Enantiodivergent Combination of Natural Product Scaffolds Enabled by Catalytic Enantioselective Cycloaddition

Article abstract of DOI:10.1002/anie.201602084

An efficient strategy has been established for the enantiodivergent synthesis of natural product inspired compounds embodying both tropane and pyrrolidine natural product fragments. This strategy includes the enantioselective kinetic resolution of racemic tropanes by means of a copper(I)-catalyzed [3+2] cycloaddition and allows the preparation of two enantiopure products in a one-pot reaction in high yield and with high diastereo- and enantioselectivity by using one chiral catalyst.

Full text of DOI:10.1002/anie.201602084

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Communications
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International Edition: DOI: 10.1002/anie.201602084
German Edition: DOI: 10.1002/ange.201602084
[3+2] Cycloaddition
Enantiodivergent Combination of Natural Product Scaffolds Enabled
by Catalytic Enantioselective Cycloaddition
Hao Xu, Christopher Golz, Carsten Strohmann, Andrey P. Antonchick,* and
Herbert Waldmann*
Abstract: An efficient strategy has been established for the
The synthesis of both enantiomers from a single chiral
enantiodivergent synthesis of natural product inspired com- intermediate, usually by multistep transformations, has been
pounds embodying both tropane and pyrrolidine natural documented[5] and, recently, a few more streamlined solutions
product fragments. This strategy includes the enantioselective to this problem were found for the synthesis of compounds
kinetic resolution of racemic tropanes by means of a copper(I)- with one stereocenter.[6] However, efficient methods for the
catalyzed [3+2] cycloaddition and allows the preparation of enantiodivergent synthesis of complex molecular architec-
two enantiopure products in a one-pot reaction in high yield tures with multiple stereocenters are rare.[6f] Here we report
and with high diastereo- and enantioselectivity by using one a catalytic enantiodivergent synthesis of enantiopure complex
chiral catalyst.
natural product inspired compounds which embody different
natural product fragments and scaffolds and carry multiple
B
ioactive natural products define biologically prevalidated stereocenters. Importantly, both enantiomers can be accessed
scaffold structures because they encode the areas of chemical rapidly and efficiently using just one chiral ligand with
space explored by nature during evolution.[1] Since fragment- a defined absolute configuration.
based design principles allow large fractions of biologically
The tropane scaffold, that is, 8-azabicyclo[3.2.1]octane,
relevant chemical space to be covered efficiently with defines the core structure of more than 600 alkaloids with
a limited number of small molecules,[2] it would be highly multiple bioactivities (Figure 1),[7] and tropanes have been
desirable to unite them with hypothesis-generating
approaches that take inspiration form natural product struc-
tures, in particular biology-oriented synthesis (BIOS).[1,2] We
have recently described the cheminformatic dissection of
natural products to arrive at fragments that represent natural
product structures and their properties, in particular stereo-
genic character.[3] Combinations of such natural product
fragments and scaffolds may give access to novel classes of
bioactive compounds since they will inherit natural product
structure and properties.[4] The corresponding syntheses need
to address the fact that the bioactivity of natural products is
often tied to their absolute configuration, which can hardly be
predicted for the novel scaffolds derived from the combina-
tion of chiral fragments. The development of enantiodiver-
gent syntheses that provide efficient access to both possible
enantiomers would provide a powerful solution to this
problem.
[*] Dr. H. Xu, Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Figure 1. Design of natural product hybrid structures derived from the
tropane and pyrrolidine alkaloids. Bz=benzoyl.
Max-Planck-Institut für Molekulare Physiologie
Abteilung Chemische Biologie
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: andrey.antonchick@mpi-dortmund.mpg.de
subjected to numerous synthetic and biological studies.[8]
However, most of the synthesis methods yield racemic
compounds, and general methods for the asymmetric catalytic
herbert.waldmann@mpi-dortmund.mpg.de
C. Golz, Prof. Dr. C. Strohmann
Technische Universität Dortmund
Fakultät Chemie und Chemische Biologie, Anorganische Chemie
synthesis of functionalized tropanes are in high demand.[9]
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
The 1,3-dipolar cycloaddition of azomethine ylides[10–12] with
different olefins gives efficient access to pyrrolidines, which
Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Technische Universität Dortmund
define the characteristic fragment core structure of numerous
alkaloids.[7c,13] We envisioned that the combination of this
cycloaddition with racemic tropanes (readily accessible by
Fakultät Chemie and Chemische Biologie, Chemische Biologie
Otto-Hahn-Strasse 4a, 44227 Dortmund (Germany)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602084.
means of
a
[5+2] cycloaddition of 3-oxidopyrylium
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betaines[14,15]
)
with alkenes could provide
a
powerful
DIPEA (20 mol%) as the base in CH2Cl2 at room temper-
ature (Scheme 1). Under these reaction conditions, the exo-
cycloadduct (À)-3a was obtained in 82% yield with 99% ee
(Scheme 1).
approach to complex polycyclic natural product inspired
architectures incorporating both the tropane and pyrrolidine
fragment structures.
