Directing the Activation of Donor–Acceptor Cyclopropanes Towards Stereoselective 1,3-Dipolar Cycloaddition Reactions by Br?nsted Base Catalysis

Article abstract of DOI:10.1002/anie.201706150

The first stereoselective organocatalyzed [3+2] cycloaddition reaction of donor-acceptor cyclopropanes is presented. It is demonstrated that by applying an optically active bifunctional Br?nsted base catalyst, racemic di-cyano cyclopropylketones can be activated to undergo a stereoselective 1,3-dipolar reaction with mono- and polysubstituted nitroolefins. The reaction affords functionalized cyclopentanes with three consecutive stereocenters in high yield and stereoselectivity. Based on the stereochemical outcome, a mechanism in which the organocatalyst activates both the donor-acceptor cyclopropane and nitroolefin is proposed. Finally, chemoselective transformations of the cycloaddition products are demonstrated.

Full text of DOI:10.1002/anie.201706150

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Accepted Article
Title: Directing the Activation of Donor-Acceptor Cyclopropanes To-
wards Stereoselective 1,3-Dipolar Cycloaddition Reactions by
Brønsted Base Catalysis
Authors: Karl Anker Jørgensen, Jakob Blom, Andreu Vidal-Albalat,
Julie Jørgensen, Casper L. Barløse, Kamilla S. Jessen, and
Marc V. Iversen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706150
Angew. Chem. 10.1002/ange.201706150
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10.1002/anie.201706150
Angewandte Chemie International Edition
COMMUNICATION
Directing the Activation of Donor-Acceptor Cyclopropanes To-
wards Stereoselective 1,3-Dipolar Cycloaddition Reactions by
Brønsted Base Catalysis
Jakob Blom, Andreu Vidal-Albalat, Julie Jørgensen, Casper L. Barløse, Kamilla S. Jessen, Marc V.
Iversen and Karl Anker Jørgensen*
Abstract: The first organocatalyzed stereoselective [3+2] cycloaddi-
tion reaction of donor-acceptor cyclopropanes is presented. It is
demonstrated that applying an optically active bifunctional Brønsted
base catalyst, racemic bis-cyano cyclopropylketones can be activated
to undergo a stereoselective 1,3-dipolar reaction with mono- and pol-
ysubstituted nitroolefins. The reaction affords functionalized cyclopen-
tanes with three consecutive stereocenters in high yield and stereose-
lectivity. Based on the stereochemical outcome a mechanism in which
the organocatalyst activates both the donor-acceptor cyclopropane
and nitroolefin is proposed. Finally, chemoselective transformations
of the cycloaddition products are demonstrated.
This was followed by activation of cyclopropylacetaldehydes us-
ing aminocatalysis leading to two different reactions depending
on the reagents (Scheme 1B). The reaction with an activated ole-
fin provides a [2+2] cycloadduct via a dienamine intermediate,[6]
while 2-aminobenzaldehydes give nucleophilic addition to an
iminium-ion intermediate, causing an iminium-enamine-cascade
reaction.[7] According to the best of our knowledge, only two other
enantioselective organocatalytic reactions have been presented.
