Construction of Tropane Derivatives by the Organocatalytic Asymmetric Dearomatization of Isoquinolines

Article abstract of DOI:10.1002/anie.201605736

A chiral-NHC-catalyzed highly diastereo- and enantioselective dearomatizing double Mannich reaction of isoquinolines was developed that provides a powerful and straightforward synthetic route toward substituted tropane derivatives with four contiguous ste

Full text of DOI:10.1002/anie.201605736

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201605736
German Edition: DOI: 10.1002/ange.201605736
Asymmetric Catalysis
Construction of Tropane Derivatives by the Organocatalytic
Asymmetric Dearomatization of Isoquinolines
Jin-Hui Xu, Sheng-Cai Zheng, Ji-Wei Zhang, Xin-Yuan Liu, and Bin Tan*
Abstract: A chiral-NHC-catalyzed highly diastereo- and
enantioselective dearomatizing double Mannich reaction of
isoquinolines was developed that provides a powerful and
straightforward synthetic route toward substituted tropane
derivatives with four contiguous stereocenters. A unique
feature of this strategy is the use of readily available isoquino-
lines to provide two reactive sites for dearomatization, thus
opening up an unprecedented approach to tropane derivatives
with excellent stereoselectivity. The four-component reactions
proceeded smoothly with good results. Thus, the present
method is suitable for the diversity-oriented synthesis of
useful tropane derivatives with high efficiency.
Although isoquinolines are readily available, cheap, and
versatile feedstocks for the synthesis of chiral multifunction-
alized alkaloids, and frequently appear as a structural core in
natural products, the catalytic asymmetric dearomatization of
isoquinoline and its derivatives remains underdeveloped.[8,9]
In the context of CADA reactions of isoquinoline derivatives,
the main focus has been on Reissert-type reactions. The
elegant examples reported by Shibasaki,[9a,b] Jørgensen,[9c]
Jacobsen,[9d] Seidel,[9e] Cozzi,[9f] and Glorius[9g] all involved
nucleophilic attack at the C1 position (Scheme 3a), which
restricted their application for the construction of complex
molecules. It is well-known that a,b-unsaturated aldehydes
(enals) can behave as nucleophiles with two nucleophilic
centers for enantioselective annulation reactions[10] through
polarity inversion by means of organocatalysis by chiral N-
heterocyclic carbenes (NHCs).[11] Inspired by Robinsonꢀs
classic total synthesis of tropinone on the basis of the strategy
of a double Mannich reaction,[12] we envisioned that isoquino-
line derivatives may provide two reactive sites at the C1 and
C2 positions for a double Mannich reaction with the above-
mentioned two nucleophilic centers (Scheme 3b) to enable
the construction of the tropane skeleton in an asymmetric
manner (Scheme 2b).
In this scenario, several challenges were identified: 1) The
dearomatization reaction of isoquinolines has never been
investigated in enantioselective double Mannich reactions for
difunctionalization; 2) appropriate reaction conditions had to
be found to increase the reaction efficiency, control reactivity
at sites C1 and C2, and inhibit most undesirable side
reactions; 3) we needed to find a suitable chiral NHC
organocatalyst to efficiently induce the desired stereoselec-
tivity; and 4) the formation of four contiguous stereocenters
in multisubstituted tropane derivatives with bridged ring
systems was a particularly challenging task. As part of our
ongoing interest in asymmetric organocatalysis on core-
structure-motivated reactions,[13] we describe herein a chiral-
NHC-catalyzed highly diastereo- and enantioselective dear-
omatizing double Mannich reaction of isoquinolines. This
reaction provides a powerful and straightforward synthetic
route to substituted tropane derivatives with four contiguous
stereocenters. Such structural motifs are important compo-
nents of various biologically active natural products and
pharmaceutical compounds.[1–3]
T
he tropane (8-azabicyclo[3.2.1]octane) skeleton is wide-
spread in both natural products and synthetic compounds
with a wide range of biological activity.[1] Many tropane
derivatives play a key role in a large number of neurological
and psychiatric diseases, such as Parkinsonꢀs disease, depres-
sion, and panic disorder (Scheme 1, left).[2] Maraviroc, with
a tropane structural core, has been used in the treatment of
HIV infection and deserves considerable attention.[3] Benzo-
tropane, containing a phenyl ring in the tropane moiety, also
occurs in numerous lead compounds and pharmaceuticals for
the treatment of type 2 diabetes and antitumor drug candi-
dates (Scheme 1, right).[4] The medicinal relevance of tropane
derivatives has stimulated considerable interest among syn-
thetic chemists, and several catalytic methods have been
developed for the construction of optically pure tropane
frameworks.[5] In contrast, only one route has been presented
for the enantioselective synthesis of benzotropane scaffolds.[6]
In their pioneering study, the groups of Waldmann and
Antonchick developed a very efficient copper-catalyzed
highly stereoselective [3+2] cycloaddition reaction of 1,3-
fused cyclic azomethine ylides and nitroalkenes for the
synthesis of functionalized benzotropane scaffolds (Sche-
me 2a). The development of further highly efficient routes to
enantiomerically enriched tropanes from readily available
starting materials is highly desirable.
