Breaking symmetry with symmetry: Bifacial selectivity in the asymmetric cycloaddition of anthracene derivatives

Article abstract of DOI:10.1002/chem.201300142

Push to activate: A new catalytic strategy for the activation of anthracene derivatives has been developed. From symmetrical starting materials, enantioselective cycloaddition reactions can be achieved by employing a C ₂-symmetric aminocatalyst. This selectivity is due to the gain or loss of conjugation between the enamine and the anthracene in the two transition-state structures. This methodology is demonstrated in 14 examples with 70-96 % yield and 76-95 % ee. Copyright

Full text of DOI:10.1002/chem.201300142

DOI: 10.1002/chem.201300142
Breaking Symmetry with Symmetry: Bifacial Selectivity in the Asymmetric
Cycloaddition of Anthracene Derivatives
Carles Rodrꢀguez-Escrich, Rebecca L. Davis, Hao Jiang, Julian Stiller,
Tore K. Johansen, and Karl Anker Jørgensen*[a]
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Chem. Eur. J. 2013, 19, 2932 – 2936

COMMUNICATION
The selectivities in Diels–Alder reactions are determined
by a set of well-understood orbital interactions, which ac-
count for the experimentally observed regioselectivity and
endo/exo selectivity in these cycloadditions.[1] By combining
the governing interactions with a chiral catalyst, high enan-
tioselectivity can be achieved.[2] However, when employing
symmetrical dienes and dienophiles, the enantioselectivity in
Diels–Alder reactions is difficult to control (Scheme 1a). In
Figure 1. Rationalization of the superiority of a C2-symmetric catalyst.
Scheme 1. Stereoselectivities in Diels–Alder reactions of Cs-symmetric
dienes and C2h-symmetric dienes (anthracenes).
provide the chirality necessary to obtain the product in high
enantioselectivity.
Initial development of this method was accomplished with
a combination of synthesis and DFT calculations. It was ob-
served that the C2-symmetric catalyst (2R,5R)-2,5-diphenyl-
pyrrolidine (3a) could catalyze the reaction between 2-(an-
thracen-9-yl)acetaldehyde (1a) and N-methylmaleimide to
give the desired Diels–Alder product in 85% yield and
75% ee at room temperature.
order to achieve good enantioselectivity, the chiral catalyst
must be able to direct the approach of the dienophile. This
challenge is exemplified in the Diels–Alder reactions of an-
thracene derivatives,[3,4] in which the dienophile has to dis-
criminate between two approaches on each face of the an-
thracene ring[5] (Scheme 1b). Previously, we have described
a method in which a hydrogen-bond-donating secondary-
amine catalyst can direct the approach of the hydrogen-
bond-accepting dienophile to one face of the anthracene.[6]
However, with this approach, good enantioselectivities were
limited to systems in which both the diene and the dieno-
phile are activated by the catalyst.
The intermediate of 2-(anthracen-9-yl)acetaldehyde and a
nonsymmetric aminocatalyst is shown in Figure 1a. For such
an intermediate, three different approaches of the symmet-
ric maleimide to the diene in the central ring of the anthra-
cene moiety are possible. However, this is expected to result
in low enantioselectivity. We envisioned a C2-symmetric
DFT calculations were used to rationalize the stereocon-
trol provided by C2-symmetric catalyst 3a with 1a.[7] All
structures were optimized at the wB97xd/6-31G(d) level and
activation energies were obtained with wB97xd/6-311+G-
AHCTUNGTRENNUNG
(2df,2p) single points in chloroform.[8,9] Solvent effects were
estimated with the integral equation formalism polarizable
continuum model (IEFPCM).[10] Frequency calculations
were performed for all stationary points to identify them as
local minima or first-order saddle points and to obtain the
zero-point energies (ZPEs) and thermochemical corrections
for the free energies. All of the reported values are free en-
ergies at 298 K.
To understand the selectivity of this enantioselective reac-
tion, we examined the cycloaddition of the reactive inter-
mediate with N-methylmaleimide approaching from both
the left and the right. Calculations suggest that both reaction
pathways are concerted and highly exothermic.[11] Examina-
tion of the transition-state structures for both approaches of
the N-methylmaleimide shows a clear energetic preference
