Controlling Asymmetric Remote and Cascade 1,3-Dipolar Cycloaddition Reactions by Organocatalysis

Article abstract of DOI:10.1021/jacs.6b03546

The regio- and stereoselective control of cycloaddition reactions to polyconjugated systems has been demonstrated by applying asymmetric organocatalysis. Reaction of 2,4-dienals with nitrones allows for a highly regio- and stereoselective 1,3-dipolar cycl

Full text of DOI:10.1021/jacs.6b03546

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Communication
Controlling Asymmetric Remote and Cascade 1,3-
Dipolar Cycloaddition Reactions by Organocatalysis
Pernille H. Poulsen, Stefania Vergura, Alicia Monleón,
Danny Kaare Bech Jørgensen, and Karl Anker Jørgensen
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b03546 • Publication Date (Web): 10 May 2016
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Pernille H. Poulsen, Stefania Vergura, Alicia Monleón, Danny Kaare Bech Jørgensen, Karl Anker Jør-
gensen*
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Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
We decided to try to develop novel regio- and stereoselective
cycloaddition reactions based on the concepts in Figure 1. It was
envisioned that this might be possible by choosing a suitable 4-
system for the cycloaddition, such as a nitrone.2 Nitrones can
react as 1,3-dipoles with the nucleophilic oxygen interacting with
the electrophilic carbon generated in either the - or ζ-position of
the 2,4-dienal or 2,4,6-trienal, respectively, by vinylogous-3 or
bis-vinylogous iminium-ion activation with a chiral organocata-
lyst.
Enantioselective 1,3-dipolar cycloaddition reactions of nitrones
with olefins is a very useful methodology for the formation of
isoxazolidines.4 These heterocycles are present in different bioac-
tive compounds5 and have been applied as precursors for the
asymmetric synthesis of natural products.6 In addition, the isoxa-
zolidine ring can be converted into a chiral -amino alcohol,7
very often applied in organic chemistry.8
ABSTRACT: The regio- and stereoselective control of cycload-
dition reactions to polyconjugated systems has been demonstrated
by applying asymmetric organocatalysis. Reaction of 2,4-dienals
with nitrones allows for a highly regio- and stereoselective 1,3-
dipolar cycloaddition in the presence of an aminocatalyst. The
first cycloaddition on the remote olefin can be followed by either
a cascade reaction or by other selective reactions of the remaining
olefin. The chiral products are obtained in good to high yields and
excellent diastereo- and enantioselectivities. The remote selective
concept has been extended to 2,4,6-trienals by means of a novel
enantioselective triple cascade 1,3-dipolar cycloaddition reaction.
The formation of chiral poly 1,3-amino alcohols is also demon-
strated.
Herein we describe a highly regio- and stereoselective 1,3-
dipolar cycloaddition of nitrones to the remote olefin of 2,4-
dienals, which can be followed either by a cascade reaction at the
remaining olefin, or by its functionalization with another reagent
(Figure 1, left). This regioselective strategy to functionalize con-
jugated olefins is based on vinylogous iminium-ion activation of
2,4-dienals and represents the first vinylogous cycloaddition
reaction utilizing LUMO-lowering activation with an aminocata-
lyst.9 Moreover, we introduce unprecedented examples of bis-
vinylogous iminium-ion mediated 1,3-dipolar cycloadditions of
2,4,6-trienals generating a ζ,ε,δ,γ,β,α-functionalized product with
9 contiguous stereocenters (Figure 1, right). Finally, we will
present a transformation which affords chiral poly 1,3-amino
alcohols.10
Control of cycloaddition reactions of polyconjugated systems is a
challenge as multiple reaction sites are available. For polyenals
the challenge is not only to control which olefin reacts in the
cycloaddition, but also to control the stereoselectivity in such
cycloadditions at e.g. the distant olefin. Remote reactions will
allow for further activation and selective functionalization of the
remaining olefin(s) which are still in conjugation with the alde-
hyde. This concept is outlined for 2,4-dienals and 2,4,6-trienals in
Figure 1. For 2,4-dienals (Figure 1, left) the first cycloaddition
can proceed selectively to the distant olefin by reaction with A.