The catalytic asymmetric dearomatization (CADA) reac-
tion has emerged as a powerful organic transformation for the
construction of complex molecules from relatively simple
aromatic compounds, such as indoles, pyrroles, and phenols.[7]
We investigated the feasibility of this approach by
evaluating the reaction between cinnamaldehyde (1a) and
isoquinolinium bromide 2a in dichloromethane at room
temperature in the presence of the chiral triazolium-salt
catalyst C1, first reported by Rovis and co-workers[14]
(Table 1). The desired tropane product 3a was isolated in
39% yield with complete diastereomeric control (d.r. > 20:1)
[*] J.-H. Xu, S.-C. Zheng, J.-W. Zhang, Prof. Dr. X.-Y. Liu, Prof. Dr. B. Tan
Department of Chemistry
South University of Science and Technology of China
Shenzhen, 518055 (P.R. China)
E-mail: tanb@sustc.edu.cn
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201605736.
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Scheme 1. Representative natural products and biological active compounds with tropane frameworks. Boc=tert-butoxycarbonyl.
Table 1: Optimization of the reaction conditions.[a]
Entry
NHC
T [8C]
Solvent
Yield [%][b]
d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C6
C6
C6
C6
RT
RT
RT
RT
RT
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
39
6
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
48
27
60
88
91
90
93
89
93
93
18
39
30
42
57
58
66
67
RT
À20
À20
À20
À20
9[e]
10[f]
CH2Cl2
CH2Cl2
[a] Unless otherwise specified, the reaction was conducted on
a 0.1 mmol scale with 1a (0.2 mmol, 2.0 equiv), 2a (0.1 mmol,
Scheme 2. a) A reported strategy and b) our strategy for the construc-
tion of functionalized tropane derivatives.
1.0 equiv), KOAc (2.0 equiv), and the catalyst (10 mol%) in 2 mL of
solvent with EtOH (100 mL) at room temperature for 1 day or at À208C
for 4 days. [b] Yield of the isolated product. [c] The diastereomeric ratio
was determined by 1H NMR spectroscopy of the crude reaction mixture.
[d] The ee value was determined by HPLC analysis on a chiral stationary
phase. [e] The reaction was carried out with 10 equivalents of KOAc.
[f] The reaction was conducted on a 0.2 mmol scale in 4 mL of CH2Cl2
with 200 mL of EtOH.
and moderate enantioselectivity (48% ee). This proof-of-
principle result clearly suggested that the dearomatizing
double functionalization of isoquinolines with an NHC
organocatalyst was feasible. Having thus proven the efficiency
of the Rovis-type catalyst in our system, we moved on to
investigate catalyst substituent effects[11c] (Table 1, entries 2–
6) and found that the newly synthesized organocatalyst C6
displayed the best results in term of the chemical yield and
Scheme 3. Strategies for the dearomatization of isoquinoline.
