Exo-selective asymmetric Diels-Alder reaction of 2,4-dienals and nitroalkenes by trienamine catalysis

Article abstract of DOI:10.1002/anie.201102013

Raising the HOMO: 2,4-Dienals can react with nitroalkenes in trienamine-catalyzed asymmetric Diels-Alder reactions (see scheme). Crucial for the success is raising the HOMO energy of the diene through the introduction of appropriate substituents. The reaction exhibits unusually high enantioselectivity and exo selectivity; endo addition is possibly disfavored because of the electrostatic repulsion shown in the scheme. Copyright

Full text of DOI:10.1002/anie.201102013

Communications
DOI: 10.1002/anie.201102013
Diels–Alder Reaction
exo-Selective Asymmetric Diels–Alder Reaction of 2,4-Dienals and
Nitroalkenes by Trienamine Catalysis**
Zhi-Jun Jia, Quan Zhou, Qing-Qing Zhou, Peng-Qiao Chen, and Ying-Chun Chen*
The asymmetric Diels–Alder reaction continues to generate
research interest in organic chemistry because it provides one
of the most powerful protocols to prepare six-membered
carbo- or heterocycles with multiple chiral centers. The
asymmetric Diels–Alder reaction is dominated by the activa-
tion of the LUMO of electron-poor dienophiles with chiral
metal complexes[1] or organic molecules.[2] However, over the
past decade, an alternative strategy has emerged in which the
asymmetric Diels–Alder reaction can be promoted and
controlled by raising the energy of the HOMO of the
dienophile (inverse electron demand) or the diene (normal
electron demand) through enamine[3] or dienamine cataly-
sis.[4,5] Very recently, our research group and Jørgensen and
co-workers[6] further expanded the synthetic potential of such
an activation mode. It was discovered that a trienamine
intermediate, which was generated in situ from 2,4-hexadie-
nal and a chiral secondary amine, could serve as a diene in a
normal-electron-demand Diels–Alder reaction with electron-
deficient dienophiles, such as 3-olefinic oxindoles. The
reaction exhibited exclusive regioselectivity and afforded
the endo products in excellent ee and d.r. values [Eq. (1),
Boc = tert-butyloxycarbonyl].[6]
Unfortunately, we subsequently found that the reaction is
limited to highly activated dienophiles, such as alkylidene-
cyanoacetates. Although nitroalkenes typically demonstrate
good dienophilicity in numerous Diels–Alder reactions,[7] the
cycloaddition of 2,4-hexadienal and b-nitrostyrene did not
proceed even at higher temperature (808C).[8] Although
nitro-containing materials have great synthetic versatility in
organic chemistry, there is still scarce precedence for catalytic
stereoselective Diels–Alder reactions of nitroalkenes[9,10] in
comparison with the wealth of asymmetric Michael addition
reactions.[11] As a result, the development of such an
asymmetric Diels–Alder reaction would be highly desirable.
We envisioned that the electron-donating effect of appropri-
ate alkyl substituents could further raise the HOMO level of
the trienamine intermediate (Scheme 1),[12] such that the
reaction barriers of the desired cycloaddition might be
overcome.
Scheme 1. Diels–Alder reaction of nitroalkenes with 2,4-dienals by the
strategy of raising the HOMO energy.
Based on the above-mentioned considerations, 5-methyl-
2,4-hexadienal (2a) was prepared and tested in the possible
reaction with b-nitrostyrene 3a catalyzed by the chiral
secondary amine 1a and o-fluorobenzoic acid in CHCl3 at
ambient temperature.[13] Gratifyingly, the desired Diels–
Alder reaction occurred, which verified the beneficial effect
of the 5-methyl group in raising the HOMO energy of the
trienamine intermediate.[14] After 72 h, cycloadduct 4a was
isolated in moderate yield as an inseparable mixture of
diastereomers, but with high diastereo- and enantioselectivity
(Table 1, entry 1). Moreover, the reaction could be greatly
accelerated at higher temperatures, providing 4a in higher
yield and with maintained stereocontrol (Table 1, entry 2).
Much poorer results were achieved when other solvents were
used (Table 1, entries 3–5). In addition, slightly lower yields
were obtained when either benzoic acid or p-methoxybenzoic
acid were applied (Table 1, entries 6 and 7). Subsequently, a
few chiral secondary amines were explored. The results could
not be improved when the bulkier catalysts 1b and 1c were
[*] Z.-J. Jia, Q. Zhou, Q.-Q. Zhou, P.-Q. Chen, Prof. Dr. Y.-C. Chen
Key Laboratory of Drug-Targeting and
Drug Delivery System of the Education Ministry
Department of Medicinal Chemistry
West China School of Pharmacy
Sichuan University
Chengdu, 610041 (China)
E-mail: ycchenhuaxi@yahoo.com.cn
Prof. Dr. Y.-C. Chen
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041(China)
[**] We are grateful for financial support from the NSFC (20972101 and
21021001) and the National Basic Research Program of China (973
Program, 2010CB833300).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102013.
8638
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Angew. Chem. Int. Ed. 2011, 50, 8638 –8641

