Dienamine-mediated inverse-electron-demand hetero-diels-alder reaction by using an enantioselective H-bond-directing strategy

Article abstract of DOI:10.1002/anie.201207122

The first H-bond-directed inverse-electrondemand hetero-Diels-Alder reaction proceeding via a dienamine intermediate was developed. Under optimized reaction conditions, the corresponding dienamine species underwent regio- and stereoselective functionalization at the remote double bond, five bonds away from the stereogenic center of the catalyst, to give dihydropyran derivatives bearing three contiguous stereogenic centers. High stereoselectivities were obtained by employing a bifunctional squaramide-containing aminocatalyst, and the rationalization for the stereochemical outcome of the reaction was provided. Furthermore, the possibility to employ the introduced chiral framework for the synthesis of tetrahydropyrans as well as polycyclic compounds was demonstrated.

Full text of DOI:10.1002/anie.201207122

Angewandte
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DOI: 10.1002/anie.201207122
Asymmetric Catalysis
Dienamine-Mediated Inverse-Electron-Demand Hetero-Diels–Alder
Reaction by Using an Enantioselective H-Bond-Directing Strategy**
Łukasz Albrecht, Gustav Dickmeiss, Christian F. Weise, Carles Rodrꢀguez-Escrich, and
Karl Anker Jørgensen*
The reaction between an electron-rich diene and an electron-
poor dienophile, commonly known as the Diels–Alder
reaction, was discovered in 1928.[1] This [4+2] cycloaddition
constitutes one of the most fundamental reactions in organic
chemistry and still attracts much attention.[2] Its inverse-
electron-demand variant, where an electron-poor diene reacts
with an electron-rich dienophile, was discovered later, and
immense progress within this field has been made over the
years.[3] Importantly, asymmetric versions of this reaction
utilizing both transition metal catalysis and organocatalysis
have also been developed.[4] In this context, asymmetric
aminocatalytic strategies involving HOMO activation of the
dienophile constitute an important alternative to classical
LUMO-lowering pathways.[5]
Already in 2003, shortly after asymmetric organocatalysis
was rediscovered and when the entire field was still in its
infancy, the possibility to employ enamine chemistry in the
inverse-electron-demand hetero-Diels–Alder reaction was
Scheme 1. Enamines and dienamines in the inverse-electron-demand
demonstrated (Scheme 1, top).[5a] Chen and co-workers later
hetero-Diels–Alder reaction. Ts=toluenesulfonyl, TMS=trimethylsilyl.
developed a modification of this reaction, namely an aza-
Diels–Alder reaction, to access chiral tetrahydropyridine
derivatives.[5b] The same research group also showed that
dienamines were capable of participating in an inverse-
electron-demand aza-Diels–Alder reaction occurring at the
proximal double bond (enamine-like, 1,2-reactivity)
(Scheme 1, bottom).[5c] However, obtaining regioselective
3,4-reactivity at the distal alkene moiety, enabling remote,
enantioselective functionalization five bonds away from the
stereogenic center of the catalyst,[6] turned out to be problem-
atic. Such a reactivity pattern was only feasible for crotonal-
dehyde, albeit low stereoselectivity was obtained.[5b]
The dihydropyran framework constitutes a privileged
structural motif in organic and medicinal chemistry.[7] Owing
to the presence of an olefinic moiety, dihydropyrans can
undergo various chemical transformations and can easily be
converted into biologically relevant tetrahydropyran deriva-
tives.[8] Therefore, dihydropyrans constitute important inter-
mediates for the preparation of carbohydrates and related
natural products.[9]
Given the importance of the dihydropyran framework and
the difficulties in obtaining the regio- and stereoselective
inverse-electron-demand hetero-Diels–Alder reaction at the
distal double bond of the dienamine intermediate, we
envisioned that a possible solution could rely on applying
H-bond-directing aminocatalysis (Scheme 2).[10] It was antici-
pated that simultaneous activation of an a,b-unsaturated
aldehyde (through dienamine formation) and the recognition
of the heterodiene system by an H-bond donor site of the
catalyst might facilitate the reaction. Furthermore, such
a dual activation strategy should promote the inverse-
electron-demand hetero-Diels–Alder reaction to occur at
[*] Dr. Ł. Albrecht, Dr. G. Dickmeiss, Dr. C. F. Weise,
Dr. C. Rodrꢀguez-Escrich, Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University
8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
[**] This work was made possible by grants from OChemSchool,
Carlsberg Foundation, FNU, and Aarhus University. C.R.-E. thanks
the Generalitat de Catalunya for a Beatriu de Pinꢁs postdoctoral
fellowship. We thank Dr. Jacob Overgaard for performing X-ray
analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207122.
