Dynamic Catalytic Highly Enantioselective 1,3-Dipolar Cycloadditions

Article abstract of DOI:10.1002/anie.202108072

In dynamic covalent chemistry, reactions follow a thermodynamically controlled pathway through equilibria. Reversible covalent-bond formation and breaking in a dynamic process enables the interconversion of products formed under kinetic control to thermod

Full text of DOI:10.1002/anie.202108072

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Asymmetric Synthesis
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Dynamic Catalytic Highly Enantioselective 1,3-Dipolar Cycloadditions
Okan Yildirim, Michael Grigalunas, Lukas Brieger, Carsten Strohmann, Andrey P. Antonchick,*
and Herbert Waldmann*
Abstract: In dynamic covalent chemistry, reactions follow
a thermodynamically controlled pathway through equilibria.
Reversible covalent-bond formation and breaking in a dynamic
process enables the interconversion of products formed under
kinetic control to thermodynamically more stable isomers.
Notably, enantioselective catalysis of dynamic transformations
has not been reported and applied in complex molecule
synthesis. We describe the discovery of dynamic covalent
enantioselective metal-complex-catalyzed 1,3-dipolar cycload-
dition reactions. We have developed a stereodivergent tandem
synthesis of structurally and stereochemically complex mole-
cules that generates eight stereocenters with high diastereo- and
enantioselectivity through asymmetric reversible bond forma-
tion in a dynamic process in two consecutive Ag-catalyzed 1,3-
dipolar cycloadditions of azomethine ylides with electron-poor
olefins. Time-dependent reversible dynamic covalent-bond
formation gives enantiodivergent and diastereodivergent ac-
cess to structurally complex double cycloadducts with high
selectivity from a common set of reagents.
formation of strong covalent bonds.[1,2] The irreversible
nature of the reaction guarantees that, once the particular
product is formed, it is stable and will not be reformed or
converted into another product.[1]
As an alternative to selective product formation, Rowan
et al. introduced the concept of dynamic covalent chemistry
(DCC).[2] In DCC covalent bonds can be formed and broken
reversibly in a fast equilibrium and under conditions in which
equilibrium control leads to efficient formation of products
under thermodynamic control.[2] DCC has been proposed
primarily in the context of supramolecular chemistry includ-
ing applications in combinatorial chemistry.[3,4] The reversible
nature of reactions permits “error checking” and “proof
reading” for interconverting components to access the
thermodynamically most stable adduct.[4–7] However, while
in supramolecular chemistry weak noncovalent interactions
dominate, for DCC more robust covalent bonds are relevant
with slower kinetics of bond cleavage and formation. In DCC
the relative stability of the products (i.e., thermodynamic
parameters) determines the product distribution rather than
the relative magnitudes of energy barriers of each pathway
(i.e., kinetic parameters) (Scheme 1a). Since both the ther-
modynamic and the kinetic parameters are functions of
reaction parameters, the outcome is highly dependent on
reaction conditions such as temperature, catalyst and reaction
time required to reach an equilibrium.[7,8] Turner et al.
employed DCC in enzyme catalysis. They used an aldolase
for preparation of a dynamic combinatorial library through
stereoselective carbon-carbon bond formation and enabled
change in equilibrium in product distribution in presence of
a thermodynamic trap.[9]
Introduction
The synthesis of organic compounds is dominated by
kinetically controlled reactions, which enables irreversible
[*] O. Yildirim, Dr. M. Grigalunas, Prof. Dr. A. P. Antonchick,
Prof. Dr. H. Waldmann
Max Planck Institute of Molecular Physiology, Department of
Chemical Biology
Otto-Hahn-Strasse 11, 44227 Dortmund (Germany)
E-mail: herbert.waldmann@mpi-dortmund.mpg.de
O. Yildirim, Prof. Dr. A. P. Antonchick, Prof. Dr. H. Waldmann
Technichal University Dortmund, Faculty of Chemistry, Chemical
Biology
DCC was also observed for non-enzymatic aldol/retro-
aldol reactions,[5,10] for Diels–Alder cycloadditions at higher
temperature,[11] and for additional transformations including
Michael additions,[12] alkene cross-metathesis.[13] and [2+2]
cycloaddition.[14] However, non-enzymatic enantioselective
catalysis of DCC has not been reported and DCC has not
been observed for dipolar cycloadditions yet. Herein we
describe the discovery of catalytic and highly enantioselective
dynamic covalent chemistry in metal complex-catalyzed 1,3-
dipolar cycloaddition reactions, that is, a reaction type which
belongs to the most important and widely used transforma-
tion in organic synthesis.