Table 1: Screening studies of the Diels–Alder reaction of 5-methyl-2,4-
hexadienal 2a and b-nitrostyrene 3a[a]
Entry
1
Solvent
Acid
t [h]
Yield
[%][b]
d.r.[c]
ee
[%][d]
1[e]
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
CHCl3
CHCl3
MeCN
toluene
dioxane
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
OFBA
OFBA
OFBA
OFBA
OFBA
BA
PMBA
OFBA
OFBA
OFBA
OFBA
72
2
96
96
96
6
6
3
3
96
17
59
87
43
55
75
79
71
87
75
31
85
93:7
93
93
86
87
91
92
93
93
89
75
86
90:10
84:16
95:5
95:5
91:9
90:10
89:11
91:9
>95:5
85:15
10
11[f]
[a] Unless noted otherwise, reactions were performed with 2a
(0.2 mmol), 3a (0.1 mmol), 1 (0.02 mmol), and acid (0.02 mmol) in
solvent (0.5 mL) at 558C. [b] Yield of isolated inseparable diastereomers.
[c] Determined by 1H NMR analysis. [d] Determined by HPLC analysis on
a chiral stationary phase after conversion of the product into the alcohol,
for the major diastereomer. [e] At RT. [f] At 1.0 mmol scale. BA=benzoic
acid, OFBA=o-fluorobenzoic acid, PMBA=p-methoxybenzoic acid,
TMS=trimethylsilyl, TES=triethylsilyl.
applied (Table 1, entries 8 and 9). Although the reaction that
was catalyzed by amine 1d bearing electron-withdrawing aryl
groups resulted in an excellent diastereomeric ratio, the
conversion was quite low and the enantioselectivity was also
dramatically decreased (Table 1, entry 10). Finally, we tested
the cycloaddition reaction on a larger scale under the
optimized conditions; slightly lower stereoselectivity with
high yield was attained (Table 1, entry 11).
Scheme 2. Substrate scope of the Diels–Alder reaction. Reactions
leading to 4a–4p were performed with 2 (0.2 mmol), 3 (0.1 mmol),
catalyst 1a, and OFBA (20 mol%) in CHCl3 (0.5 mL) at 558C; in
reactions leading to 4q–4t, 2 (0.1 mmol) and 3 (0.2 mmol) were used.
The yields are those of isolated inseparable diastereomers. The d.r.
values were determined by 1H NMR analysis. The ee values (major
diastereomer) were determined by HPLC analysis on a chiral stationary
phase after conversion of the product into the corresponding alcohol.
The absolute configuration of 4n was determined by X-ray analysis
after conversion into the 2,4-dinitrobenzenehydrazone (see the Sup-
porting Information).[16] The other products were assigned by analogy.
cHex=cyclohexyl, Nap=naphthyl.
Next, an array of diversely substituted 2,4-dienals and
nitroalkenes were explored for this new asymmetric Diels–
Alder reaction (Scheme 2). At first, a number of nitroalkenes
bearing aryl or heteroaryl groups were reacted with 5-methyl-
2,4-hexadienal (2a). The substitution patterns were well
tolerated, and in general products 4a–4j were obtained with
good yields and in high diastereo- and enantioselectivities. We
also paid much attention to the substrate scope of and
limitations on the 2,4-dienals. 4-Alkyl-substituted 2,4-hexa-
dienals and 2,4-heptadienals could be utilized, affording
cyclohexenes 4k–4n with good stereocontrol. Interestingly,
2,4-dienals with a 4-phenyl group exhibited even higher
reactivity,[12] and excellent yield and stereoselectivity were
attained for products 4o and 4p. Moreover, the combinations
with nitroalkenes carrying linear or branched alkyl groups
were also compatible and provided products 4q and 4r with
high d.r. and ee values. Importantly, bicyclic compounds 4s
and 4t, whose skeletons are common motifs in natural
products, could be efficiently constructed, although polyhy-
dronaphthalene 4s was only isolated in modest yield because
of incomplete conversion. In addition, we tested some tri- and
tetrasubstituted nitroalkenes, but the results were not satisfy-
ing (see the Supporting Information).[15]
The multifunctionality of the Diels–Alder adducts enables
further transformations to access chiral compounds with
higher degrees of molecular complexity. As outlined in
Scheme 3, the alcohol generated from Diels–Alder adduct
4a was readily converted to tetrahydrofuran derivative 5 as an
isolable single diastereomer by an iodoetherization process.
Moreover, the domino Michael addition/aldol reaction of 4a
and acrolein proceeded smoothly by tetramethylguanidine
catalysis, affording the fused bicyclic product 6 bearing a
quaternary chiral center.[17,18]
Angew. Chem. Int. Ed. 2011, 50, 8638 –8641
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www.angewandte.org 8639