This will allow for either a cascade reaction1 with A, or a reaction
with another reagent (B) at the next olefin. The concept can po-
tentially be extended to 2,4,6-trienals and a triple cascade reaction
might be possible (Figure 1, right). This will, in the case of enan-
tioselective cycloaddition reactions, generate multiple stereocen-
ters in highly substituted and stereochemically dense compounds.
Preliminary results have shown that the ortho-methyl-phenyl
substituted nitrone 2a is a promising substrate for the remote 1,3-
dipolar cycloaddition with 2,4-dienals. Therefore, we initiated our
studies by reacting hexa-2,4-dienal 1a with nitrone 2a applying 5
Figure 1. Stereoselective Remote Cycloaddition and Cycloaddi-
tion Cascade Reactions of 2,4-Dienals (left). Triple Cycloaddition
Cascade Reactions with 2,4,6-Trienals (right).
mol
% of TfOH and 20 mol % of (R)-2-(diphenyl-
(trimethylsilyloxy)methyl)-pyrrolidine 3a as the catalyst in CHCl3
at room temperature. Disappointingly, no product formation was
observed after 40 h (Table 1, entry 1). Studies have revealed that
the trifluoromethyl-substituted diarylprolinol-silyl ether is a more
reactive catalyst than the diphenylprolinol-silyl ether in iminium-
ion/neutral nucleophilic reactions.11 We therefore tested catalyst
3b under the same reaction conditions, and delightfully, conver-
sion to the desired single addition product 4a was observed albeit
with poor enantio- and diastereoselectivity (entry 2). Notably,
complete selectivity for the remote double bond was obtained
without formation of any detectable amount of regioisomeric
products. Catalyst 3c, protected with a more bulky silyl group,
resulted in both improved stereoselectivity and conversion for the
isoxazolidine product 4a (entry 3). Performing the reaction in
other solvents as those shown in entries 4-7 gave addition of 2a to
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both olefins in 1a, and 4a was obtained with lower enantioselec-
sented in entries 8-10, providing the corresponding isoxazolidines
1
2
3
4
5
6
7
8
tivity. We were pleased to observe that exchanging water with sat.
aq. KCl provided 4a in a highly stereoselective manner (entries
8,9). It should be noted that performing the reaction applying a
nitrone having a C-phenyl substituent, rather than the ortho-
methyl-phenyl substituted nitrone 2a, gave a mixture of the single
and double addition products, without being able to control the
remote selectivity exclusively (vide infra). The ortho-substituent
in 4a is expected to introduce steric bulk near the remaining dou-
ble bond in the single addition product making the second cy-
cloaddition reaction less favorable.
4h-j in good yields, high diastereo-, and enantioselectivities. An
exception is for nitrone 2g having phenyl and ortho-methyl phe-
nyl substituents as R2 and R3, respectively (entry 7), for which
47% ee is obtained. This low enantiomeric excess is remarkable
compared with the cascade reaction (vide infra) which proceeds
with high stereoselectivity (Table 3).
Table 2. Scope of the Remote 1,3-Dipolar Cycloaddition Reac-
tion of Nitrones to 2,4-Dienals.a
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Table 1. Remote 1,3-Dipolar Cycloaddition of Nitrone 2a to
2,4-Dienal 1a. Screening Results.a
entry R1
R2,R3
yield
(%)
4a-80
drb,c
eed
(%)
93
1
Me (1a)
Bn,o-MeC6H4
(2a)
Bn,o-BrC6H4
(2b)
Bn,1-naphthyl
(2c)
Bn,4-MeO-1-
naphthyl (2d)
Bn,1-Br-2-
naphthyl (2e)
Me,o-MeC6H4
(2f)
Ph,o-MeC6H4
(2g)
Bn,o-MeC6H4
(2a)
20:1
(14:1)
20:1
(3:1)
20:1
(20:1)
20:1
(20:1)
6:1
(6:1)
20:1
(5:1)
20:1
(20:1)
20:1
2
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
4b-56
4c-73
4d-85
4e-63
4f-66
4g-99
4h-60
4i-72
4j-78
81
92
94
88
93
47
89
90
93
3
entry
solvent
conv.b
(%)
time
drc
eed
(%)
3
4
5
1
CHCl3
CHCl3
CHCl3
CH2Cl2
EtOAc
MeCN
toluene
CHCl3
CHCl3
nr
40 h
40 h
40 h
40 h
40 h
40 h
40 h
48 h
5 d
-
-
3a
3b
3c
3c
3c
3c
3c
3c
3c
2
83
2:1
9:1
5:1
7:1
1:2
20:1
20:1
14:1
62
85
80
78
55
76
89
93
6
3
94
7
4
100
100
46
8
n-hexyl
(1b)
(7:1)
20:1
(20:1)
20:1
5
9
Ph-C2H4
(1c)
Bn,o-MeC6H4
(2a)
Bn,4-MeO-1-
naphthyl (2c)
6
10
Ph-C2H4
(1c)
(20:1)
7
100
88
a Reactions were performed on a 0.1 mmol scale. Diastereomeric ratio
b
determined by H NMR analysis of the isolated product.c Ratio in paren-
1
8e
9e,f
theses refer to the diastereomeric ratio determined by 1H NMR analysis of
d
the crude reaction mixture. Enantiomeric excess was determined by
UPC2 analysis (see Supporting Information).
