Organocatalytic enamine-activation of cyclopropanes for highly stereoselective formation of cyclobutanes

Article abstract of DOI:10.1021/ja512573q

A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a design in which a reactive donor-acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropylacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is investigated by the application of a combined computational and experimental approach. The activation can be traced to a favorable orbital interaction between the π-orbital of the enamine and the σ_C-C orbital of the cyclopropyl ring. Furthermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation of cyclobutanes, functionalizing at the usually inert sites of the donor-acceptor cyclopropane. By the application of 3-olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzofuranone can be obtained in good yields, high diastereomeric ratios, and excellent enantiomeric excesses. The mechanism of the reaction is discussed and two mechanistic proposals are presented.

Full text of DOI:10.1021/ja512573q

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Article
An Organocatalytic Enamine-Activation of Cyclopropanes
for Highly Stereoselective Formation of Cyclobutanes
Kim Søholm Halskov, Florian Kniep, Vibeke Henriette Lauridsen, Eva
Høgh Iversen, Bjarke Skyum Donslund, and Karl Anker Jørgensen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja512573q • Publication Date (Web): 09 Jan 2015
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Kim Søholm Halskov, Florian Kniep, Vibeke Henriette Lauridsen, Eva Høgh Iversen, Bjarke Sky-
um Donslund and Karl Anker Jørgensen*
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Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
Supporting Information Placeholder
ABSTRACT: A novel organocatalytic activation mode of cyclopropanes is presented. The reaction concept is based on a
design in which a reactive donor-acceptor cyclopropane intermediate is generated by in situ condensation of cyclopropy-
lacetaldehydes with an aminocatalyst. The mechanism of this enamine-based activation of cyclopropylacetaldehydes is
investigated by the application of a combined computational and experimental approach. The activation can be traced to
a favorable orbital interaction between the orbital of the enamine and the *C-C orbital of the cyclopropyl-ring. Fur-
thermore, the synthetic potential of the developed system has been evaluated. By the application of a chiral secondary
amine catalyst, the organocatalytically activated cyclopropanes show an unexpected and highly stereoselective formation
of cyclobutanes, functionalizing at the usually inert sites of the donor-acceptor cyclopropane. By the application of 3-
olefinic oxindoles and benzofuranone, biologically relevant spirocyclobutaneoxindoles and spirocyclobutanebenzo-
furanone can be obtained in good yields, high diastereomeric ratios and excellent enantiomeric excesses. The mechanism
of the reaction is discussed and two mechanistic proposals are presented.
Cyclopropanes are highly strained moieties, which exhibit
a remarkable reactivity.1 The inherent features of cyclo-
propanes have caused them to be exploited in organic
synthesis.2 Since the late ꢀꢁꢂꢃꢄs it has been known that the
installation of vicinal donor and acceptor substituents on
the cyclopropane increases the reactivity of the C-C
bond.3 The potential of such molecules, which are re-
ferred to as donor-acceptor (D-A) cyclopropanes, has only
been recognized in more recent years, in which their
reactivity and application have become an increasingly
popular field of research.4 Typically, the reaction of D-A
cyclopropanes is promoted by a Lewis acid, which in-
crease their electrophilicity by coordination to the accep-
tor unit. This approach has found application in ring-
opening reactions,5 addition reactions,6 [3+2]-,7 [3+3]-8
and [4+3]-cycloadditions9 as well as rearrangement reac-
tions10 (Figure 1, a). The developed methodologies and the
asymmetric versions hereof have been applied in the
synthesis of biologically relevant compounds.11
Within the last 15 years, organocatalysis has been es-
tablished as the third pillar of asymmetric catalysis.12
Initial research in the field focused on the development of
additions of electrophiles and nucleophiles, via enamine13
and iminium-ion catalysis,14 respectively. In the following
years, other applications of organocatalysis were investi-
gated and established, such as cascade reactions,15 SOMO-
catalysis,16 activation of poly-unsaturated systems by vi-
nylogous aminocatalysis17 and application in target-
oriented synthesis.18
organocatalysis we envisioned an unprecedented and
useful reaction concept, in which a chiral aminocatalyst
would activate a cyclopropane and promote stereoselec-
tive reactions of the in-situ activated system. A crucial
feature in this design would be the installation of appro-
priate substituents on the cyclopropane. The dormant
cyclopropane should carry an acceptor unit as well as a
molecular handle in form of an aldehyde functionality.
