Cross-trienamines in asymmetric organocatalysis

Article abstract of DOI:10.1021/ja3068269

Cross-conjugated trienamines are introduced as a new concept in asymmetric organocatalysis. These intermediates are applied in highly enantioselective Diels-Alder and addition reactions, providing functionalized bicyclo[2.2.2]octane compounds and γ′-addition products, respectively. The nature of the transformations and the intermediates involved are investigated by computational calculations and NMR analysis.

Full text of DOI:10.1021/ja3068269

Communication
pubs.acs.org/JACS
Cross-trienamines in Asymmetric Organocatalysis
Kim Søholm Halskov, Tore Kiilerich Johansen, Rebecca L. Davis, Marianne Steurer, Frank Jensen,
and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
S
* Supporting Information
might be possible. This cross-conjugated trienamine inter-
ABSTRACT: Cross-conjugated trienamines are intro-
duced as a new concept in asymmetric organocatalysis.
These intermediates are applied in highly enantioselective
Diels−Alder and addition reactions, providing function-
alized bicyclo[2.2.2]octane compounds and γ′-addition
products, respectively. The nature of the transformations
and the intermediates involved are investigated by
computational calculations and NMR analysis.
mediate could then hopefully undergo either a [4 + 2]-
cycloaddition reaction, forming γ′,δ-functionalized products, or
a γ′-selective addition reaction (Figure 1b).
Herein, we present the first asymmetric organocatalyzed
Diels−Alder reaction via cross-trienamine intermediates, which
provides the enantioselective functionalization at the γ′,δ-
carbon centers of cyclic dienals. Furthermore, highly γ′-selective
additions have been developed using more polarized olefins.
The methodologies presented represent novel reactivity and
selectivity concepts in organocatalysis. In contrast to previous
work on cross-conjugated dienamines,8 where the enone
substrates employed often require specific substitution patterns
to ensure exclusive formation of desired products,9 the present
approach provides exclusive cross-conjugated reactivity, despite
being able to form alternative conjugated intermediates. The
cross-conjugated trienamine Diels−Alder reaction shows the
conversion of cyclic 2,4-dienals into functionalized
bicyclo[2.2.2]octanes or octenes with four stereocenters.
These polycyclic compounds have a widespread presence in
nature;10 however, their synthesis is not trivial and the
development of effective methods, which exhibit high
selectivity, still represents a challenge.11
ovalent activation of carbonyl compounds, facilitated by
Cchiral amines, plays a dominant role in asymmetric
catalysis.1 The past decade has witnessed the development of α-
functionalization by enamine catalysis,2 β-functionalization via
iminium ion catalysis3 and γ-functionalization by dienamine
catalysis.4 Recently, trienamine catalysis has emerged as a new
mode of activation involving chiral amine catalyzed, asymmetric
Diels−Alder reactions of electron-poor dienophiles with 2,4-
dienals5 or 2,4-dienones.6
Trienamine catalysis has focused on the promotion of
asymmetric functionalization of the β,ε-carbon centers in the
trienamine intermediate, leading to functionalized cyclohexene
products (Figure 1a). As recently highlighted by Melchiorre et
al., cross-conjugated trienamines have until now been perceived
as nonproductive reaction intermediates.7 However, we
envisioned that a new development in organocatalysis, in
which cross-conjugated trienamine intermediates are involved,
In the present study, we focus first on 3-olefinic oxindoles
and 5-olefinic azlactones as dienophiles. The [4 + 2]-
cycloaddition of the trienamine intermediate with these
dienophiles provides spirocyclic oxindoles and azlactones.
Substituted oxindoles are found in a number of natural
products exhibiting biological activity12 and have attracted a
lot of attention.13 The products obtained from the reaction
with the 5-olefinic azlactones are highly functionalized amino
acid precursors.14
Initial studies revealed that 3-olefinic oxindoles were indeed
suitable dienophiles for the [4 + 2]-cycloaddition. Reaction of
2,4-dienal 1a (1:1 E/Z mixture) with the 3-olefinic oxindole 2a,
20 mol % diphenylprolinol silyl ether catalyst 3, and 20 mol %
o-fluorobenzoic acid (o-FBA) in CDCl3 at 40 °C gave full
conversion to 4a within 20 h (Table 1, entry 1).