100
Encouraged by the good regioselectivity observed for the single
1,3-dipolar cycloaddition reaction, we decided to investigate the
possibility of the subsequent functionalization of the remaining
olefin in the substrate. We envisioned a stereoselective cascade
reaction functionalizing both olefins in the 2,4-dienals applying an
additional equivalent of nitrone relative to the amount of alde-
hyde. Gratifyingly, reacting C-phenyl nitrone 2h with hexa-2,4-
dienal 1a under the conditions for the single addition reaction
provided the chiral bi-isoxazolidine product 5a as one diastereoi-
somer in 73% yield and 99% ee without formation of regioiso-
meric products (Table 3, entry 1). In spite of the generation of six
stereocenters, we were pleased to observe that only one stereoi-
somer was formed. Nitrones having different substituents in the
C-phenyl ring were examined in the reaction. It was found that
both electron-donating and electron-withdrawing groups in the
para-position were well tolerated and the corresponding products
5b,c were formed in good yields and excellent stereoselectivities
(entries 2,3). Interestingly, nitrones with ortho- and meta-
substituents also reacted smoothly in the cascade cycloaddition
reaction (entries 4,5). Employing 2-naphthyl-substituted nitrone
2m afforded product 5f in good yield as a single stereoisomer
a Reactions were performed on a 0.1 mmol scale using 1a (2 equiv) and 2a
(1 equiv). b Determined by 1H NMR analysis of the crude reaction mixture.
1
c Diastereomeric ratio was determined by H NMR analysis of the crude
reaction mixture. d Enantiomeric excess was determined by UPC2 analysis
(see Supporting Information). e 0.25 equiv of sat. aq. KCl was used instead
of water. f Performed at 4 °C.
The reaction conditions developed in Table 1 allowed us to di-
rect the stereoselective 1,3-dipolar cycloaddition of nitrones to the
remote olefin of 2,4-dienals. Some representative results are
presented in Table 2. It should be noted that no regioisomeric
products were observed in the 1H NMR analysis of the crude
reaction mixtures. Hexa-2,4-dienal 1a reacted smoothly with
different C-aryl-N-benzyl nitrones. The ortho-methyl-phenyl
substituted nitrone 2a gave the isoxazolidine 4a in high yield,
excellent diastereomeric ratio, and 93% ee (entry 1). Similar
results were obtained for nitrones having C-naphthyl substituents
bearing electron-donating and electron-withdrawing substituents
(entries 3-5). Replacing the N-benzyl substituent with N-methyl
provided the isoxazolidine 4f in good diastereoselectivity and
93% ee (entry 6). The remote 1,3-dipolar cycloaddition reaction
allowed also for varying the substituent in the 2,4-dienal as pre-
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(entry 6). In a similar manner the N-methyl- and N-phenyl-C-
Scheme 1. Diastereodivergent 1,3-Dipolar Cycloaddition
1
2
3
4
5
6
7
8
phenyl nitrones 2n,o reacted with 1a to give 5g,h in very high
diastereoselectivities and up to 99% ee (entries 7,8). The high
stereoselectivity in entry 8 is remarkable compared to the result in
Table 2, entry 7. We attribute the lower enantioselectivity in
Table 2, entry 7 either to the ortho-methyl phenyl substituent
present in nitrone 2f, or that the reaction proceeds faster leading to
lower selectivity. The substituted 2,4-dienals 1b,c also underwent
the stereoselective cascade reaction with nitrone 2h providing the
double 1,3-dipolar cycloaddition products 5i,j in moderate to
good yields and excellent stereoselectivities (entries 9,10).
and Aziridination of Product 4a.