for one approach over the other (Figure 2). To our surprise,
the selectivity of this system does not appear to be based on
steric shielding of one side of the anthracene, as the phenyl
rings are almost perpendicular to the anthracene ring
system, allowing them to take advantage of T-shaped, p-
stacking interactions. The selectivity appears to be largely
the result of distortions in the C1-C2-C3-C4 dihedral angle
(Figure 2, top). In TS-A, steric repulsion between the ap-
cataACHTUNGTRENNUNGlyst that would take advantage of the symmetry of the
anthracene ring system by directing the approach of the di-
enophile on both faces, giving rise to the same enantiomeric
product (Figure 1b). The symmetry of such a catalyst should
[a] Dr. C. Rodrꢁguez-Escrich, Dr. R. L. Davis, Dr. H. Jiang, Dr. J. Stiller,
T. K. Johansen, Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, Langelandsgade 140
8000 Aarhus C (Denmark)
Fax : (+45)8715-5956
E-mail: kaj@chem.au.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300142.
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K. A. Jørgensen et al.
Table 1. Optimization of the reaction conditions.[a]
Cat
Solvent
Additive[b]
T [8C]
t [h][c]
ee [%][d]
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3a
3a
3a
3a
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
PhMe
EtOH
CHCl3
BA
BA
BA
RT
RT
RT
RT
RT
RT
RT
À30
1
0.5
6
10
2
2
5
24
86
77
14
34
77
81
74
92
DEA[e]
BA
BA
BA
BA
[a] Reactions carried out on a 0.1 mmol scale. [b] DEA=N,N-diethyl-
acetamide; BA=benzoic acid. [c] Indicates the approximate time to full
AHCTUNGTRENNUNG
conversion. [d] Determined by chiral ultraperformance convergence
Figure 2. Transition-state structures for both approaches of the N-methyl-
maleimide. Activation energies are Gibbs free energies from wB97xd/6-
chromatography (UPC2). [e] 1.0 Equivalent of additive employed.
311+GACHTUNGTRENNUNG(2df,2p)//wB97xd/6-31G(d) single points in chloroform. Bond
lengths are in [ꢂ]. Dihedral angles [8] are reported in bold and italics.
ditives (or absence thereof) were screened, but none of
these provided an improvement of the results obtained com-
pared to benzoic acid. It should also be noted that the reac-
tion rates were unusually high for an organocatalytic pro-
proaching maleimide and the enamine subunit pushes the
enamine into conjugation with the anthracene subunit, re-
sulting in increased HOMO activation of the diene fragment
in the anthracene system.[12] It should also be noted that in
TS-A the carbonyl oxygen atom of the maleimide is able to
AHCTUNGTREGcNNNU ess. Therefore, to achieve the best selectivities without
compromising the reactivity, temperature is a crucial factor.
Gratifyingly, conducting the reaction at À308C, full conver-
sion was achieved within 24 h to furnish 4a in 92% ee.
Once the reaction conditions had been optimized, we de-
cided to test the generality of the system. A series of aro-
matic maleimides were found to undergo [4+2] cycloaddi-
tion to furnish cycloadducts 4a–e (Table 2). Remarkably, the
reaction worked with electron-poor, heteroaromatic, poly-
À
form a favorable C H···O interaction with the hydrogen
atom of the enamine, further contributing to the energetic
preference for this approach. In TS-B, steric repulsion be-
tween the maleimide and the phenyl ring of the catalyst
forces the latter to rotate, pushing the enamine out of conju-
gation with the anthracene subunit. The gain and loss of
conjugation in the two transition-state structures leads to an
energy difference of 1.3 kcalmolÀ1. This difference in energy
is in good agreement with the initial experimentally ob-
served enantioselectivity.
AHCTUNGTREGcNNUN yclic, and electron-rich maleimides with excellent yields
and enantioselectivities. Moreover, the absolute configura-
tion of 4b could be unambiguously determined by single-
crystal X-ray diffraction[14] (Figure 3). The remaining prod-
ucts were assigned by analogy. Non-aromatic maleimides
also reacted smoothly: for example, methoxycarbonyl male-
Based on the initial synthetic and computational results,
the cycloaddition of 2-(anthracen-9-yl)acetaldehyde (1a)
and N-phenylmaleimide (2a) was investigated. The C2-sym-
metric catalyst 3a provided the Diels–Alder product 4a in
86% ee (Table 1, entry 1). To ensure that the C2-symmetry
