Letter

Cite This: Org. Lett. XXXX, XXX, XXX−XXX pubs.acs.org/OrgLett

Enantioselective Synthesis of Fused Polycyclic Tropanes via

Dearomative [3 + 2] Cycloaddition Reactions of 2‑Nitrobenzofurans
Zhen Wang, Dong-Chao Wang,* Ming-Sheng Xie, Gui-Rong Qu, and Hai-Ming Guo*
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key Laboratory of Green Chemical Media and
Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals,
School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China
*
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ABSTRACT: A straight synthetic approach to fused polycyclic tropane scaffold formation through an asymmetric
dearomatization cycloaddition process of 2-nitrobenzofurans with cyclic azomethine ylides was successfully developed. In
the presence of a chiral copper complex, derived from Cu(OAc)2 and a diphosphine ligand, a series of fused polycyclic tropane
derivatives were obtained in high yields (75−91%) with excellent enantioselectivities (90−98%). The utility of this method was
showcased by the facile transformation of product.

N atural products are the main source of drugs or lead

compounds.1 The development of efficient and general
methods for constructing complex and diverse natural product
scaffolds is in high demand. The tropane framework (8-
azabicyclo[3,2,1]octane) is widely found in natural products
and drug molecules with important physiological functions.2
Many tropane alkaloids play pivotal roles in the clinical
treatment of immune, neurological, psychiatric diseases, etc.3
In particular, fused polycyclic tropane frameworks are found in
natural products and biologically active compounds such as
MK-801,4 and himandrine-, stemofoline-, and hetisine-type
alkaloids5 (Figure 1), which exhibit a broad spectrum of
biological activities including NMDA receptor antagonist,
antiarrhythmia, anticancer, deaddiction, antiepileptic, and anti-
inflammatory activities. Guan-fu base A (Figure 1) has been
Figure 1. Structures of representative alkaloids and drug molecules
containing the fused polycyclic tropane framework.
approved in 2005 in China as an antiarrhythmia agent.5d
Synthetic methods to build up enantiomerically pure tropane
scaffolds have been used for some time, but most of them need
to start from the chiral raw material and reagents and often
generate structurally simple tropane coumpounds.6 The direct
catalytic asymmetic construction of the structurally complex
tropane scaffold remains challenging. Stereoselective [4 + 3]
cycloadditions of pyrrole have been reported early for the
asymmetric synthesis of structurally simple tropanes.7 In 2013,
the research groups of Waldmann and Antochick first reported
their pioneering work on the catalytic enantioselective [3 + 2]
cycloaddition of cyclic azomethine ylides and nitroalkenes for
the construction of indole- or benzole-fused tropanes (Scheme
1a).8 Subsequently, the enantioselective [3 + 2] cycloaddition
of cyclic azomethine ylides was successfully developed as a
method. 9 In 2016, Tan and coworkers developed a
straightforward synthetic route toward benzotropane scaffold
construction by chiral-NHC-catalyzed double Mannich asym-
metric dearomatization of isoquinolines (Scheme 1b).10
Recently, Deng and coworkers extended a novel strategy for
constructing indole-fused tropanes via asymmetric [3 + 3]
annulation of cyclic azomethine ylides (Scheme 1c).11 To the
best of our knowledge, cyclic azomethine ylides have not been
used in dearomative cycloaddition to date.
The catalytic asymmetric dearomatization (CADA) reac-
tions are powerful tools for the rapid assembly of enantio-
Received: November 17, 2019

© XXXX American Chemical Society A DOI: 10.1021/acs.orglett.9b04108

Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters Letter

Scheme 1. Enantioselective Construction Strategy of Table 1. Optimization of Reaction Conditionsa