One is a NHC-catalyzed activation of a formyl substituted accep-
tor cyclopropane, trapping the ring-opening of the in situ formed
D-A cyclopropane in an hetero [4+2] cycloaddition reaction,[8]
while the other is an enantioselective synthesis of 1,3-dichlorides
by an electrophilic activation of formyl substituted meso-cyclopro-
panes.[9]
Cyclopropanes are important organic molecules that display in-
teresting properties in various fields of chemistry. An attractive
feature of cyclopropanes is their diverse reactivity towards differ-
ent reaction types, which has resulted in their use in contemporary
organiccy synthesis.[1] The outcome of these reactions is depend-
ent on the substituent pattern of the cyclopropanes and the acti-
vation mode.[2]
Although cyclopropanes are thermodynamically unstable,
ring-opening and rearrangement reactions of unactivated cyclo-
propanes require high activation energy and therefore they be-
have as kinetically stable molecules with limited use as reactants
in organic synthesis.[1a] To overcome this limitation, various acti-
vation strategies have been developed to release the synthetic
potential of cyclopropanes.[2] The introduction of vicinal donor and
acceptor substituents attached to the cyclopropyl ring, termed do-
nor-acceptor (D-A) cyclopropanes, promoted the synthetic appli-
cation of cyclopropanes.[3]
In recent years the major focus on D-A cyclopropanes has
been devoted to stereoselective reactions.[3h] The dipolar nature
of D-A cyclopropanes allows for both electrophilic and nucleo-
philic activation. Lewis acid catalysis can promote the activation
of D-A cyclopropanes, leading to an increased electrophilic char-
acter of the system which has resulted in e.g. ring-opening-, ad-
dition- and cycloaddition reactions.[2e-f,3h,4] In contrast to the elec-
trophilic activation of D-A cyclopropanes, nucleophilic activation
strategies are less common and only little progress has been
achieved since the initial work by Reissing[3a-f] and Wenkert.[3g]
The application of organocatalysis has recently led to innova-
tive examples of nucleophilic activation strategies, which has al-
lowed for further development of enantioselective systems. The
first enantioselective organocatalytic reaction was a ring-opening
rearrangement of a meso-cyclopropane cyclopentanone applying
a bifunctional quinine-based thiourea catalyst (Scheme 1A).[5]
Scheme 1. Selected examples of enantioselective organocatalytic reactions of
D-A cyclopropanes through a nucleophillic activation strategy.
The [2+2] cycloaddition in Scheme 1B proceeds via a 1,2-di-
pole generated at the non-activated carbon-carbon bond in the
cyclopropane moiety and previous organocatalytic attempts to de-
velop enantioselective [3+2] cycloadditions across the D-A-acti-
vated bond in cyclopropanes has not been achieved.[10] We envi-
sioned that the challenge to develop organocatalytic [3+2] cy-
cloaddition reactions with D-A cyclopropanes might be due to a
mis-match of the activation mode with the D-A cyclopropanes
chosen. In the present work, we will demonstrate that this chal-
lenging reactivity can be achieved by the application of an opti-
cally active Brønsted base and bis-cyano-substituted D-A cyclo-
propylketones (Scheme 1C).
[a]
J. Blom, Dr. A. Vidal-Albalat, J. Jørgensen, C. L. Barløse, K. S.
Jessen, M. V. Iversen and Prof., Dr. K. A. Jørgensen
Department of Chemistry, Aarhus University
Langelandsgade, DK-8000 Aarhus C, Denmark
E-mail: kaj@chem.au.dk
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201706150
Angewandte Chemie International Edition
COMMUNICATION
Reaction design: Inspired by the enamine induced activation of
the cyclopropylacetaldehyde (Scheme 2A) which provided the
[2+2] cycloadduct in Scheme 1B, we questioned if it was possible
to facilitate a novel activation mode of the cyclopropylacetalde-
hyde that promotes the 1,3-dipole, rather than the 1,2-dipole pre-
viously observed. The strategy chosen is based on a Brønsted
base activation of bis-cyano substituted cyclopropylketones
(Scheme 2B). The reason for choosing this less common sub-
strate is that bis-ester cyclopropylacetaldehyde (Scheme 2A) has
previously shown limitations towards activation when applying a
tertiary amine as the Brønsted-base catalyst[6,11] and so far has
only reacted as the 1,2-dipole (vide supra). It was hypothesized
that the bis-cyano cyclopropyl analogue would present the de-
sired complementary reactivity. One of the reasons for the differ-
ences in reactivity between the bis-ester- and bis-cyano cyclopro-
pane is readable from the 13C NMR shift of the disubstituted car-
bon atom in the cyclopropyl ring. The chemical shift of the bis-
ester carbon is shifted approximately 30 ppm down-field com-
pared to that of the bis-ester analogue (see Supporting Infor-
mation).[12] Thus, in the bis-cyano system, this carbon atom pos-
sesses a higher electron density, indicating an increased polari-
zation of the labile carbon-carbon bond which promotes the 1,3-
dipolar character of the system (Scheme 2C). Furthermore, the
anion formed from ring-opening of the bis-cyano cyclopropane
should be more stabilized than the corresponding bis-ester anion
according to the pKa-values of the related acids (pKa (DMSO)
different families of optically active Brønsted bases were tested
as catalysts (see Supporting Information).