In the course of a program aimed at the synthesis of
pseudo-natural products,[15–21] which contain two or more
natural product (NP) derived fragments in novel and
structurally complex arrangements, we intended to combine
two pyrrolidine fragments in an unprecedented manner. To
this end, it was envisaged to subject cyclopentenones con-
taining both an endocyclic and an exocyclic conjugated
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
L. Brieger, Prof. Dr. C. Strohmann
Technichal University Dortmund, Faculty of Chemistry, Inorganic
Chemistry
Otto-Hahn-Strasse 6, 44221 Dortmund (Germany)
Prof. Dr. A. P. Antonchick
Nottingham Trent University, Department of Chemistry and Foren-
sics
Cifton Lane NG11 8NS Nottingham (UK)
E-mail: andrey.antonchick@ntu.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202108072.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
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Scheme 1. a) Free energy profile illustrating thermodynamically and kinetically controlled reactions. Double ended black arrows represent
reversible reactions. b) Establishment of the enantioselectively catalyzed, double 1,3-dipolar cycloaddition of enones and azomethine ylide derived
from amino acid ester imine 2a.
double bond (Scheme 1b), to a sequence of two subsequent
enantioselectively catalyzed 1,3-dipolar cycloadditions with
azomethine ylides generated in situ from imines.[21–26]
a methyl substituent was introduced at the endocyclic double
bond of the dipolarophile (R = CH3). Monocycloaddition of
cyclic enone and the ylide derived from glycine methyl ester
imine 2a resulted in formation of spirocycle rac-4b in 57%
yield and with good diastereoselectivity (10:1). The product
rac-4a reacts with glycine methyl ester imine 2a to form rac-
3a with high diastereoselectivity (> 20:1) and 75% yield
under the same reaction conditions.
In order to explore the enantioselective synthesis of
tricyclic compound 3a, different chiral ligands, metal cata-
lysts, bases and solvents were investigated (Supplementary
Table 2). Optimization experiments indicated that the best
result could be obtained using AgOAc (6 mol%) as a Lewis
acid in combination with the S,P-ferrocenyl ligand (R)-
Fesulphos, (L1 6.5 mol%) in dichloromethane using cesium
carbonate (Cs2CO3; 40 mol%) as a base at room temperature
after 24 h. Under these conditions, tricyclic compound 3a was
obtained in 81% yield with high diastereoselectivity (d.r.
> 20:1) and excellent enantioselectivity (99% ee; Table 1).
Results and Discussion
To establish the reaction sequence initial screening studies
were conducted with cyclic enone (R = H) and glycine methyl
ester imine 2a in dichloromethane in the presence of base
(Scheme 1b, Supplementary Table 1). We found that the
double 1,3-dipolar cycloaddition can be catalyzed efficiently
with AgOAc to yield cycloadduct rac-3a with 82% yield and
high diastereoselectivity (d.r. > 20:1). The regioselectivity of
the first addition was investigated by treating cyclic enone
(R = H) with 1.1 equiv of imine 2a under the same reaction
conditions which resulted in the regioselective formation of
rac-4a with high diastereoselectivity (> 20:1) in 72% yield
(Scheme 1b). A change in regioselectivity was observed when
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Table 1: Results of the enantioselective synthesis of the chiral compounds 3.[a]
absolute configuration of product
3a was determined by crystal struc-
ture analysis (Supporting Informa-
tion, Crystal Data), which revealed
that product 3a is formed by dou-
ble endo-selective cycloaddition.