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enantioselectivity. We varied the base, solvent, reaction
temperature, catalyst loading, and the number of equivalents
of KOAc (Table 1, entries 7–10; see also Table S1 in the
Supporting Information) and identified the following proto-
col as optimal: When 1a (0.4 mmol) was treated with 2a
(0.2 mmol) in the presence of catalyst C6 (10 mol%) in
CH2Cl2 at À208C for 4 days, the benzotrapone derivative 3a
was isolated in 67% yield with 93% ee and d.r. > 20:1
(Table 1, entry 10).
We first examined the scope of the reaction with respect to
the enal substrate under the optimized conditions (Scheme 4).
Different substituents and substitution patterns on the phenyl
ring of the enal substrate were tolerated. Regardless of the
type of substituent on the aromatic ring, electron-donating
(Me, OMe, NMe2), electron-neutral, or electron-withdrawing
(N3, F, Br), the corresponding products 3a–h were obtained in
good yield (45–70%) with 84– > 99% ee. Moreover, the
phenyl substituent of substrate 1a could be replaced with
a heteroaryl substituent without any evident effect on the
reaction outcome (3i,j). Aliphatic enals gave the desired
products in poor yield and enantioselectivity (see Scheme S1
in the Supporting Information).
Scheme 4. Scope of the reaction for the construction of tropane
To further explore the scope of this transformation, we
next evaluated the use of various isoquinolinium salts as
reactants (Scheme 5). Most reactions reached completion
within 4 days and gave the desired product in moderate to
good yield (36–84%) with excellent enantioselectivity (83–
95% ee) and diastereoselectivity (d.r. > 20:1). The position
and electronic properties of substituents (Ph,
derivatives with respect to the enal substrate. Under the optimized
reaction conditions (Table 1, entry 10), all products were obtained with
d.r.>20:1. Yields are for the isolated product, and ee values were
determined by HPLC analysis on a chiral stationary phase.
Me, OMe, Br, OH, NH2, CHO) on the iso-
quinoline skeleton appeared to have a very
limited effect on stereoselectivity (products
3k–q). Most importantly, the very reactive
free-hydroxy, amine, and aldehyde functional
groups were also compatible with the standard
reaction conditions (products 3o–q): These
reactions proceeded with good stereoselectiv-
ity, albeit in rather low yield. Encouraged by
these results, we expanded the generality of the
reaction by varying the N-benzyl functional
group (Scheme 5, products 3r–w). The desired
products were obtained with good stereoselec-
tivity, and the transformation proceeded almost
equally well with a range of groups with
different electronic properties, thus demon-
strating the broad generality of this approach
for the synthesis of tropane derivatives. Nota-
bly, the presence of a Cl or Br substituent in the
obtained tropane derivatives is very important
for setting up a compound library in the drug-
discovery field because halides are very reac-
tive in many transition-metal-catalyzed reac-
tions,[15] which offer opportunities for further
modification at these positions.
To demonstrate the utility of this trans-
formation, we carried out a preparative-scale
synthesis of product 3x (Scheme 6). The reac-
tion occurred in 50% yield with high stereose-
lectivity (99.5% ee, d.r. > 20:1), thus suggesting
Scheme 5. Scope of the reaction for the construction of tropane derivatives with respect
to the isoquinolium salt. Under the optimized reaction conditions (Table 1, entry 10), all
products were obtained with d.r.>20:1. Yields are for the isolated product, and
ee values were determined by HPLC analysis on a chiral stationary phase.
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rationalize the course and stereose-
lectivity of the reaction. When the
reaction of acrylaldehyde with 2a
was conducted under the otherwise
identical conditions, the intermedi-
ate product 5a was formed in
almost quantitative yield without
the formation of the desired prod-
uct (Scheme 8). This result pro-
vided evidence for a stepwise mech-
anism. Product 5a is unstable and
could be readily transformed into
5b by reduction with NaBH4 for
further analysis.[19] On the basis of
the above observations and previ-
ous reports on NHC catalysis,[10,11]
Scheme 6. Preparative-scale synthesis of product 3x and further transformation of 3a.
that this method has the potential for large-
scale chemical production. The absolute con-
figuration of 3x was determined by X-ray
diffraction analysis[16] (Scheme 6), and that of
other products was assigned by analogy. We
also found that the benzyl group in 3a could
be readily removed by using Pd/C as the
catalyst without any effect on enantioselec-
tivity (Scheme 6).