Table 1. Catalyst optimization towards the enantioselective [3+2] cycloaddition
reaction of cyclopropyl methylketone 1a with trans-β-nitrostyrene 2a.
Entry
Cat.
Reaction
times
30 h
dr[b]
ee[c]
(%)
62
51
65
69
66
71
79
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
4g
4h
4i
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
n.d.
11 d[d]
8 d
MeCH(CN)2: 12.5,[13a] pKa (DMSO) MeCH(CO2Me)2: 18.0[13b]
(Scheme 2C).
)
30 h
13 d[f]
5 d[e]
30 h
10 d[d,g]
n.r.
43
n.d.
79
4j
40 h
>20:1
[a] All reactions were performed with 0.05 mmol of 1a, 0.06 mmol of 2a, and
20 mol% 4 in 0.50 mL of CH2Cl2 at -25 °C. n.r. = no reactivity; n.d.= not
determined. [b] Determined from 1H NMR of the crude mixture. [c] Determined
by chiral stationary phase UPC2. [d] At room temperature instead of -25 °C.
[e] 50% conv. [f] 70% conv. [g] 15% conv.
The commercially available bifunctional Takemoto catalyst[15]
4a gave the most promising enantioselectivity (52% ee in CH2Cl2
at room temperature) of the initially tested bases. Lowering the
reaction temperature to -25 °C increased the enantioselectivity to
62% ee (Table 1, entry 1). However, further attempts using 4a
under various reaction conditions did not improve the enantiose-
lectivity (see Supporting Information). Inspired by the bifunctional
character of 4a, a library of bases based on this scaffold was pre-
pared. We first addressed our attention to the tertiary amine moi-
ety of the catalyst. Exchanging the N,N-dimethyl with N,N-dipropyl
(4b) resulted in a significant decrease in both the catalyst reactiv-
ity and enantioselectivity (Table 1, entry 2). Likewise, implement-
ing a N-pipiridyl group as the Brønsted base (4c) also led to a less
active catalyst, but with a slight increase on the enantioselectivity
(Table 1, entry 3). Decreasing the ring size to a N-pyrrolidinyl
group (4d) recovered the reactivity of the catalyst and gave an
improvement of the enantioselectivity compared to 4a (Table 1,
entry 4). Next, we centered our efforts towards the H-bond donor
moiety in the catalyst by varying the substitution pattern in the ar-
omatic ring. A catalyst with a non-substituted phenyl group (4e)
was prepared and tested for the model reaction. Unfortunately,
despite showing similar results in terms of enantioselectivity, a
drastic drop in reactivity was observed (Table 1, entry 5). Intro-
ducing a Cl-substituent in the para-position (4f) led to a minor in-
crease in the enantioselectivity, however, the catalyst still suffered
from low reactivity (Table 1, entry 6). We assumed that an in-
crease in the electron-withdrawing ability of the substituents
Scheme 2. Comparison of previous nucleophilic activation strategy and this
work.
The stereoselective synthesis of multiple functionalized car-
bocyclic compounds from 1,3-dipole synthons represents an at-
tractive, but challenging synthetic transformation.[14] In this paper,
we present the first diastereo- and enantioselective Brønsted
base promoted activation of cyclopropylketones, trapping the
generated 1,3-dipole in a [3+2] cycloaddition reaction with ni-
troolefins (Scheme 1C). The strategy is based on a dynamic res-
olution of racemic D-A cyclopropanes to give highly functionalized
cyclopentanes with three stereocenters. Optically active polysub-
stituted cyclopentanes are common motifs in a wide variety of nat-
ural products and bioactive compounds.[14] A varied substituent
pattern gives a useful handle to which chemoselective transfor-
mations can be performed to further increase the complexity and
the synthetic value of the formed cyclopentane products.