The scope of the tandem reac-
tion is wide. Regardless of the
substitution pattern of the aromat-
ic ring, enones 1 react with various
azomethine ylides derived from
imines 2 with moderate to good
yields of 40–81% with high dia-
stereo- (> 20:1) and enantioselec-
tivity (91–99% ee, 3a–3y in Ta-
ble 1). In the presence of electron-
donating substituents such as
methyl- or methoxy groups (3e
and 3g, respectively), the yield
was reduced to 60–63% whereas
electron-neutral or -withdrawing
substituents such as bromine or
fluorine (3a and 3 f) led to higher
yields. Heterocycle-containing azo-
methine ylides reacted to provide
products (3i and 3j) in moderate
yield and with high enantioselec-
tivity (95% ee). In general, the
enantioselectivity of the double
cycloaddition remained consistent
regardless of substitution pattern.
When an enone with a sterically
hindering tert-butyl substituent on
the exocyclic olefin was employed,
the double cycloaddition product
(3v) was obtained in 21% yield,
and high enantioselectivity was still
observed (93% ee). Furthermore,
introduction of a methyl substitu-
ent to the endocyclic double bond
of the enone yielded 3x with two
quaternary centers with high enan-
tioselectivity (93% ee).
Product
R1
R2
R3
R4
Yield [%][b]
ee[c]
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-NO2-C6H4
4-NO2-C6H4
4-MeO-C6H4
4-Me-C6H4
2-naphtyl
3-Br-C6H4
3-Br-C6H4
2-Br-C6H4
3-Br-C6H4
4-Cl-C6H4
tButyl
4-Br-C6H4
3-Br-C6H4
2-Br-C6H4
4-Cl-C6H4
4-MeO-C6H4
4-F-C6H4
4-Me-C6H4
2-naphtyl
3-furyl
2-furyl
4-Br-C6H4
4-F-C6H4
3-Br-C6H4
4-F-C6H4
4-F-C6H4
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
81
72
65
81
60
75
63
66
40
45
21
80
72
65
60
65
81
60
80
55
80
21
75
40
48
99
91
96
98
98
98
93
97
95
95
91
95
91
98
98
95
91
91
95
91
95
93
95
93
94
4-F-C6H4
4-Br-C6H4
2-Br-C6H4
4-Br-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Br-C6H4
4-F-C6H4
3s
3t
3u
3v
3w
3x
3y
3-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
[Fe(h5-C5H5)( h5-C5H4)]
[a] For General Procedure A, see Supplementary Methods. [b] Isolated yields of the pure major
enantiomer after column chromatography. Diastereomeric ratio for all products is >20:1. [c] Deter-
mined by HPLC analysis using a chiral stationary phase. Me, methyl; Ph, phenyl.
Table 2: Results of the enantioselective synthesis of the tandem cycloadditions with two different
imines.[a]
Product
R1
R2
R3
Yield [%][b]
ee[c]
A more hindered a-phenyl sub-
stituted ylide, afforded product 3k
in 21% yield but with high enan-
tioselectivity (91% ee), thereby
inducing formation of three qua-
ternary centers. For all of examples
shown in Table 1, the products
were formed as single diastereo-
mers (d.r. > 20/1) after 24 h.