of the catalyst was important for the selectivity of the reac-
tion, the nonsymmetric aminocatalysts 3b and c and the
dual activation catalyst 3d[13] were tested in this reaction. In
all of these cases, lower selectivities were observed (Table 1,
entries 2–4). Further screening showed that CHCl3 proved
superior to other solvents both in terms of reaction rate and
enantioselectivity (Table 1, entries 1,5–7). Several other ad-
Figure 3. X-ray structure of 4b.
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Asymmetric Cycloaddition of Anthracene Derivatives
Table 2. Dienophile scope.[a]
COMMUNICATION
Table 3. Scope of the anthracene derivative.[a]
[a] All reactions were carried out at a 0.2 mmol scale in 1 mL of CHCl3.
In an attempt to study the influence of the catalyst on the
overall process, we decided to test a case of double stereose-
lection. Thus, we were pleased to observe that 3a was able
to promote the reaction between the enantiopure maleimide
2l and 1a in a highly diastereoselective fashion (d.r.>10:1,
Scheme 2). In contrast, the reaction in the presence of ent-
3a is sluggish, indicating a mismatched case. However, a
competition experiment using 3a and two equivalents of
(Æ)-2l indicated only a slight preference for the 2l over its
enantiomer, resulting in a 2:1 diasteromeric mixture of the
cycloadduct 4o.
[a] All reactions were carried out at a 0.2 mmol scale in 1 mL of CHCl3.
[b] Reaction carried out at À308C for 40 h. [c] Determined after reduc-
tion to the alcohol. [d] Reaction carried out at RT for 40 h.
ACHTUNGTRENNUNGimide 2 f gave the desired cycloadduct 4 f in 95% yield and
95% ee. As for the N-alkyl maleimides, the reactions were
somewhat slower and the stereoselectivities decreased
slightly, although the enantioselectivities were always
ꢀ85% ee. It is worth emphasizing that, even though the
aminocatalytic a-addition of aldehydes to maleimides via an
enamine has been described,[15] no such products were ob-
served in the course of our study.
To our delight, the scope was not limited to maleimides
(Table 3). While noncyclic dienophiles (cis or trans) proved
unreactive, maleic anhydride also participated in the reac-
tion and the corresponding cycloadduct 4j was isolated in
80% yield and 91% ee. As for the cyclopentenedione, it re-
quired mild heating and longer reaction times to drive the
reaction to completion (408C for 2 d), but cycloadduct 4k
was obtained in 93% yield and 90% ee. With the dienophile
scope established, we turned our attention to the anthracene
derivative. The introduction of an electron-withdrawing
group in the 10-position entailed a loss in reactivity. The re-
action could be driven to completion after 48 h at room
temperature, but the stereoselectivity in 4l dropped to
76% ee. However, when these substituents were located on
the outer rings, the Diels–Alder cycloaddition products 4m
and n were obtained in 90–96% yield and 88–90% ee.
Scheme 2. Double stereoselective reaction: matched case.
In summary, a new catalytic strategy for the activation of
anthracene derivatives has been successfully developed
using a combination of synthetic and computational meth-
ods. Using a C2-symmetric aminocatalyst 3a, the cycloaddi-
tion reaction takes place with excellent yields and stereose-
lectivities. This selectivity was not the result of steric shield-
ing, as originally envisioned, but was instead due to the gain
or loss of conjugation between the enamine and the anthra-
Chem. Eur. J. 2013, 19, 2932 – 2936
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K. A. Jørgensen et al.
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Acknowledgements
This work was made possible by grants from Aarhus University, OChem-
School, Carlsberg Foundation, and FNU. C. R-E. acknowledges the Gen-
eralitat de Catalunya for a Beatriu de Pinꢃs post-doctoral fellowship. We
thank Solveig R. Madsen and Dr. Jacob Overgaard for performing the X-
ray analysis.
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Keywords: anthracene activation · asymmetric catalysis ·
density functional calculations · Diels–Alder reaction ·
organocatalysis
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Received: November 27, 2012
Published online: February 1, 2013
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Chem. Eur. J. 2013, 19, 2932 – 2936