The desired [3+2] cycloaddition reaction of racemic cyclo-
propylmethylketone 1a with trans-β-nitrostyrene 2a to give cy-
cloadduct 3a proceeds in the presence of a catalytic amount of
Et3N, while the corresponding bis-ester analogue showed no re-
activity under the same conditions (see Supporting Information).
Satisfyingly, cycloadduct 3a was formed in 80% yield and as one
single diastereoisomer. In the absent of the base, no product for-
mation was observed. Encouraged by these results, a number of
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10.1002/anie.201706150
Angewandte Chemie International Edition
COMMUNICATION
would be correlated with an increase in reactivity and indeed, in-
Encouraged by the tolerance towards the different D-A cyclo-
stalling a NO2-substituent in the para-position gave a catalyst (4g), propylketones, the generality of the system was probed on a
which provided full consumption of 1a within 30 h and gave an
enantioselectivity of 79% ee (Table 1, entry 7). Changing the po-
sition of the NO2-substituent to an ortho-position (4h) severely de-
creased the reactivity and caused lower enantioselectivity (Table
1, entry 8). It is hypothesized that the bulk of the ortho-substituent
forces the aromatic moiety to position itself out of the plane of the
thiourea and that this may cause weaker coordination between
substrate and catalyst. The para-NO2-substituted benzylic ana-
logue (4i) was inactive (Table 1, entry 9). Finally, substituting the
thiourea moiety of catalyst 4g with the less donating urea (4j)
gave similar reactivity and enantioselectivity (Table 1, entries 7,
10). As bifunctional thiourea catalysts have been shown to suffer
less from aggregation than their urea counterparts,[16] further op-
timization was based on the para NO2-substituted thiourea cata-
lyst (4g).
scope of different nitroolefins 2 (Table 3). Electron-rich trans-β-
nitrostyrenes was found to give similar results as nitroolefin 2a, in
the reaction with 1a (Table 3, 3j,k). Disubstituted nitroolefins al-
lowed not only for the formation of a quaternary stereocenter, but
also for the use of electron-poor trans-β-nitrostyrenes, while main-
taining the high yields and enantioselectivity (Table 3, 3l-n). Ali-
phatic nitroolefins also underwent a smooth reaction with the D-A
cyclopropanes and the cycloadducts were isolated in very high
yields (up to 98%) without observing a drop in enantioselectivity
(Table 3, 3o-q). The reaction of 1a with nitroolefin oxetane 2r
gave the spirocyclic cycloadduct 3r, indicating that trisubstituted
nitroolefins are tolerated as well. Finally, 1-nitrocyclohexene was
tested in the reaction with the D-A cyclopropylketones 1e-i. To our
satisfaction, the more synthetically complex bicyclic products
were isolated in high yield and high optical purity (up to 90% ee)
(Table 3, 3s-w).
Table 2. Reaction scope of the Brønsted base catalyzed [3+2] cycloaddition
reaction of cyclopropylketones 1 with trans-β-nitrostyrene 2a.
Table 3. Scope of the Brønsted base catalyzed [3+2] cycloaddition reaction with
different nitroolefins 2.
[a]
All reactions were performed with 0.20 mmol of 1, 0.30 mmol of 2a, and 20
mol% 4g in 2.0 mL of CH2Cl2 at -25 °C; results in brackets: after recrystallization
from toluene. [b] Determined from 1H NMR of the isolated products. [c] Determined
by chiral stationary phase UPC2. [d] 71 h. [e] 70 h at 5 °C. [f] 0.30 mmol of 1d and
0.20 mmol of 2a, 4 d at room temperature.