5a
5b
5c
5d
5e
5 f
5g
5h
5i
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Me-C6H4
4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4
2-naphtyl
4-MeO-C6H4
4-Br-C6H4
2-Br-C6H4
4-MeO-C6H4
4-F-C6H4
77
65
56
75
70
65
56
69
78
72
85
82
84
89
85
90
90
89
90
87
5j
4-Br-C6H4
To rapidly expand the chemical
space accessible via the double
cycloaddition, we explored wheth-
er a sequential multicomponent
transformation could give access
[a] General procedure B can be found in Supplementary Methods. [b] Isolated yields of the pure major
enantiomer after column chromatography. Diastereomer ratio for all products is >20:1. [c] Determined
by HPLC analysis using a chiral stationary phase. Me, methyl; Ph, phenyl.
Notably, this reaction created eight stereocenters including
one quaternary center in a one-pot transformation. The
to cycloadducts formed from two different imines. Following
optimization, a sequence was established in which cyclic
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enones 1 were treated with 1.1 equiv of an iminoester 2 in the
1.1 equiv of iminoester 2a in the presence of 12 mol%
presence of (R)-Fesulphos (L1, 6.5 mol%), AgOAc
(6 mol%) and Cs2CO3 (40 mol%) in dichloromethane for
3 h (Supplementary Methods, procedure B) followed by
treatment with a second, different iminoester 2’ for 24 h.
Based on the different reactivity of the double bonds, the first
cycloaddition occurs with the endocyclic double and the
second cycloaddition targets the exocyclic double bond,
which results in selective formation of mixed double cyclo-
addition products 5 by means of a sequential one-pot, three-
component reaction (5a–5j in Table 2). The mixed double
cycloaddition products 5 were obtained with high diastereo-
selectivity but, unexpectedly, with lower enantioselectivity
(82–91% ee) relative to the two-component double-cyclo-
addition products 3, for which the products were formed with
up to 99% ee.
To explain the findings we hypothesized that both cyclo-
additions, that is, formation of 3 and 4, may be the result of an
enantioselectively catalyzed dynamic covalent process. In this
process the double cycloaddition first proceeds reversibly
through a kinetically controlled pathway due to the lower
energy barrier of the transition state followed by an inter-
conversion to the thermodynamically more stable product by
a fast equilibrium process. To validate this mechanistic
hypothesis changes in enantioselectivity of the double cyclo-
addition were investigated stepwise (Table 3, Table 5). Upon
instead of 6.5 mol%(R)-Fesulphos L1, AgOAc (6 mol%) and
Cs2CO3 (40 mol%) in DCM, leads to formation of mono-
adduct 4a with 90–95% ee after 3 h but with only 80% ee
after 16 h (Table 3, Supporting Information, Experimental
studies).
Cycloaddition product 3a is formed with 99% ee regard-
less of the AgOAc/(R)-Fesulphos ratio. These results indicate
that one enantiomer of monoadduct 4a is involved in
a retrocycloaddition as it matches with the chiral environment
of the Ag/(R)-Fesulphos complex in a selective manner. In
order to confirm that retrocycloaddition is an enantioselective
process, enantioenriched mono adduct 4a (81% ee) was
subjected to reaction with (R)-Fesulphos L1 (12 mol%),
AgOAc (6 mol%) and Cs2CO3 (40 mol%) in DCM and
a decrease of enantiomeric excess for the recovered mono
adduct 4a was observed (74% ee) (Table 4, Supporting
Information, Experimental studies). Furthermore, racemic
mono adduct 4a was treated under identical conditions and
was recovered with À10% ee (Table 4, Scheme 2).
Table 4: Treatment of mono-adduct 4 using chiral catalyst.
Table 3: Results of the time dependent enantioselective synthesis of
chiral mono-adducts (Æ)4.
Entry ee of 4a before reaction t [h] Yield [%] ee[a] of 4a after reaction
1
2
81
0 (rac)
24 94
24 95
74
À10
[a] Determined by HPLC analysis using a chiral stationary phase.