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Table 3. Scope of the 1,3-Dipolar Cycloaddition Cascade
Reaction of Nitrones to 2,4-Dienals.a
entry R1
R2,R3
yield
(%)
5a-73
drb
eec
(%)
99
We wanted to extend the disclosed concept to the functionaliza-
tion of trienes in conjugation with an aldehyde. Reactions of all
three double bonds are only possible if the first cycloaddition
proceeds at the most distal double bond. We anticipated that this
challenge could be solved by activating the system as a bis-
vinylogous iminium-ion intermediate. To the best of our
knowledge this will be the first time this activating mode has been
described.13 In order to test this concept, we decided to apply the
general conditions developed to the reaction between 2,4,6-trienal
1d and 3 equivalents of N-phenyl-para-substituted nitrone 2p
(Scheme 2). Satisfyingly, the three conjugated olefins in 1d par-
ticipated in a triple cascade of 1,3-dipolar cycloadditions generat-
ing the desired product 8a in excellent enantiomeric excess, albeit
with low diastereoselectivity. Similar results were obtained when
the C-naphthyl nitrone 2q was reacted with aldehyde 1d.
1
2
3
4
5
6
7
8
9
Me (1a)
Bn,Ph
(2h)
Bn,p-MeOC6H4
(2i)
Bn,p-BrC6H4
(2j)
Bn,o-MeOC6H4
(2k)
Bn,m-MeC6H4
(2l)
Bn,2-naphthyl
(2m)
Me,Ph
(2n)
Ph,Ph
(2o)
Bn,Ph
(2h)
Bn,Ph
(2h)
20:1
20:1
20:1
20:1
20:1
20:1
20:1
12:1
20:1
20:1
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
5b-52
5c-60
5d-60
5e-60
5f-61
5g-56
5h-86
5i-47
5j-72
99
99
99
99
99
92
99
99
99
Scheme 2. Triple 1,3-Dipolar Cycloaddition Cascade Reac-
tion of Nitrones to Octa-2,4-6-trienal.
n-hexyl
(1b)
10
Ph-C2H4
(1c)
a
Reactions were performed on a 0.1 mmol scale. b Diastereomeric ratio
was determined by 1H NMR analysis of the crude reaction mixture.
c
Enantiomeric excess was determined by UPC2 analysis (see Supporting
Information).
The absolute configuration of the products is determined by X-
ray analysis of the alcohol of 5c and the stereochemistry of the
remaining compounds is based on analogue (see Supporting In-
formation).
The olefin present in the isoxazolidine substituted enal 4 can not
only react in cascade cycloadditions with one type of nitrone, but
is also reactive toward different nitrones as well as other nucleo-
philes. First, a diastereodivergent reaction of 4a with the 2-
naphthyl-substituted nitrone 2m was demonstrated affording the
diastereomeric products 6a and 6b in decent yields and 99% ee
(Scheme 1). Some degree of match/mismatch is observed as the
products are obtained in very good, but slightly different diastere-
omeric ratios. Second, the product 4a was reacted with TsONH-
Boc in an organocatalytic aziridination reaction.12 The product 7
was obtained in good yield and excellent stereoselectivity using
catalyst 3b (Scheme 1).
The isoxazolidine ring formed in the described 1,3-dipolar cy-
cloaddition reactions is a common precursor for the formation of
1,3-amino alcohols. Therefore, the chiral highly functionalized
isoxazolidine rings in the products 5 and 8 are interesting for the
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iminium-ion activation, see e.g.: (e) Marigo, M.; Schulte, T.; Franzén, J.;
synthesis of poly 1,3-amino alcohols which contain 6 and 9 stere-
ocenters, respectively. Treatment of product 5c with SmI2 led to
the chiral poly 1,3-amino alcohol 9 with no loss of enantiomeric
purity as outlined in Scheme 3.
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. (f) Enders, D.;
Hüttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861. (g) Ko-
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metal or NHC activation see e.g.: (h) Belot, S.; Vogt, K. A.; Besnard, C.;
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G.-L.; Córdova, A. Tetrahedron Lett. 2007, 48, 5976. For an example of a
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formed 2,4-dienal, see: (j) Zhou, Z.; Feng, X.; Yin, X.; Chen, Y.-C. Org.