Communications
observed product exo-4n.[21] Nevertheless, more studies are
still required to elucidate this exo-selective Diels–Alder
reaction.
In conclusion, we have presented the first asymmetric
Diels–Alder reaction of 2,4-dienals and nitroalkenes by a
newly developed trienamine catalysis. The strategy of raising
the HOMO energy through the introduction of appropriate
substituents in the skeleton of 2,4-dienals proved to be
successful since unsubstituted 2,4-hexadienal and 2,4-hepta-
dienal were inactive under the same catalytic conditions.
Many diversely substituted 2,4-dienals and nitroalkenes have
been explored, generally giving densely substituted chiral
cyclohexene derivatives in high diastereo- and enantioselec-
tivities. Moreover, an unexpected exo selectivity was observed
in this Diels–Alder reaction, and a plausible mechanism
based on electrostatic repulsion between the nitro group of
the dienophile and the p electrons of the enamine motif was
proposed. We also believe that the strategy of raising the
HOMO energy for trienamine catalysis could be applicable to
more cycloadditions or other types of reactions of 2,4-dienals.
These studies are currently under way in our laboratory and
the results will be reported in due course.
Scheme 3. Synthetic transformations of Diels–Alder adduct 4a.
TMG=tetramethylguanidine.
To study the selectivity of the reaction, we obtained the X-
ray structure of enantiopure 4n after conversion to its 2,4-
dinitrobenzenehydrazone derivative.[16] Surprisingly, the
product displays an exo configuration in contrast to the
previous endo-favored stereoselectivity of 3-olefinic oxin-
doles.[6] Although an exo-selective Diels–Alder reaction[19] of
nitroalkenes with Danishefsky’s diene was reported to be
based on electrostatic repulsion between the nitro group and
the silyloxy group of the diene,[20] the O-trimethylsilyl
(OTMS) ether moiety of catalyst 1a would not account for
the exo selectivity in a similar way in the present study. As
shown in Scheme 4, catalysts 1e and 1 f delivered the same
Received: March 22, 2011
Revised: June 28, 2011
Published online: July 22, 2011
Keywords: asymmetric catalysis · cycloaddition · 2,4-dienals ·
.
enantioselectivity · trienamine catalysis
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