This cyclopropane will remain inert until condensation of
the aldehyde with the aminocatalyst by which a donor
substituent, an enamine, is formed. An activated D-A
cyclopropane has now been generated and might partici-
pate in stereoselective reactions due to the presence of a
stereoinducing unit in the aminocatalyst.
Herein, we present a novel organocatalytic reaction
concept describing the activation of cyclopropylacetalde-
hydes and their subsequent reactivity in stereoselective
reactions. We demonstrate, by applying a computational
approach, that the activation of the cyclopropane by a
secondary amine catalyst is based on a favorable orbital
interaction between the orbital of the enamine and the
*C-C orbital of the cyclopropane. Following a study of the
activation of the cyclopropane, an application in a stere-
oselective reaction is presented. Interestingly, the optical-
ly active product formed does not originate from a [3+2]-
cycloaddition at the expected carbon atoms in the cyclo-
propyl ring. Instead, the unique properties of the organo-
catalytically activated cyclopropyl functionality provides a
product, which is based on a novel stereoselective [2+2]-
cycloaddition of the dipolarophile at the usually inert C-C
bond in the cyclopropane (Figure 1, b).
Given the high potential of cyclopropanes in asym-
metric catalytic transformations4-11 and the versatility of
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The presented approach for activation of cyclopropanes propane, we initially investigated a series of model sys-
tems by computational methods. Using wB97XD/pcseg-125
we calculated the bond lengths of the relevant cyclopro-
pane C-C bonds as a function of the nature of the vicinal
substituents on the cyclopropane ring (Figure 2).
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is based on a HOMO-raising strategy and is thus in con-
trast to traditional approaches based on LUMO-lowering
strategies using Lewis acids. Previously applied organo-
catalytic strategies for activation of D-A cyclopropanes
include the application of N-heterocyclic carbenes as
donor-activating organocatalysts,19 activation of the ac-
ceptor moiety by a boronate urea catalyst20 and acceptor-
activation by an aminocatalyst via iminium-ion catalysis.21
In contrast, this activation strategy represents the first
case in which the donor unit of a D-A cyclopropane is
generated by the condensation with an aminocatalyst.
Furthermore, the synthetic potential of the developed
method is highlighted by the ability to participate in ste-
reoselective cycloadditions to form substituted cyclobu-
tane structures. Cyclobutanes are prevalent in natural
products and biologically relevant compounds.22 Futher-
more, they have found use as intermediates in synthesis,
in which they often allow for facile assembly of larger ring
systems via strain-releasing fragmentation reactions.23
The direct access to cyclobutanes via asymmetric [2+2]-
cycloadditions is a challenging task, since the process is
not thermally allowed and photochemical reactions are
notoriously difficult to perform stereoselectively.24 Typi-
cally, D-A-cyclopropanes react as 3-atom components7-9
and the ability to carry out a stereoselective [2+2]-
cycloaddition highlights the complementarity of the de-
veloped organocatalytic approach to the established
methods.
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Figure 2: Top: Calculated C1-C2 and C1-C3 bond lengths for
unactivated- and activated cyclopropyl moiety with dif-
ferent acceptor patterns in CHCl3. Bottom: Optimized
structure of activated enamine intermediate with R1, R2 =
CO2Me and MO-explanation of the activation of the cy-
clopropyl moiety by the enamine functionality.