The fact that product 4a results from a cross-conjugated
trienamine intermediate is surprising given that the formation
of the linear-trieneamine intermediate is not suppressed. To
understand why the cycloaddition occurs via the cross-
conjugated trienamine, a combination of computational and
NMR studies were performed. Calculations (MPW1K/6-
31+G(d,p)) on a simplified model system of the two
Received: July 13, 2012
Published: July 26, 2012
Figure 1. Linear and cross-conjugated trienamines in organocatalysis.
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
reaction of B+C. Both products (D1 and D2) resulting from
cycloaddition of A+C are higher in energy than the products
(E1 and E2) produced by the cycloaddition of B+C.
Comparison of the two thermodynamic products of A+C and
B+C (D1 and E1, respectively) shows E1 to be 8.8 kcal/mol
lower in energy than D1. It should be noted that the
thermodynamic product E1 corresponds to the observed
product (4a). The increased thermodynamic stability of the
products of the [4 + 2]-cycloaddition through the cross-
trienamine B results from the formation of a conjugated π-
system, which is not formed in the cycloaddition of A with C.
The data suggest that if the reaction was under kinetic
control, the products resulting from the [4 + 2]-cycloaddition
of the linear-trienamine intermediate should be the major
products. However, the only observed product is that resulting
from the cycloaddition with the cross-trienamine intermediate.
This suggests that the reaction is thermodynamically driven.
Motivated by the initial synthetic and computational results,
a screening of reaction conditions was performed. Decreasing
the catalyst and additive loadings to 10 mol % each lowered the
conversion (Table 1, entry 2). Acid additives were shown to be
necessary for high conversion (entry 3). By employing HOAc
as an additive, full conversion and similar diastereoselectivities
as for o-FBA were obtained; however, the enantioselectivity
dropped significantly (entry 4). Changing the additive to
benzoic acid (BA) also resulted in a lower enantioselectivity
(entry 5), whereas o-nitrobenzoic acid (o-NBA) provided
similar conversion and selectivities as o-FBA (entry 6). The
enantioselectivity seems to correlate with the acidity of the
additive.
Table 1. Optimization of the Cross-Conjugated Trienamine
Asymmetric Diels−Alder Reaction of the Cyclic 2,4-Dienal
a
1a and 3-Olefinic Oxindole 2a
b
b
c
ent
3 (mol %)
add (mol %)
conv (%)
dr
ee (%)
1
2
3
4
5
6
20
10
20
20
20
20
o-FBA (20)
o-FBA (10)
none
>95
44
8:1
8:1
8:1
8:1
8:1
8:1
97
d
nd
d
53
nd
HOAc (20)
BA (20)
>95
>95
70
80
97
o-NBA (20)
>95
a
b
1
See Supporting Information. Determined by H NMR of the crude
c
d
mixture of 4a. Determined by chiral stationary phase HPLC. nd: not
determined.
trienamine intermediates A (linear-trienamine intermediate)
and B (cross-trienamine intermediate) show that A is favored
by 4.2 kcal/mol relative to B (Figure 2).15 This is consistent
with the hypothesis that deprotonation at the ε-position is
favored over deprotonation at the γ′-position because it
provides a fully conjugated π-system. Based on this energy
difference, it should be expected that the linear-trienamine
intermediate is present in higher concentrations than the cross-
1
trienamine. This was confirmed by H NMR studies, which
The absolute configuration of compound 4a was established
to be (S,S,S,S) by X-ray analysis, based on a chloro-analogue of
4a.20
showed that only the linear trienamine could be detected (see
Supporting Information (SI) for NMR studies).
Next, the effect of substituents on dienal 1 was investigated
(Table 2). A 1:1 E/Z mixture of 2,4-dienal 1b, which contains a
methyl substituent in the δ-position, gave similar, excellent
selectivities as those obtained with 1a (entries 1,2). The γ-
substituted 2,4-dienals provided products 7, which contain an
endocyclic double bond, after reaction with Wittig reagent 5
(entries 3−6). The lack of tautomerization in these cases is
probably due to stabilization of the endocyclic double bond by
the electron-donating γ-substituent. Alkyl substituents in the γ-
position furnished their respective products in excellent
enantioselectivities (entries 3,4). Excellent results were also
obtained when methoxy and tert-butyldimethyl silyl ether
(OTBDMS) substituents were used (entries 5,6).