Entry
t [h]
Yield [%]
ee[b]
These results indicate that the mono addition reaction in
the presence of Ag/(R)-Fesulphos is a reversible process in
which the forward cycloaddition is enantioselective whereas
the retrocycloaddition undergoes kinetic resolution. Similarly
investigations with enone 1a and imine 2g further confirmed
a dynamic covalent mono cycloaddition (Supporting Infor-
mation, Experimental studies).
1
2
3
3
59
59
59
58
57
95
87
84
80
70
12
24
16
24
4[a]
5[a]
[a] 12 mol% of (R)-Fesulphos was used. [b] Determined by HPLC
analysis using a chiral stationary phase.
For examination of the second cycloaddition in the
sequence from 4a to 3a enantioenriched mono addition
product 4a (70% ee) was treated with 1 equiv of iminoester
2a under racemic conditions. No change in enantioselectivity
was observed for the double cycloaddition product 3a (70%
ee Table 5, Supporting Information, Experimental studies),
thereby confirming that the stereochemistry is already set in
the first step of the reaction sequence. However, employing
enantioenriched 4a (70% ee) in the presence of a chiral
catalyst led to a decrease in enantioselectivity for the double
cycloaddition product 3a (60% ee, Table 5; Supporting
Information, Experimental studies).
treatment of cyclic enone 1a with 1.1 equiv of iminoester 2a
in the presence of (R)-Fesulphos L1 (6.5 mol%), AgOAc
(6 mol%) and Cs2CO3 (40 mol%) in DCM, monoadduct 4a
can be formed with varying enantioselectivity in the range of
70–95% ee (Table 3, Supporting Information, Experimental
studies). The lower and varying enantioselectivity for for-
mation of monoadduct 4a in comparison to double cyclo-
addition product 3a (99% ee, Table 1) indicates that, indeed,
enantioselective retro-cycloaddition catalyzed by the Ag/(R)-
Fesulphos complex may occur, which changes the enantio-
meric ratio during the reaction. The decrease in enantiose-
lectivity for formation of monoadduct 4a is even more
obvious when the ratio of AgOAc and (R)-Fesulphos is
changed (Table 3). Treatment of cyclic enone 1a with
Furthermore, when racemic mono addition product rac-
4a was subjected to the cycloaddition in the presence of (R)-
FeSulphos and AgOAc with 1 equiv of iminoester 2a, double
cycloaddition product 3a was obtained as an opposite
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Scheme 2. Establishment of stereodivergent synthesis in the enantioselectively catalyzed, double 1,3-dipolar cycloaddition.
((À)3a and (+)6a) decreases to 13% and À13% ee,
respectively. Furthermore, the product ratio changes through-
out the course of the reaction with more endo, endo-product
3a being formed over time while the yield of the endo, exo-
product 6a decreases over time (Supporting Information,
Experimental studies, Supplementary Table 3). A similar
trend was observed by performing the kinetic experiment
by subjecting racemic mono adduct rac-4a to cycloaddition
with iminoester 2g under chiral conditions (Supporting
Information, Experimental studies, Supplementary Table 4).
Since rac-4a is converted into two stereoisomers (À)3a
and (+)6a with varying ratios and eeꢀs over time, it implies the
formation of kinetically and thermodynamically controlled
products during an enantioselective dynamic covalent process
resulting in interconversion of those stereoisomers. (Sche-
me 3a, Supporting Information Figure 1). The endo, exo-
stereoisomer (+)6a is the kinetically favored product and is
formed faster than the thermodynamically more stable
product (À)3a.
Table 5: Catalytic 1,3-dipolar cycloaddition of enantioenriched/racemic
mono-adduct 4.
Entry
Ligand
ee of 4a
Yield [%]
ee[a] of 3a
1
2
3
(R)-Fesulphos
PPh3
(R)-Fesulphos
70
70
0 (rac)
71
75
72
60
70
À20
[a] Determined by HPLC analysis using a chiral stationary phase.
enantiomer (À)3a with 20% ee (Table 5, Scheme 2) and was
confirmed by crystal structure analysis (Supporting Informa-
tion, Experimental studies, Crystal Data). The decreased
enantioselectivity observed for 3a employing a chiral catalyst
may be due the enantioselective retrocycloaddition of 4a as
discussed above (Table 5).