Calculation of the C1-C2-bond length of the unactivated,
iminium- and enamine-activated cyclopropyl moiety with
different acceptor patterns in CHCl3 is presented in Figure
2 (see Supporting Information for calculation of the C1-C2-
bond length in gas-phase, H2O and further details). The
calculated C1-C2-bond length in uncondensed cyclopropy-
lacetaldehydes, bearing no, one or two ester substituents
as acceptors differentiate only to a minor extend. The
same is true for their related iminium-ion activated sys-
tems. The most activated systems in these series are the
diester substituted cyclopropyl rings (R1, R2 = CO2Me).
However, when an enamine is present as the donor func-
tionality of the diester substituted D-A-cyclopropane, the
length of the C1-C2-bond increases significantly and elon-
gates to 1.559 Å. Therefore, this bond becomes more acti-
vated compared to the analogous bonds in the uncon-
densed cyclopropylacetaldehyde (1.517 Å) and in the imin-
ium-ion-activated system (1.522 Å). These findings are in
correspondence with the systematic study by Werz et al.,
who showed that the cyclopropane C-C bond becomes
increasingly labile with more electron-rich donors and
more electron-deficient acceptors as the vicinal substitu-
ents.26 It is also notable from the results in Figure 2, that
the C1-C3-bond is relatively unaffected by the nature of
the substituents.
Figure 1: Traditional and the developed organocatalytic
approaches for activation of cyclopropanes.
In order to test our hypothesis that the condensation of
an aminocatalyst could facilitate the activation of a cyclo-
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Furthermore, some interesting structural changes take
were made in the absence of PhCO2H (for details on these
studies, see Supporting Information).
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place when forming the enamine from the cyclopropyla-
cetaldehyde. The optimized structure of the enamine-
activated cyclopropane is presented at the bottom of
Figure 2. For the enamine-activated cyclopropane, the
cyclopropyl moiety is rotated to be almost perpendicular
to the enamine moiety, compared to the cyclopropyla-
cetaldehyde, in which the C1-C2-bond to be activated is in
the same plane as the aldehyde functionality (see Sup-
porting Information for details). This rotation allows for a
favorable interaction between the orbital of the
enamine and the *C-C orbital of the cyclopropyl moiety as
outlined at the bottom of Figure 2.
Having ascertained the ability of catalyst 2a to activate
racemic cyclopropylacetaldehyde 1a, we set out to investi-
gate, if it was possible to use this in-situ generated species
in subsequent reactions. We were delighted to observe a
reaction occurring when 3-olefinic oxindoles were em-
ployed; however, the reaction proceeded with an unex-
pected outcome. Instead of acting as a 1,3-dipole in the
expected [3+2]-cycloaddition pathway, the organocatalyt-
ically activated cyclopropyl substrate participated, to our
surprise, in a [2+2]-cycloaddition yielding a spirocyclobu-
taneoxindole. Spirocyclic oxindoles are prominent struc-
tures, due to their presence in biologically active com-
pounds.29 More specifically, the spirocyclobutaneoxindole
core structure has been found e.g. in Welwitindolinone A
isonitrile, which has been isolated from blue-green algae
Hapalosiphon welwitschii and Westiella intricate (Figure
3).30 Following its discovery, it has been the target of a
number of total syntheses.31
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Figure 3: Structure of Welwitindolinone A isonitrile con-
taining the spirocyclobutaneoxindole core (marked in
red).
We proceeded to optimize the reaction conditions in
order to develop a procedure for the stereoselective for-
mation of spirocyclobutaneoxindoles based on the activa-
tion of cyclopropylacetaldehyde 1a (a one-pot Wittig
functionalization was performed after the organocatalytic
reaction for handling and characterization purposes). Our
initial result revealed that the reaction proceeded in a fast
manner and full conversion was achieved in 2 h. The ste-
reoselectivity was promising, although there was room for
improvement (Table 1, entry 1). By lowering the tempera-
ture to 4 ˚C, a significant improvement in the enantiose-
lectivity was observed (entry 2). It was found that the
diastereoselectivity could be improved by lowering the
temperature to -20 ˚C (entry 3). A further improvement in
the diastereoselectivity was achieved by reducing the
catalyst loading at the cost of a prolonged reaction time
(entry 4). The acid additive did not influence the rate of
the reaction to any significant degree; however, when it
was omitted a slight drop in diastereoselectivity was ob-
served (entry 5). It was found that it was necessary to use
2 eq. of cyclopropylacetaldehyde 1a in order to achieve
full conversion of 3-olefinic oxindole 3a.