[a]
All reactions were performed with 0.20 mmol of 1, 0.30 mmol of 2, and 20
mol% catalyst in 2.0 mL of CH2Cl2 at -25 °C. [b] Determined from 1H NMR of the
isolated products. [c] Determined by chiral stationary phase UPC2. [d] 0.10 mmol
of 1, 0.15 mmol of 2, and 20 mol% 4g in 1.0 mL of CH2Cl2 at -25 °C.
Based on the results obtained with catalyst 4g, further optimi-
zation focused on the yield of the reaction and led to a minor
change in reaction conditions before the final conditions were ob-
tained (see Supporting Information). The scope of the reaction
conditions was investigated on cyclopropylketones 1a-i (Table 2).
We were pleased to find that the [3+2] cycloadducts, 3a-i were
obtained in good yields, high enantio- and diastereoselectivities.
The system tolerates both aliphatic and aromatic substituents,
though it was observed that increasing the steric hindrance of the
ketone substituent led to a less reactive reactant (Table 2, entries
3a-d). We were pleased to observe, that both electron-poor and
electron-rich aromatic substituents gave similar results and did
not cause limitations in the system (Table 2, entries 3e-i). The
enantiomeric excess of the cycloadducts can be improved to give
highly enantioenriched products as shown for 3a,b,e,i by recrys-
tallization from toluene.
The experimental results and stereochemical outcome of the
reaction promoted us to propose the mechanistic pathway out-
lined in Scheme 3. Initially, the catalyst acts as a Brønsted base
and deprotonates the cyclopropylketone providing the reactive D-
A cyclopropane. This acid-base reaction generates the proto-
nated organocatalyst, which now has three hydrogen-bond do-
nors which can interact with the generated enolate and the two
cyano groups as shown in Scheme 3 I. We expect that the energy
differences between the possible hydrogen bonding interactions
are low and therefore open up for a high degree of mobility in the
coordination sphere of the catalyst.[17] This allows the approach of
the nitroolefin to the substrate-catalyst complex I from the less
hindered face to form intermediate II. Now the nitroolefin is acti-
vated and in proximity of the nucleophilic carbon of the D-A cyclo-
propane which promotes the addition to the -position of the ni-
troolefin giving intermediate III. The final bond formation takes
place by the nitronate attacking the cyclopropyl moiety, now act-
ing as the acceptor, affording the product-catalyst complex IV.
The absolute configuration of the products 3, was determined
on the basis of the X-ray crystal structure of the cycloadduct 3i.
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10.1002/anie.201706150
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COMMUNICATION
[3]
For initial work on D-A cyclopropanes, see: a) H.-U. Reissig, E. Hirsch,
Angew. Chem. Int. Ed. Engl. 1980, 19, 813-814. b) H.-U. Reissig, E.
Hirsch, Angew. Chem. Int. Ed. Engl. 1980, 19, 813-814. c) H.-U. Reissig,
Tetrahedron Lett. 1981, 22, 2981-2984. d) E. L. Grimm, H.-U. Reissig, J.
Org. Chem. 1985, 50, 242-244. e) C. Brückner, H.-U. Reissig, Angew.
Chem. Int. Ed. Engl. 1985, 24, 588-589. f) C. Brückner, H.-U. Reissig, J.
Org. Chem. 1988, 53, 2440-2450. g) E. Wenkert, Acc. Chem. Res. 1980,
13, 27-31. For a recent review see: h) T. F. Schneider, J. Kaschel, D. B.
Werz, Angew. Chem. Int. Ed. 2014, 53, 5504-5523.
Scheme 3. Proposed mechanistic pathway.
To further expand the synthetic value of the presented meth-
odology, chemoselective transformations of the cycloadducts
have been performed. It was found that a Cu(II) catalyzed stere-
oselective monohydrolysis of one of the two geminal cyano-sub-
stituents was possible (Scheme 4). This allows for the formation
of amide 5 with an additional quaternary stereocenter formed in
86% yield as a single diastereomer. The relative configuration of
the newly formed stereocenter was determined by X-ray analysis
(see Supporting Information). Furthermore, we achieved a
chemoselective reduction of the nitro group with Cl3SiH/DIPEA as
reducing agent, followed by an intramolecular condensation af-
fording the bicyclic imine 6 in 75% yield.