To explain the decrease in enantioselectivity and the
change in product ratio over time, in accordance to the
observation in Scheme 2, we investigated the stability of
(+)6a. Compound (+)6a (37% ee) was subjected to AgOAc
(6 mol%), (R)-Fesulphos (6.5 mol%) and Cs2CO3
(40 mol%) and was partially converted to the more stable
and thermodynamically favored endo, endo-product (+)3a
with 59% ee (37% yield) while (+)6a was recovered with
a lower ee of 20% (51% yield) (Scheme 3a, Supporting
Information, Experimental studies). This result provides
further evidence that (+)6a is labile under the reaction
conditions and that the change of enantioselectivity is due to
an enantioselective dynamic process in which the main
enantiomer of the kinetically favored product ((+)6a) is
converted to the minor enantiomer ((+)3a) of the thermo-
dynamically stable product (Scheme 3a/b). Furthermore,
highly enantiopure endo, exo-product (+)6a (95% ee) was
treated under identical conditions and was converted to the
stable thermodynamically favored endo, endo-product (+)3a
(95% ee, 92% yield) with retention of enantioselectivity
(Scheme 3a).
To further elucidate the reaction pathway, we performed
a kinetic experiment by reacting rac-4a with imine 2a
employing chiral catalyst (Supporting Information, Experi-
mental studies, Supplementary Table 3). In the early stages of
the reaction, 4a is rapidly converted into the endo, endo-
product (À)3a and an endo, exo-diastereomer (+)6a (Sche-
me 3a, Supporting Information, Experimental studies, Sup-
plementary Table 3). X-Ray analysis of the stereoisomeric
endo, exo-product (+)6a revealed that it is formed through an
exo-selective cycloaddition of iminoester 2a to the endo
monoaddition product (+)4a (Supporting Information, Crys-
tal Data). After three minutes, (À)3a and (+)6a are formed
with noticeable ee (40% and 37% ee, respectively) (Support-
ing Information, Experimental studies, Supplementary Ta-
ble 3). Over the course of the reaction, the ee of both products
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Scheme 3. a) Establishment of the stereodivergent catalyzed, double 1,3-dipolar cycloaddition of enone 1a and selected azomethine ylides and
control of enantioselectivity. b) Proposed mechanism and intermediates for the AgOAc/(R)-Fesulphos mediated retrocycloaddition and
interconversion.
To clarify through which intermediate the stereoisomeric
endo, exo-product (+)6a is converted to product (+)3a,
compound (+)6a (37% ee) was treated with iminoester 2g
(2 equiv) in the presence of AgOAc (6 mol%), (R)-Fesulphos
(6.5 mol%) and Cs2CO3 (40 mol%) in DCM. An imine
exchange reaction was observed on the spirocycle affording
product 5k in moderate yield (65%) and 33% ee (Scheme 3a,
Supporting Information, Experimental studies). The imine
exchange on the spirocycle indicates that the transformation
of endo, exo-product (+)6a to 5k proceeds through mono-
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Table 6: Results of the enantioselective synthesis of the chiral endo-exo
adducts 6.[a]
addition product (+)4a as an intermediate. Therefore, the
thermodynamically less stable endo, exo-product 6a is con-
verted to mono addition product 4a through a retro cyclo-
addition followed by an endo-selective cycloaddition with
iminoester 2g to regenerate the spirocycle (Scheme 3a,
Supporting Information, Experimental studies). A chiral
(Ag-/(R)-Fesulphos) mediated dynamic covalent process is
occurring in which covalent bonds are cleaved through a retro
cycloaddition and reformed again by cycloaddition.