Multicomponent reactions (MCRs) are
a powerful chemical tool for the preparation
of complex molecules owing to their atom and
Scheme 7. Successful attempt at a multicomponent reaction with commercially available
step economy, as well as the high efficiency in
generating complex molecules through the
structural modulation of each component.[17]
On the basis of our comprehension of the
above-mentioned protocol, we
investigated the possibility of
performing the reaction as a mul-
ticomponent reaction in a one-
pot fashion from simple com-
mercially available starting
materials. A model four-compo-
nent reaction proceeded very
smoothly to produce the desired
tropane product 3a with almost
the same chemical yield and
enantioselectivity, regardless of
whether isoquinoline or benzyl
bromide was used in excess
(Scheme 7). The present process
is a rather general and straight-
forward method for the diver-
sity-oriented synthesis of useful
tropane derivatives in high effi-
ciency, and clearly complemen-
tary to previous synthetic meth-
ods.[5,6]
starting materials.
Since the current reaction
could proceed in
a stepwise
manner or a concerted formal
[5+2] mechanism,[18] we carried
Scheme 8. Proposed mechanism and isolation of a key intermediate.
out
a control experiment to
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Chicchi, M. M. Kurtz, C. London, P. Raubo, A. Wheeldon, J. J.
we propose a catalytic cycle for the double Mannich reaction
of an isoquinolinium salt with an enal in Scheme 8. Thus, the
addition of the NHC catalyst to enal 1 yields an NHC-bonded
homoenolate intermediate A containing a nucleophilic b-
carbon center. Nucleophilic Mannich attack at the C1
position of isoquinonium 2 results in the formation of enol
intermediate B, followed by proton transfer to generate the
enolate C with an active iminium ion moiety, which partic-
ipates in an intramolecular Mannich reaction to deliver the
key tropane skeleton D. A final esterification reaction leads
to ester formation through attack by ethanol and regenerates
the catalyst C6. During the course of proton transfer, the side
product 5 may be produced if the reaction proceeds via
another active intermediate C’.
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In summary, we have successfully developed the first
chiral-NHC-catalyzed asymmetric dearomatizing double
Mannich reaction of isoquinolines to enable the straightfor-
ward and efficient synthesis of biologically important tro-
panes bearing four contiguous stereogenic centers with high
levels of diastereo- and enantioselectivity. Aunique feature of
this strategy is the use of readily available isoquinolines to
provide two reactive sites for dearomatization reactions. This
highly convergent and functional-group-tolerant strategy
enables the rapid construction of complex compounds from
simple, readily available starting materials. Furthermore, the
tropane derivatives can be synthesized through four-compo-
nent reactions in one-pot fashion with good results, thus
indicating that the present process is a rather general and
straightforward protocol for diversity-oriented synthesis with
high efficiency. We anticipate that this promising strategy will
motivate the design of related processes for the efficient
synthesis of complex natural products and bioactive mole-
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We are thankful for financial support from the National
Natural Science Foundation of China (No. 21572095) and
Shenzhen Special Funds for the Development of Biomed-
icine, Internet, New Energy, and New Material Industries
(JCYJ20150430160022510). B.T. thanks the Thousand Young
Talents Program for financial support.
Keywords: asymmetric catalysis · dearomatization ·
isoquinolines · N-heterocyclic carbenes · tropanes
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Received: June 14, 2016
Published online: && &&, &&&&
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Communications
Asymmetric Catalysis
J.-H. Xu, S.-C. Zheng, J.-W. Zhang,
X.-Y. Liu, B. Tan*
&&&& — &&&&
Construction of Tropane Derivatives by
the Organocatalytic Asymmetric
Dearomatization of Isoquinolines
Fab four: A highly stereoselective dearo-
matizing double Mannich reaction of
readily available isoquinolines, which
provided two reactive sites for dearoma-
tization, smoothly produced substituted
benzotropanes with four contiguous ste-
reocenters. In particular as a four-com-
ponent reaction, this transformation
shows high potential for the efficient
diversity-oriented synthesis of useful tro-
pane derivatives (see scheme).
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