Scheme 2. Aminocatalytic H-bond-directing strategy for the inverse-
electron-demand hetero-Diels–Alder reaction.
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the distal olefinic moiety of the dienamine intermediate,
thereby resulting in regioselective 3,4-functionalization. In
particular, the application of alkyl 2-oxo-4-arylbut-3-enoates
as heterodienes seemed promising, since the a-ketoester
moiety is a well-recognized motif in H-bonding catalysis.[11]
To evaluate the concept, the reaction between methyl 2-
oxo-4-phenylbut-3-enoate (2a) and (E)-4-phenylbut-2-enal
(1a) in the presence of various aminocatalysts was performed
(Table 1). It was found that both steric shielding catalyst 4
(Table 1, entry 1) and H-bond-directing catalysts 5a,b
survey (Table 1, entries 6–11) indicated that the use of THF
resulted in pronounced increase in selectivity, albeit longer
reaction times were required to achieve high conversion
(Table 1, entry 11). Further screening concerning concentra-
tion and additives applied did not lead to improvement of the
results (see the Supporting Information for details).
After having optimized the conditions for the inverse-
electron-demand hetero-Diels–Alder reaction, the scope of
the methodology was evaluated. Initially, various b,g-unsatu-
rated a-ketoesters 2 with different substitution patterns and
electronic properties were examined (Table 2). Gratifyingly,
ketoesters 2e–l bearing different electron-withdrawing sub-
Table 1: Enantioselective dienamine-mediated inverse-electron-demand
hetero-Diels–Alder reaction: optimization studies.[a]
Table 2: Enantioselective dienamine-mediated inverse-electron-demand
hetero-Diels–Alder reaction: b,g-unsaturated a-ketoester scope.[a]
Entry R (2)
t [h] Yield [%] (3)
d.r.[b] ee [%][c]
1
2
3
4
5
6
7
8
Ph (2d)
96 82 (3d)
42 74 (3e)
24 66 (3 f)
120 64 (3g)
72 75 (3h)
24 73 (3i)
48 60 (3j)
24 74 (3k)
27 78 (3l)
72 51 (3m)
48 59 (3n)
24 42 (3o)
11:1
11:1
9:1
3:1
6:1
90
90
91
79
91
93
87
91
90
85
89
90
4-Br-C6H4 (2e)
3-Br-C6H4 (2 f)
2-Br-C6H4 (2g)
2-F-C6H4 (2h)
4-CF3-C6H4 (2i)
4-CO2Me-C6H4 (2j)
4-NO2-C6H4 (2k)
2,6-Cl2-C6H3 (2l)
4-CH3-C6H4 (2m)
3-pyridyl (2n)
Me (2o)
Entry Cat. R (2)
Solvent t [h] Conv. [%][b] d.r.[c] ee [%][d]
1[e]
2
3
4
5
6
7
8
9
4
Me (2a) CH2Cl2
Me (2a) CH2Cl2
Me (2a) CH2Cl2
20
20
48
20
18
48
72
96
48
91
>95
83
>95
>95
90
90
92
80
93
6:1 25
9:1 78
6:1 18
8:1 76
7:1 71
9:1 82
14:1 79
13:1 82
11:1 86
11:1 85
11:1 90
10:1
8:1
5a
5b
5a
5a
5a
5a
5a
5a
5a
5a
11:1
>20:1
17:1
10:1
10:1
Et (2b)
Bn (2c)
CH2Cl2
CH2Cl2
9
10
11
12[d]
tBu (2d) CH2Cl2
tBu (2d) Et2O
tBu (2d) MTBE
tBu (2d) DME
tBu (2d) dioxane 96
tBu (2d) THF 90
[a] Reactions performed on a 0.2 mmol scale (see the Supporting
Information for details). [b] Determined by 1H NMR spectroscopy.
[c] Determined by chiral-stationary-phase HPLC or ultraperformance
convergence chromatography (UPC2; see the Supporting Information for
details). [d] Isolated after reduction to the corresponding alcohol. Yield
over two steps given.