Product
R1
R2
Yield [%][b]
ee[c]
d.r.
6a
6b
6c
6d
4-Br-C6H4
4-Br-C6-H4
4-Br-C6H4
4-Br-C6H4
4-Br-C6H4
4-MeO-C6H4
4-F-C6H4
2-furyl
65
60
51
49
95
93
97
95
4:1
7:1
4:1
7:1
We also investigated whether endo, endo-product 3a can
be converted to its stereoisomer endo, exo-product 6a.
Racemic endo, endo 3a was treated with AgOAc (6 mol%),
(R)-Fesulphos (6.5 mol%) and Cs2CO3 (40 mol%) with and
without iminoester 2a. Compound 3a was not converted to
product 6a which confirms the stability of endo, endo-product
3a compared to its stereoisomeric endo, exo-analog 6a under
the reaction conditions (Supporting Information, Experimen-
tal studies).
These findings suggest that the double cycloaddition of
enone 1 with imine 2 is in general a dynamic covalent process
which can be divided in two cycles (Supporting Information,
Figure 2). First, a Ag-/(R)-Fesulphos-catalyzed mono addi-
tion occurs to generate the chiral mono addition product 4 in
which the chirality is set. The initial enantiopurity of the mono
addition is > 95% ee.
Over time, a selective retro-cycloaddition for the major
enantiomer of mono adduct 4 is catalyzed by Ag-/(R)-
Fesulphos which induces its decomposition and results in
a decreased ee of monoaddition product 4 from > 95% ee to
70–80% ee (Table 3, Supporting Information, Figure 2). The
main enantiomer of mono adduct 4 matches with the chiral
environment of the Ag-/(R)-Fesulphos complex as its decom-
position is faster compared to its enantiomer, resulting in
decrease of ee for mono adduct. In a second cycle starting
from the enantioenriched mono addition product 4, a second
cycloaddition takes place to generate a double cycloaddition
product. Here, two diastereomers are formed, the kinetically
favored non-stable endo, exo product 6 and the thermody-
namically controlled stable endo, endo product 3 (Sche-
me 3a). Through a dynamic covalent process, enantioselec-
tive retro-cycloaddition of non-stable kinetic product endo,
exo-6a occurs generating mono addition product 4, which is
then converted to the thermodynamically favored and stable
endo, endo product 3 (Scheme 3b, Supporting Information,
Figure 2).
6e
4-Br-C6H4
48
95
7:1
6 f
6g
4-Br-C6H4
4-Br-C6H4
3-Me-C6H4
3-furyl
46
52
89
95
3:1
6:1
[a] For General Procedure A, see Supplementary Methods. [b] Isolated
yields of the pure major enantiomer after column chromatography.
[c] Determined by HPLC analysis using a chiral stationary phase. Me,
methyl; Ph, phenyl.
6a to 3a is much slower in the aqueous solvent system relative
to DCM. The interconversion of the less stable kinetically
favored endo, exo product 6 to the thermodynamically
controlled product 3 might be a slow equilibrium process
which results in the kinetically controlled endo, exo product as
major diastereomer in THF:H2O (Scheme 4). Thus the speed
of isomerization of the stereoisomers is decreased. In DCM
the interconversion to reach the thermodynamically con-
trolled equilibrium may proceed faster, since the retro
cycloaddition from kinetically favored endo, exo product 6
to mono adduct 4 is more accelerated (Scheme 4). This was
confirmed by analysis of the interconversion of the non-stable
kinetic product endo, exo-6a to its thermodynamically more
stable endo, endo product 3a in both solvent systems.
Subjecting Compound (+)6a (95% ee) to AgOAc
(6 mol%), (R)-Fesulphos (6.5 mol%) and Cs2CO3
(40 mol%) in DCM afforded (+)3a with 37% yield after
1 h, while only traces were observed in aqueous conditions
after 1 h (Table 7). Expansion of the substrate scope con-
firmed the diastereoselectivity trend favoring 6 over its
thermodynamically more stable stereoisomer 3 when an
aqueous solvent system (THF:H2O) was employed (Table 6).