[4]
For organocatalytic example of electrophillic activation of 1,3-dipole, see:
(a) L- Li, Z. Li, Q. Wang, Synlett. 2009, 11, 1830-1834. For example of
photocatalytic intramolecular ring expansion, see b) J. L.-Barrera, V. L.-
Martín, T. Rigotti, F. Peccati, X. S.-Monfort, M. Sodupe, R. M.-Ballesté,
M. Liras, J. Alemán, Angew. Chem. Int. Ed. 2017, 56, 7826-7830.
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K. A. Jørgensen, J. Am. Chem. Soc. 2015, 137, 1685-1691.
E. S.-Díez, D. L. Vesga, E. Reyes, U. Uria, L. Carrillo, J. L. Vicario, Org.
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3122-3123. b) H. Xu, J.-P. Qu, S. Liao, H. Xiong, Y. Tang, Angew. Chem.
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Scheme 4. Chemoselective transformations of the cycloadducts.
[11] Similar limitations was observed with a formyl substituted bis-ester cy-
clopropane: H. Xie, L. Zu, H. Li, J. Wang, W. Wang, J. Am. Chem. Soc.
2007, 129, 10886-10894.
In conclusion, we have presented a new organocatalytic nu-
cleophilic activation mode for D-A cyclopropanes resulting in an
unprecedented [3+2] cycloaddition which proceeds in high yield
and stereoselectivity. An optically active Brønsted base catalyst
promoted the desired 1,3-dipolar reactivity of a series of cyclo-
propylketones with nitroolefins to give substituted cyclopentanes
with three contiguous stereocenters in enantioselectivities up to
91% ee. It has been demonstrated that the enantiomeric excess
can be increased by recrystallization to >99% ee. In addition, we
have also presented a proposal for a mechanistic pathway that
explains the observed stereoselectivity. Finally, we have shown
that the optically active cyclopentanes can undergo chemoselec-
tive transformations, e.g. a stereoselective reduction of a cyano
group to form the corresponding amide and reduction of the nitro
group to generate a bicyclic imine.
[12] The chemical shift of the bis-ester cyclopropylketone is expected to be
similar to that of the bis-ester cyclopropylacetaldehyde.[6]
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Acknowledgements
Dr. Kim. S. Halskov is acknowledged for his guidiance in the initial
part of this project. Line D. Næsborg and Dr. Jeremy Erickson are
thanked for peforming the X-ray analysis. Thanks are expressed
to the Carlsberg Semper Ardens and Aarhus University for finan-
cial support.
Keywords: Asymmetric organocatalysis • Brønsted base cataly-
sis • donor-acceptor cyclopropanes • enantioselective [3+2] cy-
cloaddition reaction • enantiodiscriminating 1,3-dipoles.
[1]
For general review regarding the bonding properties and their chemical
consequences, see: a) A. De Meijere, Angew. Chem. Int. Ed. 1979, 18,
809-826. For overview of reactions with unactivated cyclopropanes see:
b) R. Verhé, N. De Kimpe in The Chemistry of The Cyclopropyl Group,
Vol. 1 (Ed.: Z. Rappoport), John Wiley & Sons, 1987, pp. 445-564.
For initial work on electrophilic cyclopropanes, see: a) S. Danishefsky, G.
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[2]
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10.1002/anie.201706150
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Jakob Blom, Andreu Vidal-Albalat, Julie
Jørgensen, Casper L. Barløse, Kamilla
S. Jessen, Marc V. Iversen and Karl
Anker Jørgensen*
Page No. – Page No.
Directing the Activation of Donor-Ac-
ceptor Cyclopropanes Towards Stere-
oselective 1,3-Dipolar Cycloaddition
Reactions by Brønsted Base Cataly-
sis
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