Meher, N. K.; Fettinger, J. C.
J. Am. Chem. Soc. 2008, 130, 13532–13533. doi:10.1021/ja805686u
3. Mascal, M.; Hext, N. M.; Shishkin, O. V. Tetrahedron Lett. 1996, 37,
131–134. doi:10.1016/0040-4039(95)02091-8
4. Jiao, H. J.; Halet, J.-F.; Gladysz, J. A. J. Org. Chem. 2001, 66,
3902–3905. doi:10.1021/jo001800v
5. Gussenhoven, E. M.; Jevric, M.; Olmstead, M. M.; Fettinger, J. C.;
Mascal, M.; Balch, A. L. Cryst. Growth Des. 2009, 9, 1786–1792.
doi:10.1021/cg800906x
Conclusion
6. Hext, N. M.; Hansen, J.; Blake, A. J.; Hibbs, D. E.; Hursthouse, M. B.;
Shishkin, O. V.; Mascal, M. J. Org. Chem. 1998, 63, 6016–6020.
doi:10.1021/jo980788s
In summary, we provide here a facile access to chiral 10-hetero-
azatriquinanes from enantiopure asymmetric cis-2,5-disubsti-
tuted pyrrolidines through one-pot tandem cyclization reactions,
and their configurations are confirmed by X-ray single-crystal
diffraction analysis. The applications of these novel 10-hetero-
azatriquinanes are currently being investigated in our labora-
tory.
7. Mascal, M. J. Org. Chem. 2007, 72, 4323–4327.
doi:10.1021/jo070043z
8. Jevric, M.; Zheng, T.; Meher, N. K.; Fettinger, J. C.; Mascal, M.
Angew. Chem., Int. Ed. 2011, 50, 717–719.
doi:10.1002/anie.201006470
268

Beilstein J. Org. Chem. 2013, 9, 265–269.
9. Wang, P.-A.; Xu, Z.-S.; Chen, C.-F.; Gao, X.-G.; Sun, X.-L.;
Zhang, S.-Y. Chirality 2007, 19, 581–588. doi:10.1002/chir.20424
10.He, L.; Zhang, Y. R.; Huang, X. L.; Ye, S. Synthesis 2008, 17,
2825–2829. doi:10.1055/s-2008-1067216
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
11.Lv, H.; Chen, X.-Y.; Sun, L.-h.; Ye, S. J. Org. Chem. 2010, 75,
6973–6976. doi:10.1021/jo101318u
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
12.Huang, X.-L.; Chen, X.-Y.; Ye, S. J. Org. Chem. 2009, 74, 7585–7587.
doi:10.1021/jo901656q
13.Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett. 2008, 10,
277–280. doi:10.1021/ol702759b
14.Wang, X.-N.; Shao, P.-L.; Lv, H.; Ye, S. Org. Lett. 2009, 11,
4029–4031. doi:10.1021/ol901290z
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
15.Zhu, L.; Shabbir, S. H.; Gray, M.; Lynch, V. M.; Sorey, S.; Anslyn, E. V.
J. Am. Chem. Soc. 2006, 128, 1222–1232. doi:10.1021/ja055817c
16.Tsurumaki, E.; Saito, S.; Kim, K. S.; Lim, J. M.; Inokuma, Y.; Kim, D.;
Osuka, A. J. Am. Chem. Soc. 2008, 130, 438–439.
doi:10.1021/ja078042b
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
17.Stepanenko, V.; De Jesús, M.; Correa, W.; Bermúdez, L.; Vázquez, C.;
Guzmán, I.; Ortiz-Marciales, M. Tetrahedron: Asymmetry 2009, 20,
2659–2665. doi:10.1016/j.tetasy.2009.11.009
doi:10.3762/bjoc.9.32
18.Montalbano, F.; Candeias, N. R.; Veiros, L. F.; André, V.; Duarte, M. T.;
Bronze, M. R.; Moreira, R.; Gois, P. M. Org. Lett. 2012, 14, 988–991.
doi:10.1021/ol203224n
19.Funk, T. W.; Berlin, J. M.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128,
1840–1846. doi:10.1021/ja055994d
20.Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.; Kataoka, O.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 12502–12508.
doi:10.1021/ja0302228
21.Janin, Y. L.; Huel, C.; Flad, G.; Thirot, S. Eur. J. Org. Chem. 2002,
1763–1769.
doi:10.1002/1099-0690(200206)2002:11<1763::AID-EJOC1763>3.0.C
O;2-Q
22.Selva, M.; Tundo, P. J. Org. Chem. 1998, 63, 9540–9544.
doi:10.1021/jo980914s
23.Padmanabhan, S.; Reddy, N. L.; Durant, G. J. Synth. Commun. 1997,
27, 691–699. doi:10.1080/00397919708003343
24.Kumar, H. M. S.; Reddy, B. V. S.; Mohanty, P. K.; Yadav, J. S.
Tetrahedron Lett. 1997, 38, 3619–3622.
doi:10.1016/S0040-4039(97)00684-9
25.Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011, 76,
4260–4336. doi:10.1021/jo2005445
26.Denmark, S. E.; Gould, N. D.; Wolf, L. M. J. Org. Chem. 2011, 76,
4337–4357. doi:10.1021/jo2005457
269