Finially we investigated whether changes in reaction
conditions would enable a selective synthesis of kinetic Conclusion
diastereomer 6. To this end, a solvent screen revealed that
in the aqueous system THF:H2O (4:1) a switch in diaster-
eoselctivity occurs. Treatment of enone 1a with 2.2 equiv of
iminoester 2a in the presence of (R)-Fesulphos L1
(6.5 mol%) AgOAc (6 mol%) and Cs2CO3 (40 mol%) in
this aqueous solvent system yields the endo, exo-product 6a
(95% ee, 60% yield) as the main diastereomer relative to
endo, endo product (+)3a (d.r. 4:1) (Table 6).
In contrast, in DCM the endo, endo-product 3a is
selectively obtained. The inversion in diastereoselectivity
may be due to a more favorable exo-selective transition state
in the aqueous environment. Alternatively interconversion of
In summary, we have discovered an enantioselectively
catalyzed dynamic covalent one-pot-tandem cycloaddition of
azomethine ylides to a’-alkylidene-2-cyclopentenones. High
diastereo- and enantioselectivity was obtained for the for-
mation of the double cycloaddition products in a thermody-
namically controlled equilibrium process. A stereodivergent
synthesis was achieved since a switch in diastereoselectivity is
observed in aqueous solvent system (THF:H2O) and an
enantiodivergent selectivity is recorded for reactions starting
from racemic intermediate. Owing to differences in the
reactivity of the endo- and exocyclic double bonds of the a’-
&&&&
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Research Articles
Chemie
Scheme 4. Proposed intermediates and transition states for formation of kinetically and thermodynamically favoured products 3 and 6 and
differences in DCM and THF:H2O.
alkylidene-2-cyclopentenones, two different dipoles could be
successfully used in a one-pot process, yielding structurally
complex molecular frameworks with up to 8 stereocenters.
Table 7: Results of the time dependent enantioselective interconversion
of enantioenriched endo, exo (Æ)6a to endo, endo (Æ)3a.
Acknowledgements
Research at the Max Planck Institute of Molecular Physiology
was supported by the Max Planck Society. Open access
funding enabled and organized by Projekt DEAL.
Conflict of Interest
Entry
t [h]
Solvent
Yield [%]
ee[a]
The authors declare no conflict of interest.
1
2
3
4
0.5
1
0.5
1
DCM
DCM
THF:H2O
THF:H2O
13
37
95
95
n.d.
n.d.
Keywords: asymmetric synthesis ·
no conversion
traces
diastereodivergent synthesis · dynamic covalent chemistry ·
enantiodivergent synthesis · pseudo-natural products ·
reversible cycloaddition
[a] Determined by HPLC analysis using a chiral stationary phase.
n.d.=not detected.
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Accepted manuscript online: July 8, 2021
Version of record online: && &&
,
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Angew. Chem. Int. Ed. 2021, 60, 2 – 11
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Angewandte
Research Articles
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Research Articles
Asymmetric Synthesis
A highly enantioselectively catalyzed
dynamic covalent one-pot-tandem 1,3-
dipolar cycloaddition of azomethine
ylides to a’-alkylidene-2-cyclopentenones
is described. Time-dependend enantio-
and diastereodivergent synthesis was
achieved by using the same set of
reagents. A reversible cycloaddition of the
kinetically favored product enables the
interconversion to its more stable ther-
modynamically favored product through
a chiral complex-mediated process.
O. Yildirim, M. Grigalunas, L. Brieger,
C. Strohmann, A. P. Antonchick,*
H. Waldmann*
&&&& — &&&&
Dynamic Catalytic Highly
Enantioselective 1,3-Dipolar
Cycloadditions
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&&&&
These are not the final page numbers!