Tropane Scaffold

yield ee
entry catalyst L solvent (%)b drc (%)d
1 Cu(OAc)2 L1 MTBE 84 17:1 4
2 Cu(OAc)2 L2 MTBE 81 >20:1 0
3 Cu(OAc)2 L3 MTBE 72 17:1 47
4 Cu(OAc)2 L4 MTBE 83 17:1 −44
5 Cu(OAc)2 L5 MTBE 75 13:1 71
enriched three-dimensional polycyclic molecules from readily 6 Cu(OAc)2 L6 MTBE 79 8:1 80
available aromatic substrates.12 The CADA reactions of 7 Cu(OAc)2 L7 MTBE 70 5:1 82
electron-rich heteroarenes (e.g., indole, pyrrole, furan, etc.) 8 Cu(OAc)2 L8 MTBE 68 6:1 82
have been successfully developed based on their inherent 9 Cu(OAc)2 L9 MTBE 87 14:1 97
nucleophilicities.12,13 However, CADA reaction of electron- 10 Cu(OTf)2 L9 MTBE 79 >20:1 88
deficient nitro-heteroarenes remains challenging and have only 11 Cu(MeCN)4ClO4 L9 MTBE 78 10:1 93
recently garnered significant research interest.14 In recent 12 Cu(MeCN)4PF6 L9 MTBE 83 10:1 94
years, our group has been exploring the dearomative 13 Cu(OAc)2 L9 DCM 62 6:1 67
cycloaddition reactions of heteroarenes.15 We hypothesized 14 Cu(OAc)2 L9 THF 43 >20:1 0
that cyclic azomethine ylides might be a suitable substrate for 15 Cu(OAc)2 L9 Et2O 80 14:1 95
an asymmetric dearomative [3 + 2] cycloaddition with 16 Cu(OAc)2 L9 CHCl3 77 10:1 94
electron-deficient arenes, thus yielding fused functionalized 17e Cu(OAc)2 L9 MTBE 87 14:1 97
polycyclic tropanes. As a part of our ongoing research on 18e,f Cu(OAc)2 L9 MTBE 87 14:1 97
dearomative reactions of heteroarenes, herein, we now report a
Unless otherwise noted, the reaction conditions were as follows: 1a
the first CADA reactions of 2-nitrobenzofurans with cyclic (0.22 mmol), 2a (0.1 mmol), Cu(OAc)2 (5 mol %), L (5 mol %), and
azomethine ylides to generate fused functionalized polycyclic K2CO3 (10 mol %) in MTBE (1.0 mL), 0 °C, N2, 10 h. bYields of
tropanes. isolated product. cDetermined by 1H NMR analysis of crude mixture.
In order to establish an efficient CADA route for d
Determined by chiral HPLC analysis. e1 mol % of Cu(OAc)2, 1 mol
constructing fused polycyclic tropanes, 3,4-dihydro-β-carboline % of L9. f0.2 mmol of 2a and 0.44 mmol of 1a were employed in
1a and 2-nitrobenzofuran 2a were employed as model MTBE (2.0 mL).
substrates in the optimization of the reaction conditions. We
initially carried out the screening of ligands at 0 °C in MTBE h, the desired cycloadduct 3aa was obtained in an 87% yield,
by using K2CO3 as the base and 5 mol % of Cu(OAc)2 as the with 97% ee and d.r. 14:1 (Table 1, entry 17). When the
catalyst. As shown in Table 1, various copper complexes, reaction was conducted on a 0.2 mmol scale, the results
derived from Cu(OAc)2 and ligands L1−L9, successfully remained consistent with previous ones (Table 1, entry 18).
catalyzed the cycloaddition reaction and produced the desired After optimizing the reaction conditions (Table 1, entry 18),
product 3aa in satisfactory yields with diverse diastereose- we explored the scope of 3,4-dihydro-β-carboline substrates 1.
lectivities (5:1−>20:1) (Table 1, entries 1−9). Among them, As shown in Scheme 2, electron-donating or electron-
ligands L1 and L2 gave a racemic product 3aa (Table 1, entries withdrawing substituents in the indole moiety all yielded the
1 and 2), and ligands L3−L8 produced 3aa in moderate to desired products 3aa−3fa in high yields with excellent ee
good enantioselectivities (44−82% ee, Table 1, entries 3−8). values with d.r. > 15:1. The ester groups and R3 of carboline
Ligand L9, however, showed the highest efficiency and resulted parts were varied under the optimized reaction conditions. Et
in the product 3aa with 97% ee and 14:1 diastereoselectivity and Bn as R2 groups were tolerated, and the corresponding
(Table 1, entry 9). The screening of various copper sources products 3ga and 3ha were obtained with the same yields and
indicated that the ee values of product 3aa produed using ee values. When the R3 group was changed to Et, the yield and
other copper salts as catalysts were not as good as those enantioselectivity of product 3ia were slightly affected (83%
produced using Cu(OAc)2 (Table 1, entries 9−12). MTBE yield, 94% ee). However, when the R3 group was changed to n-
was found to be the best solvent among the screened solvents pentyl, the yield and enantioselectivity of product 3ja
(Table 1, entries 13−16). Following solvent selection, we decreased significantly. In addition, as shown in Scheme 3,
optimized the catalyst amount and reaction temperature in different substituents at the 5-, 6-, and 7-positions of the 2-
MTBE (see Supporting Information (SI)). When the reaction nitrobenzofurans, whether electron-donating or electron-with-
was carried out using a 1 mol % catalyst loading at 0 °C for 10 drawing groups, were also well tolerated in the optimal
B DOI: 10.1021/acs.orglett.9b04108
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters Letter