Initially we investigated the reaction conditions for the
enantioselective 1,3-dipolar cycloaddition of N-4-bromoben-
zylideneglycine methyl ester (2a, 1.0 equiv) with racemic
tropane rac-1a (2.0 equiv; Scheme 1). Variation of different
Having in hand the optimized reaction conditions, we
investigated the scope of the [3+2] cycloaddition by treating
tropane (rac-1a) with various glycine ester imines 2 (Table 1).
The reaction was very versatile and displayed wide scope,
with various functional groups on the phenyl ring of imines 2
tolerated (Table 1). Unfortunately, aliphatic imines were not
reactive under the developed reaction conditions.
Table 2: Kinetic resolution of tropanes with azomethine ylides.[a]
Scheme 1. Enantioselective 1,3-dipolar cycloaddition of azomethine
ylide 2a with tropane rac-1a. DIPEA=diisopropylethylamine.
Entry rac-1
Conv. [%][b] ee (yield) [%] ee (yield) [%] s[d]
of 3[c]
of 1[c]
reaction parameters, in particular catalyst, chiral ligand, base,
solvent, and reaction temperature (see the Supporting
Information for details) revealed that the best results were
obtained with [Cu(CH3CN)4]BF4 (5 mol%) in the presence of
chiral ligand L1 (6 mol%; (R)-3,5-tBu2-MeOBIPHEP) using
1
2
3
51
50
51
99 (41)
97 (46)
119
115
47
98 (40)
94 (41)
94 (46)
91 (46)
Table 1: Scope of the asymmetric [3+2] cycloaddition.[a]
4[e]
51
97 (45)
95 (42)
81
Entry
R1
(À)-3
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
C6H5
(À)-3b
(À)-3c
(À)-3d
(À)-3e
(À)-3 f
(À)-3g
(À)-3a
(À)-3h
(À)-3i
(À)-3j
(À)-3k
(À)-3l
(À)-3m
(À)-3n
(À)-3o
(À)-3p
(À)-3q
24
24
24
24
5
5
5
5
5
24
24
24
24
24
5
73
70
90
80
75
85
82
78
81
74
87
64
74
55
91
60
76
99
98
98
>99
99
>99
99
99
98
97
97
97
>99
97
99
5
51
52
51
50
97 (44)
96 (37)
97 (43)
99 (41)
96 (44)
99 (37)
97 (47)
94 (49)
97
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-CF3-C6H4
4-CO2Me-C6H4
4-MeO-C6H4
3-MeO-C6H4
3,4-di-MeO-C6H3
4-Ph-C6H4
4-tBu-C6H4
2,3-di-Cl-C6H3
1-naphthyl
2-naphthyl
6[e]
116
119
115
9
10[d]
11
12
13
14
15
16
17
7
8
24
24
98
98
[a] Reaction conditions: rac-1 (0.2 mmol), imine 2a (0.1 mmol), DIPEA
(10 mol%), [Cu(CH3CN)4]BF4 (2.5 mol%), L1 (3 mol%), CH2Cl2
(1.0 mL), room temperature, until disappearance of the ester imines (5–
24 h). [b] Determined by 1H NMR spectroscopy. [c] The ee value was
determined by HPLC analysis on a chiral stationary phase. [d] Selectivity
factors (s), s factor=Ln[(1-conv)(1-ee1)]/Ln[(1-conv)(1+ee1)]. [e] rac-
1 (0.2 mmol), imine 2a (0.105 mmol).
[a] Reaction conditions: rac-1a (2.0 equiv), imine 2 (1.0 equiv,
0.1 mmol), DIPEA (20 mol%), [Cu(CH3CN)4]BF4 (5 mol%), L1
(6 mol%), CH2Cl2 (0.1m), room temperature, until disappearance of the
ester imines (5–24 h). [b] Yield of the isolated product after column
chromatography. [c] The ee value was determined by HPLC analysis on
a chiral stationary phase. [d] rac-1b was used instead of rac-1a.