Lett. 2014, 16, 2370.
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4
5
6
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Scheme 3. Formation of 1,3-Amino Alcohols by Reaction of
Bi-isoxazolidine 5c with SmI2.
8
9
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In conclusion we have demonstrated a novel reaction concept
by which aminocatalysis is applied for the regio- and stereoselec-
tive control of the cycloaddition reaction to the remote olefin in
polyenals. It has been shown that reaction of 2,4-dienals with
nitrones in the presence of a diarylprolinol-silyl ether catalyst
allows for a highly regio- and stereoselective remote 1,3-dipolar
cycloaddition reaction with enantioselectivities up to 94% ee. This
cycloaddition can be followed by either a cascade reaction or by
other selective reactions of the remaining olefin. In the case of the
addition of two equivalents of the nitrones by a cascade reaction,
the chiral bi-isoxazolidines are obtained in good yields, up to 20:1
dr, and 99% ee. It is also demonstrated that the remaining olefin
can react in a diastereodivergent organocatalytic 1,3-dipolar cy-
cloaddition and aziridination reaction giving 99% ee and 94% ee,
respectively. The remote selective concept was extended to 2,4,6-
trienals demonstrating for the first time an enantioselective triple
cascade 1,3-dipolar cycloaddition reaction giving the tri-
isoxazolidine product in 99% ee. Finally, a reductive ring-opening
reaction of both isoxazolidine rings in one of the chiral bi-
isoxazolidines providing a chiral poly 1,3-amino alcohol main-
taining the enantiomeric excess was facilitated.
Experimental procedures, analytical data, and NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(8) (a) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107,
767. (b) Frederickson, M. Tetrahedron 1997, 53, 403.
(9) Asymmetric vinylogous Diels-Alder reactions utilizing a chiral
Brønsted acid catalyst or a gold(III) catalyst have been reported: (a) Tian,
X.; Hofmann, N.; Melchiorre, P. Angew. Chem. Int. Ed. 2014, 53, 2997.
(b) Wu, C.-Y.; Horibe, T.; Jacobsen, C. B.; Toste, F. D. Nature 2015, 517,
449. A stepwise annulation reaction of vinylogous cyclopentenones with
-butyrolactams mediated by vinylogous iminium-ion-dienamine catalysis
has been demonstrated: (c) Gu, X.; Guo, T.; Dai, Y.; Franchino, A.; Fei,
J.; Zou, C.; Dixon, D. J.; Ye, J. Angew. Chem. Int. Ed. 2015, 54, 10249.
(10) Hanessian, S.; Vakiti, R. R.; Chattopadhyay A. K.; Dorich, S.; La-
vallée, C. Bioorg. Med. Chem. 2013, 21, 1775.
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(12) (a) Jiang, H.; Halskov, K. S.; Johansen, T. K.; Jørgensen, K. A.
Chem. Eur. J. 2011, 17, 3842. (b) Vesely, J.; Ibrahem, I.; Zhao, G.-L.;
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kaj@chem.au.dk
The authors declare no competing financial interests.
This work was made possible by support from Aarhus University
and Carlsberg Foundation. A. M. thanks the Generalitat Valencia-
na and Universitat de València (Spain) for a postdoctoral grant
(VALi+d program). S. V. thanks Universita degli Studi della
Basilicata (Italy) for a Ph.D. grant. Thanks are expressed to Line
Næsborg, and Vibeke H. Lauridsen for X-ray analysis.
(13) A regio- and stereoselective 1,8-addition of azlactones to trienyl
N-acylpyrroles catalyze by a chiral P-spiro triaminoiminophosphorane has
been described: Uraguchi, D.; Yoshioka, K.; Ueki, Y.; Ooi, T. J. Am.
Chem. Soc. 2012, 134, 19370.
(1) For recent reviews, see: (a) Wang, Y.; Lu, H.; Xu, P.-F. Acc. Chem.
Res. 2015, 48, 1832. (b) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem.
Res. 2012, 45, 1278. (c) Grondal, C.; Jeanty, M.; Enders, D. Nat. Chem.
2010, 2, 167. (d) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037.
For examples on three-component cascade reactions utilizing enamine and
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