Scheme 2. Substrate Scope of Cyclic Azomethine Ylides for Scheme 3. Substrate Scope of 2-Nitrobenzofurans for
the Dearomative [3 + 2] Cycloadditiona Dearomative [3 + 2] Cycloadditiona

a
Unless otherwise noted, the reaction conditions were: 1a (0.44
mmol), 2a (0.2 mmol), Cu(OAc)2 (1 mol %), L9 (1 mol %), and
K2CO3 (10 mol %) in MTBE (2.0 mL), 0 °C, N2, 10 h. Yields of
isolated product. The d.r. was determined by 1H NMR analysis of the
crude mixture. The ee value was determined by chiral HPLC analysis.
b
With 5 mol % of Cu(OAc)2, 5 mol % of L9. a
Unless otherwise noted, the reaction conditions were: 1a (0.44
mmol), 2a (0.2 mmol), Cu(OAc)2 (5 mol %), L9 (5 mol %), and
K2CO3 (10 mol %) in MTBE (2.0 mL), 0 °C, N2, 10 h. Yields of
reaction conditions, and the reactions proceeded to deliver the isolated product. The d.r. was determined by 1H NMR analysis of the
desired products 3ab−3al favorably (75−91% yields, d.r. 7:1− crude mixture. The ee value was determined by chiral HPLC analysis.
20:1, 90−97% ee). However, it is noted that the dearomatiza- b
With 1 mol % of Cu(OAc)2, 1 mol % of L9.
tion reactions of most 2-nitrobenzofurans (except for 2b, 2d,
and 2h) were carried out under a 5 mol % catalyst loading Scheme 4. Gram-Scale Synthesis and Transformations of
perhaps for reasons of poor solubility. The absolute Cycloadduct 3aa
configuration of product 3ak was determined to be (1R,3aS)
via single-crystal X-ray diffraction analysis.
To further explore the prospective use of this methodology,
gram-scale synthesis of fused polycyclic tropane 3aa was
carried out. As shown in Scheme 4a, in the presence of a 0.5
mol % catalyst loading, 3,4-dihydro-β-carboline 1a (6.6 mmol)
and 2-nitrobenzofuran 2a (3.0 mmol) could be smoothly
transformed to the desired product 3aa in 84% yield, d.r. 14:1,
and 95% ee. Various transformations of fused polycyclic
tropanes were also carried out (Scheme 4b). First, using zinc
dust in a hydrogen chloride−ethanol solution as a reducing
agent, the nitro in 3aa was transformed in a single step into an
amine group to generate compound 4 in 77% yield with
excellent stereocontrol. Following this, the ester group was
selectively reduced by LiAlH4 (2 equiv) in THF, and the
corresponding product 5 containing a hydroxyl group was
obtained in good yield. After treating 3aa with AIBN and
tributyltin hydrogen in toluene, the denitrated compound 6
was obtained in 71% yield and 97% ee. For the proposed
mechanism and stereochemical model for this Cu(OAc)2-
catalyzed dearomative [3 + 2] cycloaddition ring-opening
reactions, see the SI for details.
In summary, we have successfully developed an enantiose- functionalized polycyclic 8-azabicyclo[3,2,1]octane derivatives
lective dearomative [3 + 2] cycloaddition of 2-nitrobenzofur- were obtained in high yields (up to 91%) with excellent
ans with cyclic azomethine ylides, catalyzed by a copper enantioselectivity (up to 98% ee). The reaction has a general
complex derived from Cu(OAc)2 and a chiral diphosphine substrate scope for 2-nitrobenzofurans and cyclic azomethine
ligand. Under this dearomative process, a series of fused ylides. In addition, the utility of the current method was
C DOI: 10.1021/acs.orglett.9b04108
Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
showcased by a gram-scale synthesis and the facile trans-
formation of products.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04108.
Experimental procedures and compound characteriza-
tion data (PDF)
Accession Codes
CCDC 1937171 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail: wangdc@htu.edu.cn.
*E-mail: ghm@htu.edu.cn.
ORCID
Dong-Chao Wang: 0000-0002-5037-4727
Ming-Sheng Xie: 0000-0003-4113-2168
Hai-Ming Guo: 0000-0003-0629-4524
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
We are grateful for the financial support from National Natural
Science Foundation of China (21672055 and U1604283), the
111 Project (No. D17007), and the Program for Youth
Backbone Teacher Training in University of Henan Province
(2017GGJS042).
■
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