To test the generality of the reaction, structural variations
were made on the 3-olefinic oxindole 2 (Table 3). Substituents
of different electronic natures on the aromatic ring could be
tolerated in the reaction and provided their respective products
7e−i in good yields and selectivities (entries 1−5). Utilizing an
N-unprotected oxindole provided comparable good results for
compound 7j (entry 6). Finally, variations at the olefinic part of
the oxindole were examined. A benzoyl substituent gave
product 7k in a good yield and excellent diastereo- and
enantioselectivity (entry 7), whereas the nitrile-substituted
oxindole furnished 7l in a good yield and excellent
enantioselectivity, albeit with a lower diastereoselectivity
(entry 8).
Figure 2. Calculated reaction pathways for the organocatalytic [4 + 2]-
cycloaddition of the linear (top) and cross-conjugated (bottom)
trienamines. Energies are reported in kcal/mol and are relative to the
energy of A+C.
To provide insight as to why the Diels−Alder reaction occurs
via the higher energy trienamine intermediate B, the [4 + 2]-
cycloaddition of the reaction was modeled computationally.16
In this study, reactions of both A (linear-trienamine
intermediate) and B (cross-trienamine intermediate) were
examined.17,18 In both cases, the [4 + 2]-cycloaddition was
found to be a concerted, highly asynchronous process.19 The
transition state structures for the reaction of A+C are both
lower in energy than the transition state structures for the
The absolute configuration of 7 was established by X-ray
analysis of a derivatized product of the aldehyde precursor from
product 7e.20 Configurations of the other products of type 7
were assigned by analogy.
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Journal of the American Chemical Society
Communication
Table 2. Scope of the Cross-Conjugated Trienamine
Asymmetric Diels−Alder Reaction of Substituted 2,4-
Dienals 1a−f with the 3-Olefinic Oxindole Substrate 2a
Table 4. Scope of the Cross-Conjugated Trienamine
Asymmetric Diels−Alder Reaction of 2,4-Dienal 1f with β-
a
a
Aryl-Substituted Olefinic Azlactones 8
b
c
ent
Ar
yield (%)
dr
ee (%)
d
1
2
3
4
4-(CO2Me)-C6H4; 8a
3-Cl-C6H4; 8b
Ph; 8c
9a (58)
9b (54)
9c (40)
9d (34)
5:1
4:1
4:1
3:1
99
e
98
e
98
e
2-thiophenyl; 8d
92
b
c
d
a
b
ent
R1, R2
H, H; 1a
yield (%)
dr
ee (%)
See SI. Yields refer to the diastereomerically pure products 9
c
1
e
isolated by FC. Determined by H NMR of the crude mixture of the
1
6a (53)
6b (48)
7a (51)
7b (53)
7c (52)
7d (62)
8:1
8:1
97
92
98
99
99
99
d
e
aldehyde. Determined by chiral stationary phase UPC2. Determined
by chiral stationary phase HPLC.
f
2
H, Me; 1b
3
4
5
6
Me, H; 1c
9:1
Bn, H; 1d
8:1
The cross-trienamine reaction concept is not limited to
Diels−Alder reactions, as employing vinyl bis-sulfones 10 gave
a selective γ′-addition (Table 5).21 Reaction of 1,1-bis-
(phenylsulfonyl)ethylene 10a with 1f provided product 11a
in good yield and high enantioselectivity (entry 1). β-Phenyl
vinyl bis-sulfone 10b reacted with 1f and 1c (entries 2,3),
giving a good yield of the major diastereomer. The
enantioselectivity was excellent, and the configuration was
established by X-ray analysis of 11b.20
OMe, H; 1e
OTBDMS, H; 1f
11:1
>20:1
a
Reactions were performed on a 0.1 mmol scale; aldehyde 4 was
functionalized by in situ Wittig olefination, giving 6 (see SI). Yields
refer to the diastereomerically pure products 6 and 7 isolated by FC.
b
c
The value for 6 is a combined yield of E/Z isomers. Determined by
d
1H NMR of the crude mixture before addition of 5. Determined by
e
chiral stationary phase HPLC and UPC2. Reaction was performed at
f
40 °C. 20 mol % BA was used instead of o-FBA.