Scheme 1: Activation and ring-opening of cyclopropyla-
cetaldehyde 1a promoted by enamine formation with
aminocatalyst 2a.
Motivated by the computational results, we went on to
investigate our design experimentally (Scheme 1). Gratify-
ingly, we found that racemic cyclopropylacetaldehyde 1a
showed smooth ring-opening to the ꢅꢆꢇ-unsaturated
aldehyde 1b when mixed with the TMS-protected prolinol
catalyst 2a and benzoic acid (Scheme 1, a).27 In contrast,
aldehyde 1a was found to be stable in solution when no
aminocatalyst was present. We questioned however,
whether the ring-opening was facilitated by the formation
of an electron-donating enamine (Scheme 1, c) or if the
basicity of the secondary amine catalyst was promoting
ring-opening via a ꢇ-elimination pathway as observed in
previous studies by Kerr et al.28 (Scheme 1, d). This was
tested by replacing the aminocatalyst 2a with Et3N, which
has basic properties similar to 2a, but is unable to con-
dense with the aldehyde. In this case, no ring-opening of
1a was observed (Scheme 1, b). This indicates that the
ring-opening indeed takes place by activation through an
enamine intermediate. PhCO2H was added in order to
study the system under the same conditions as for the
later described [2+2]-cycloaddition. Similar observations
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Table 1: Optimization of the organocatalytic cyclopro-
pane ring-opening and asymmetric cycloaddition of cy-
Page 4 of 9
With the optimized reaction conditions in hand, we
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went on to explore the generality of the reaction. Initially
structural variations were made on the 3-olefinic oxindole
3 (Scheme 2). The reaction of cyclopropylacetaldehyde 1a
and 3-olefinic oxindole 3a formed product 5a in high
yield, high diastereoselectivity and an excellent enantiose-
lectivity of 95% ee. Various 5-substituted 3-olefinic oxin-
doles (3b-f) were then employed. It was found that elec-
tron-rich substituents such as methoxy and methyl could
be installed (3b,c), furnishing their respective products
with similar results (5b,c). 3-Olefinic oxindoles carrying
halogens in the 5-position were also tolerated (3d-f) and
provided their respective products in high yields, high
diastereoselectivity and excellent enantioselectivity (5d-
f). A 7-substituted (3g) and a 5,7-di-substituted oxindole
(3h) also performed well in the reaction yielding their
respective products with similar results (5g,h). The reac-
tion could be performed with an N-unprotected oxindole
(3i); however, significantly longer reaction time was nec-
essary in order to achieve high conversion due to solubili-
ty issues (5i). Furthermore, a slight drop in enantioselec-
tivity was observed.
clopropylacetaldehyde 1a with 3-olefinic oxindole 3a.a
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entry 2a(mol%) temp (˚C) timeb (h)
drc
6.0:1
6.5:1
8.6:1
10.0:1
8.0:1
eed (%)
70
1e
2e
3
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20
10
rt
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94
-20
-20
-20
18
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95
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5f
95
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95
a
Experiments performed on a 0.1 mmol scale. Unless otherwise
noted, PhCO2H was employed in the same molar amount as catalyst
2a. See Supporting Information for details. Required reaction time
b
c
to achieve full conversion of 1a or 3a. Determined by H NMR
1
d
analysis of the crude mixture before addition of 4. Determined by
e
chiral stationary phase UPC2. 1.5 eq. of 1a was employed. Full con-
sumption of 1a was observed with minor amounts of 3a still present. f
Reaction performed in the absence of PhCO2H.