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Despite the importance of optically enriched tropanes 1 as
ylides with differing polarity (R2 ¼ R3, Figure 2) to enable
building blocks in organic synthesis,[7,8] only a few asymmetric
catalytic methods have been developed for the synthesis of
compounds based on the tropane scaffold.[9,12c] In particular,
although there are several reports on the [5+2] cycloadditions
of 3-oxidopyrylium betaines with alkenes for the synthesis of
tropanes,[14,15] the corresponding catalytic enantioselective
version has remained elusive. To our delight, the kinetic
resolution of racemic starting material under the conditions of
the enantioselective [3+2] cycloaddition described above is
very efficient (Table 2). In general, cycloadducts (À)-3 were
obtained in yields of 37–45% and with 94–99% ee together
with a 37–49% yield of recovered starting material with 91–
99% ee (s factor: 47–119).
straightforward separation of the two products ((À)-3 and
(+)-3’) by column chromatography.
To our delight, the one-pot sequence designed accordingly
proceeds with high efficiency if a combination of [Cu-
(CH3CN)4]BF4 (10 mol%) and rac-BINAP (12 mol%) is
employed as the catalyst for the second cycloaddition. For
a variety of imines the two enantiomers were obtained in 33–
49% yield and with 88–99% ee (Table 3, entries 1–6). Nota-
Table 3: Enantiodivergent tropane synthesis by means of sequential
[1,3]-dipolar cycloaddition.[a]
The efficiency of the kinetic resolution encouraged us to
investigate whether this transformation would enable an
enantiodivergent synthesis. We hypothesized that if racemic
tropane (1) was subjected to a sequence of cycloadditions
with two different azomethine ylides, two different enantio-
merically highly enriched products could be obtained in
a one-pot reaction, and, importantly, with only one chiral
ligand (Figure 2). In the first step, 1,3-dipolar cycloaddition
with one given azomethine ylide would provide the cyclo-
adduct (À)-3 and enantioenriched tropane (++)-1 (Figure 2).
A diastereoselective 1,3-dipolar cycloaddition reaction of
(+)-1 with a second azomethine ylide would then provide
cycloadduct (+)-3’. We envisioned the use of two azomethine
Entry R1
R2
(À)-3 ee(yield)
(+)-3 ee(yield)
[%][b]
[%][b]
1
2
3
4
5
6
7
4-Br
4-CO2Me 4-Me
3-OMe
3-Me
4-Ph
4-CO2Me
(À)-3a
(À)-3i
(À)-3k
98 (48) (+)-3i
98 (43) (+)-3e 91 (42)
97 (42) (+)-3d 88 (49)
95 (48)
3-Me
3,4-di-OMe (À)-3d
95 (44) (+)-3l
97 (33)
4-OMe
(À)-3 m 99 (49) (+)-3y 90 (46)
4-OMe
2,3-di-Cl 4-OMe
2,3-di-Cl
(À)-3y
98 (40) (+)-3o 94 (48)
97 (42) (+)-3y 94 (48)
(À)-3o
[a] Reaction conditions: Step 1: imine 2 (1.0 equiv, 0.1 mmol), tropane
1 (2.0 equiv), DIPEA (20 mol%), [Cu(CH3CN)4]BF4 (5 mol%), L1
(6 mol%), CH2Cl2 (1.0 mL), room temperature, until disappearance of
the ester imines (5–24 h); Step 2: imine 2’ (1.5 equiv, 0.15 mmol),
[Cu(CH3CN)4]BF4 (10 mol%), rac-BINAP (12 mol%), CH2Cl2 (1.0 mL),
room temperature, 4 h. [b] Yield of the isolated product after column
chromatography; the ee value was determined by HPLC analysis on
a chiral stationary phase.
bly, formation of the respective opposite enantiomers can
easily be achieved by simply switching the order of the imine
addition (Table 3, entries 6 and 7). The absolute configuration
of a representative cycloadduct was determined by X-ray
diffraction (see the Supporting Information), and the absolute
configurations of all other compounds were assigned by
analogy.
In conclusion, we report the development of an efficient
enantiodivergent synthesis of natural product inspired hybrid
compounds with a maximum of eight stereocenters from
simple starting materials. The obtained products embody two
privileged natural products fragments, namely the tropane
and the pyrrolidine scaffold. The synthesis proceeds with high
diastereo- and enantioselectivity and has broad substrate
scope. Importantly, this method enables two opposing enan-
tiomers to be readily synthesized by employing only one
chiral ligand in a one-pot reaction and using a single flash
chromatographic separation.
Figure 2. Enantiodivergent synthesis. BINAP=2,2’-bis(diphenylphos-
phino)-1,1’-binaphthyl.
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Acknowledgements
H.X. is grateful to the Alexander von Humboldt Foundation
for a postdoctoral fellowship. This work was funded by the
European Union Seventh Framework Programme under
grant agreement no. HEALTH-F2-2009-241498 (“EURO-
SPIN” project) and ERC grant agreement no. 268309.
Keywords: asymmetric catalysis · cycloaddition · enantiomers ·
kinetic resolution · tropane
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Received: February 29, 2016
Published online: May 19, 2016
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