10
11
88
[a] Reactions performed on a 0.1 mmol scale (see the Supporting
Information for details). MTBE= methyl tert-butyl ether, DME=1,2-
1
dimethoxyethane. [b] Conversion of 2 as determined by H NMR
spectroscopy. [c] Determined by 1H NMR spectroscopy. [d] Determined
by HPLC using a chiral stationary phase after Ramirez olefination.
[e] Reaction performed in the absence of DEA using 20 mol% of the
catalyst. ent-3a was obtained.
stituents on the aromatic ring were easily reacted under the
established reaction conditions (Table 2, entries 2–9). In most
of the cases, good yields and high stereoselectivities were
obtained. With respect to the substitution pattern, introduc-
tion of a sterically demanding ortho-bromo substituent on the
aromatic ring of 2 led to deterioration of selectivity (Table 2,
entry 4). However, this was not the case for the smaller ortho-
fluoro substituent (Table 2, entry 5). Furthermore, an aro-
matic ring having two ortho-substituents was well-tolerated as
demonstrated for 2l affording 3l in good yield and in a highly
stereoselective manner (Table 2, entry 9). Interestingly, het-
erodiene 2m bearing an electron-rich substituent on the
aromatic ring was less reactive and yielded the target product
3m with slightly inferior results (Table 2, entry 10). Further-
more, stereoselective synthesis of heteroaromat-containing
dihydropyrans proved possible affording 3n in good yield and
(Table 1, entries 2,3) promoted the desired inverse-electron-
demand hetero-Diels–Alder reaction. Interestingly, the H-
bond-directing approach outperformed the classical steric
shielding strategy[12] in terms of both chemical efficiency and
stereoselectivity, and aminocatalyst 5a proved to be the most
effective (Table 1, entry 2). Notably, in the case of H-bond-
directing aminocatalysts 5a,b, N,N-diethylacetamide (DEA)
was used as an additive influencing the catalytic activity of the
system.[10] Further screening revealed that increasing the bulk
of the ester moiety of 2 led to improved enantiocontrol of the
reaction (Table 1, entries 2,4–6), with tert-butyl ester 2d
giving the best result (Table 1, entry 6). Subsequent solvent
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enantioselectivity (Table 2, entry 11). Importantly, the devel-
oped strategy could also be applied to aliphatic b,g-unsatu-
rated a-ketoesters as demonstrated in the synthesis of 3o
(Table 2, entry 12).
To further explore the generality of the developed
[4+2] cycloaddition, the aldehyde scope was investigated
(Scheme 3).
Scheme 4. Diastereoselective synthesis of optically active tetrahydro-
pyrans 6 and 7. Reagents and conditions: a) 1) PTSA (10 mol%),
MeOH, RT, 3 h; 2) H2 (20 bar), Pd/C, MeOH, RT, 20 h; b) 1) 2-
methoxy-1,3-dioxolane (2 equiv), PTSA (3 mol%), CH2Cl2, RT, 3 h;
2) K2OsO2(OH)4 (2 mol%), CH3SO2NH2 (1 equiv), K2CO3 (3 equiv),
K3[Fe(CN)6] (3 equiv), H2O/tBuOH (1:1), RT, 20 h. PTSA=p-toluene-
sulfonic acid.
a one-pot fashion increasing the operational simplicity of the
approach. Furthermore, diastereoselective dihydroxylation of
the dihydropyrans 3d,e was performed. In such a manner,
tetrahydropyrans 7a,b containing five contiguous stereogenic
centers were obtained as single diastereoisomers. Notably,
a quaternary stereogenic center, bearing a hemiacetal moiety
was introduced in this reaction. The high diastereoselectivity
of both processes indicates that the C-4 aryl substituent plays
an important role on the stereochemical outcome of these
reactions. It can be assumed that the dihydropyran ring
reacting in its half-chair conformation is approached from the
face opposite to the C-4 substituent.
Scheme 3. Enantioselective dienamine-mediated inverse-electron-
demand hetero-Diels–Alder reaction: a,b-unsaturated aldehyde scope
(see the Supporting Information for details).
Further application studies were focused on the possibility
to construct an additional 6-membered ring through a Frie-
del–Crafts reaction (Scheme 5).