Scheme 2: Scope of the organocatalytic cyclopropane ring-opening and asymmetric cycloaddition of cyclopropylacetal-
dehyde 1 and 3-olefinic oxindoles and benzofuranone 3.a
a
Reactions were performed on a 0.1 mmol scale using 2.0 eq of 1a. Unless indicated otherwise, the organocatalytic reac-
tion was performed for 48 h and the Wittig reaction for 2.5 h. See Supporting Information for details. The diastereomeric
1
ratios were determined by crude H NMR analysis of the aldehyde intermediate. The values given in parenthesis were
found in the isolated products. Enantiomeric excesses were determined by chiral stationary phase UPC2. Reaction per-
b
formed with 20 mol% 2a and PhCO2H. c Reaction performed at 5 ꢈC. d 72 h reaction time. e 144 h reaction time. Isolated
as the aldehyde. The enantiomeric excess was measured after transformation.
f
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Interestingly, the related 3-olefinic benzofuranone di-
compound.34 The configuration of the remaining products
was assigned by analogy assuming a common reaction
pathway.
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polarophile 3j also performed well in the reaction, yield-
ing product 5j in a good yield, high diastereoselectivity
and excellent enantioselectivity. The substituent on the
olefinic moiety of the oxindole proved to be quite influen-
tial on the reaction. Oxindole 3k carrying a methyl-
ketone performed similarly in terms of stereoselectivity,
although a slightly lower yield was obtained (5k). Oxin-
doles carrying an ester (3l) or a phosphonate (3m) could
be applied, albeit a drop in diastereoselectivity or enanti-
oselectivity, respectively, was observed (5l,m). The reac-
tion was also investigated for cyclopropylacetaldehyde 1c
carrying ethyl esters, by which similar results to the mod-
el substrate were achieved (5n).
Scheme 4: Formation of products 6a and 6b and X-ray
crystal structure of 6b.a
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It should be noted that the Boc-group in the oxindole
can be removed in quantitative yields by standard meth-
ods.
In order to further expand the scope of the developed
reaction, it was decided to investigate whether non-
carbonyl acceptors could be employed in the cyclopro-
pane aldehyde. Furthermore, we found it intriguing to
test the performance of aldehydes carrying two different
acceptors in the reaction. This substitution pattern would
give rise to an additional stereocenter, which could po-
tentially be difficult to control. For this reason cycloprop-
ylacetaldehyde 1d was synthesized and employed in the
reaction. Gratifyingly, when catalyst 2b was applied,32 the
product 5o was formed in a good yield and with a good
control of the distribution of the three diastereomers
observed in the crude reaction mixture (Scheme 3). Upon
purification a minor amount (6%) of a fourth diastere-
omer was observed. The major diastereoisomer was ob-
tained in 70% ee.
a
Reaction was performed on a 0.1 mmol scale. See Sup-
porting Information for details.
Finally, our attention turned towards the mechanism of
the reaction, which was intriguing given the unexpected
reaction outcome. In order to gain a better understanding
of the reaction, some experiments with linear ꢅ,ꢇ-
unsaturated aldehydes were performed (Scheme 5, a).
When the ring-open isomer of cyclopropylacetaldehyde 1c
was employed in the reaction, product 5n was formed in
similar results. This indicates that the reaction can pro-
ceed through an organocatalytic ring-opening of the cy-
clopropane (see Scheme 1, c). When trans-2-pentenal was
employed as the ꢅ,ꢇ-unsaturated aldehyde under the
reaction conditions a messy reaction was observed. This
result indicates that the diester functionality has an im-
portant influence on the reaction outcome. Furthermore,
it was found that an electron-withdrawing substituent on
the 3-olefinic oxindole was essential for the reaction,
since no reaction was observed, when this functionality
was not present. These observations open up for two
possible mechanisms for the formation of the spirocyclo-
butaneoxindole. An initial [3+2]-cycloaddition may take
place between the 3-olefinic oxindole 3 and the organo-
catalytically activated cyclopropane A1. Subsequently, a
ring-contracting rearrangement of the spirocyclopentane
oxindole A2 may take place to form the spirocyclobutane-
oxindole product 5 via an initial deprotonating ring-
opening to form A3 followed by a conjugated addition of
the carbanion (Scheme 5, b). Although ring-contracting
rearrangements have previously been a successfully ap-
plied strategy in the synthesis of Welwitindolinone A
isonitrile,31a,c,e this mechanism seems unlikely in this case,
since there is no obvious driving force for the ring-
contracting rearrangement.