Table 3. Scope of the Cross-Conjugated Trienamine
Table 5. Scope of the Cross-Conjugated Trienamine
Promoted, Asymmetric Diels−Alder Reaction of 2,4-Dienal
Asymmetric γ′-Addition of 2,4-Dienals 1 with Vinyl Bis-
a
a
1f with 3-Olefinic Oxindoles 2b−i
sulfones 10
b
c
d
ent
R1
R2
yield (%)
dr
ee (%)
b
c
d
ent
R1, R2
yield (%)
dr
ee (%)
1
2
3
OTBDMS
OTBDMS
Me
H
11a (73)
11b (41)
11c (48)
−
2:1
93
99
99
1
2
3
CO2Et, 5-Cl; 2b
CO2Et, 5-F; 2c
CO2Et, 5-NO2; 2d
CO2Et, 5,7-Me,Me; 2e
CO2Et, 5-OMe; 2f
CO2Et, H; 2g
7e (75)
7f (54)
7g (61)
7h (66)
7i (49)
7j (65)
7k (62)
7l (57)
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
7:1
99
99
99
99
99
99
99
99
Ph
Ph
3:1
a
b
See SI. Yields refer to the diastereomerically pure products 11
e
4
c
isolated by FC. Determined by 1H NMR of the crude mixture.
5
d
Determined by chiral stationary phase UPC2.
f
6
7
8
COPh, H; 2h
CN, H; 2i
b
In summary, we have developed a new concept in
organocatalysis, cross-trienamines. These intermediates are
demonstrated to undergo highly enantioselective Diels−Alder
reactions with 3-olefinic oxindoles and 5-olefinic azlactones,
providing an attractive path to important bicyclic structures.
Furthermore, we have also shown that cross-trienamines can
react in a highly enantioselective γ′-addition with vinyl bis-
sulfones. Additionally, calculations and NMR studies were
carried out to provide insight into the cross-trienamine
intermediates.
a
See SI. Yields refer to the diastereomerically pure products 7
c
isolated by FC. Determined by 1H NMR analysis of the crude mixture
d
of the aldehyde. Determined by chiral stationary phase HPLC.
Compound 7h was prepared at 40 °C for the Diels−Alder reaction.
N-Unprotected oxindole was used.
e
f
Finally, the cross-conjugated trienamine concept has been
extended to other dienophiles. β-Aryl-substituted olefinic
azlactones 8a−d were shown to undergo Diels−Alder reactions
yielding products 9a−d in excellent enantioselectivities (Table
4). Good yields were obtained with azlactones carrying
electron-withdrawing substituents on the aryl moiety (entries
1,2); however, by employment of electron-rich substituents the
yield dropped (entry 4).
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, analytical data, computational details,
and NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Communication
(12) (a) Bindra, J. S. The Alkaloids; Manske, R. H. F., Ed.; Academic
Press: New York, 1973; Vol. 14, p 84. (b) Galliford, C. V.; Scheidt, K.
A. Angew. Chem., Int. Ed. 2007, 46, 8748. (c) Peddibhotla, S. Curr.
Bioact. Compd. 2009, 5, 20. (d) Trost, B. M.; Brennan, M. K. Synthesis
2009, 3003.
AUTHOR INFORMATION
Corresponding Author
kaj@chem.au.dk
Notes
■
(13) Recent reviews and selected examples covering organocatalytic,
enantioselective formation of spirocyclic oxindoles: (a) Rios, R. Chem.
Soc. Rev. 2012, 41, 1060. (b) Jiang, K.; Jia, Z.-J.; Chen, S.; Wu, L.;
Chen, Y.-C. Chem.Eur. J. 2010, 16, 2852. (c) Wei, Q.; Gong, L.-Z.
Org. Lett. 2010, 12, 1008. (d) Tan, B.; Candeias, N. R.; Barbas, C. F. J.
Am. Chem. Soc. 2011, 133, 4672.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by the Aarhus University,
OChem School, FNU and the Carlsberg Foundation. Dr. Jacob
Overgaard is gratefully acknowledged for performing X-ray
analysis. Thanks are expressed to Dr. Hao Jiang for rewarding
discussions. M.S. thanks the Austrian Science Fund (FWF) for
(14) For example, see: Alba, A.-N. R.; Rios, R. Chem.Asian J. 2011,
6, 720.
(15) Calculations were performed with GAUSSIAN09. Geometries
were optimized with the MPW1K/6-31+G(d,p) level of theory and
basis set ( Lynch, B. J.; Patton, L. F.; Harris, M.; Truhlar, D. G. J. Phys.
Chem. A 2000, 104, 4811 ) in the gas phase. Reported values are zero-
point corrected electronic energies. See SI for full details and complete
references on theoretical methods.
a postdoctoral Erwin Schrodinger fellowship (J 3053-N19).
̈
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