It was found that the inverse-electron-demand hetero-
Diels–Alder reaction proceeded efficiently for the various
aldehydes tested.[13] Importantly, aldehydes bearing either
electron-donating or electron-withdrawing substituents
afforded the corresponding products in good yields and in
a highly enantio- and diastereoselective manner. However,
the obtained stereoselectivities were slightly lower than in the
b,g-unsaturated a-ketoester scope. Surprisingly, introduction
of a heteroaromatic moiety in the 4-position of the starting
a,b-unsaturated aldehyde resulted in a decrease of selectivity
as demonstrated in the synthesis of thiophene-containing
dihydropyran 3u. This result suggests that p-stacking inter-
actions between the aromatic moieties of heterodiene 2 and
the dienamine intermediate might be an important factor
influencing the cycloaddition outcome.
Scheme 5. Utilization of 3r for the diastereoselective construction of
polycyclic framework 9.
In the course of the further studies, the possibility to
utilize the chiral dihydropyran framework for the construc-
tion of more elaborate derivatives was evaluated. Initially, the
synthesis of tetrahydropyran derivatives was investigated by
stereoselective functionalizations of the olefinic moiety
present in 3 (Scheme 4). Hydrogenation of the double bond
in 3d could be successfully performed using Pd/C as the
catalyst. However, protection of the aldehyde moiety as its
corresponding dimethyl acetal prior to hydrogenation was
necessary. Gratifyingly, both reactions could be performed in
Owing to the presence of an electron-rich aromatic
moiety, dihydropyran 3r was chosen as the model substrate
for this attempt. It was found that a sequence of reactions
involving Wittig olefination of the aldehyde group in 3r with
a stabilized ylide 8 followed by Lewis acid promoted Friedel–
Crafts reaction on the electron-deficient alkene moiety
introduced in the first step afforded the corresponding
polycyclic compound 9 in high overall yield. Furthermore,
the diastereoselectivity of the cyclization was good.[14]
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The absolute configuration of the products was unambig-
uously assigned by single-crystal X-ray analysis of 7b
(Scheme 6, top).[15] To explain the stereochemical outcome,
a transition state model was proposed, and the plausible
of the developed inverse-electron-demand hetero-Diels–
Alder reaction can be assumed. This proposal is in accordance
with earlier calculations for the related formal [2+2] cyclo-
addition.[10a]
In summary, the first H-bond-directed inverse-electron-
demand hetero-Diels–Alder reaction proceeding via a dien-
amine intermediate was developed. Under optimized reaction
conditions, the corresponding dienamine species underwent
regio- and stereoselective functionalization at the remote
double bond, five bonds away from the stereogenic center of
the catalyst, to give dihydropyran derivatives bearing three
contiguous stereogenic centers. High stereoselectivities were
obtained by employing a bifunctional squaramide-containing
aminocatalyst, and the rationalization for the stereochemical
outcome of the reaction was provided. Furthermore, the
possibility to employ the introduced chiral framework for the
synthesis of tetrahydropyrans as well as polycyclic compounds
was demonstrated.
Received: September 3, 2012
Published online: November 12, 2012
Keywords: asymmetric synthesis · bifunctional catalysis ·
.
dienamines · dihydropyrans · organocatalysis
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Scheme 6. Absolute configuration assignment (C gray, O red, Br or-
ange, H white) and mechanistic considerations.
reaction mechanism is outlined in Scheme 6 (bottom). It is
postulated that initial condensation of the aminocatalyst 5
with the a,b-unsaturated aldehyde followed by deprotona-
tion/isomerization leads to the formation of the correspond-
ing dienamine intermediate 10. Subsequently, heterodiene 2,
reacting in its s-trans conformation, is recognized by the
squaramide moiety of the catalyst through H-bonding inter-
actions with its a-ketoester functionality. In such a manner,
the two reagents become independently activated—the a,b-
unsaturated aldehyde through HOMO activation and the b,g-
unsaturated a-ketoester through LUMO lowering. Moreover,
they are positioned in close spatial proximity, which further
facilitates the cycloaddition step. Interestingly, the p-stacking
interactions between the aromatic moieties of heterodiene 2
and the dienamine intermediate are postulated to play an
important role contributing to the stabilization of the
transition state. Furthermore, the H-bonding interactions
with participation of the a-ketoester moiety align the diene
above the remote double bond of the dienamine system.
Thereby, heterodiene 2 undergoes regioselective 3,4-reaction
with the dienamine from the side of the squaramide directing
group. Importantly, by taking into account the observed
diastereoselectivities of the reaction, a step-wise mechanism
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[14] As product
9 was obtained as a mixture of inseparable
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diastereomers, we were unable to unambiguously assign the
configuration of the newly introduced stereogenic center.
[15] See the Supporting Information for the crystal structure.
CCDC 899243 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
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