Scheme 3: Organocatalytic cyclopropane ring-opening
and asymmetric cycloaddition of cyclopropylacetaldehyde
1d and 3-olefinic oxindole 3a.a
a
Reaction was performed on a 0.1 mmol scale. The dia-
stereomeric ratios were determined by crude H NMR
1
analysis of the aldehyde intermediate. The value given in
parenthesis was found in the isolated product. Enantio-
meric excess for the major diastereoisomer was deter-
mined by chiral stationary phase UPC2 after transfor-
mation. See Supporting Information for details.
At this point, our attention turned towards establishing
the absolute structure of the products. In this regard, it
was found that the crude aldehyde mixture could be oxi-
dized to form compounds 6a containing a carboxylic acid
in decent overall yields.33 By recrystallization of 6b, crys-
tals suitable for X-ray analysis were obtained, and it was
possible to determine the absolute configuration of this
Another plausible mechanism involves the organocata-
lytic activation of the cyclopropyl functionality leading to
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the formation of the iminium-ion intermediate B1 by a In conclusion, we have disclosed the first example of an
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ring-opening. From this intermediate a dienamine B2 can
be formed by deprotonation. This dienamine intermedi-
ate may then react in a formal [2+2]-cycloaddition with
the 3-olefinic oxindole 3 to form the spirocyclobutaneox-
indole product 5 (Scheme 5, c). This reaction mechanism
can be supported by the fact that [2+2]-cycloadditions
have been achieved between ꢅ,ꢇ-unsaturated aldehydes
and electron-deficient alkenes by combined amino- and
hydrogen-bonding catalysis.35 Considering the presented
experimental results and the literature precedence, the
mechanism described in Scheme 5 c is deemed the most
probable at the present time.
organocatalytic enamine-based activation of cyclopro-
panes. The activation mechanism was first studied by
computational methods showing an increase of the rele-
vant C-C bond length in the enamine-activated cyclopro-
pane. This increase was accounted for by a favorable or-
bital interaction between the orbital of the enamine
and the *C-C orbital of the cyclopropyl moiety. Subse-
quently, the results of this computational approach were
underlined by experiments towards the enamine-
mediated ring-opening of cyclopropylaldehydes in solu-
tion using a chiral secondary amine catalyst. The synthet-
ic potential of the reaction was investigated and resulted
in the discovery of an unexpected and highly stereoselec-
tive cycloaddition reaction leading to optically active
cyclobutanes, in which the cyclopropane was functional-
ized at the usually inert C-C bond. Applying this method-
ology, a series of spirocyclobutaneoxindoles as well as
spirocyclobutanebenzofuranone were obtained in good
yields, high diastereoselectivities and excellent enantiose-
lectivities. Finally, the mechanism for the formation of
the cyclobutane from the organocatalytically activated
cyclopropane is discussed and two mechanistic proposals
are presented.
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Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
kaj@chem.au.dk
This work was financially supported by the Aarhus Universi-
ty, FNU and the Carlsberg Foundation. Magnus E. Jensen is
gratefully acknowledged for performing X-ray analysis.
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136, 15929. With catalyst 2a a 57:25:18 diastereomeric ratio was
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(34) See Supporting Information.
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7
this manuscript, a report appeared which describes the asym-
metric [2+2]-cycloaddition between ꢅ,ꢇ-unsaturated aldehydes
and 3-olefinic oxindoles using H-bond directing dienamine
activation: (c) Qi, L.-W.; Yang, Y.; Gui, Y.-Y.; Zhang, Y.; Chen, F.;
Tian, F.; Peng, L.; Wang, L.-X. Org. Lett. 2014, 16, 6436. This
further supports the mechanism proposed in Scheme 5, c.
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