Organocatalytic enantioselective [3+2] cycloaddition of azomethine ylides and α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/anie.200700988

(Chemical Equation Presented) One out of a possible 16: Commercially available α,α-diphenylprolinol catalyzes the [3+2] cycloaddition of α,β-unsaturated aldehydes with azomethine ylides derived from imines to produce pyrrolidines as single regioisomers wi

Full text of DOI:10.1002/anie.200700988

Communications
DOI: 10.1002/anie.200700988
Asymmetric Catalysis
Organocatalytic Enantioselective [3+2] Cycloaddition of Azomethine
Ylides and a,b-Unsaturated Aldehydes**
Jose L. Vicario,* Silvia Reboredo, Dolores Badía, and Luisa Carrillo
Asymmetric organocatalysis is a very rapidly growing field of
research as a result of both the novelty of the concept and the
high efficiency and selectivity of many organocatalytic trans-
formations.[1] The operational and economic advantages
associated with this methodology, together with the fact that
organocatalysts are environmentally friendly, robust, and very
often commercially available, have led many research groups
Scheme 1. Proposed enantioselective organocatalytic [3+2] cycloaddi-
tion of azomethyne ylides and a,b-unsaturated aldehydes.
to engage in the development of organocatalytic procedures
for transformations which are typically carried out with
transition-metal catalysts. In this context, proline and other
chiral secondary amines proved to be extremely useful
catalysts for many reactions. Recently, McMillan and co-
workers showed that cycloaddition reactions can take place in
a very efficient manner under organocatalytic conditions
owing to the formation of an iminium ion intermediate and a
consequent decrease in the energy of the lowest unoccupied
molecular orbital (LUMO) of the dienophile.[2]
The catalytic asymmetric [3+2] cycloaddition reaction can
be considered as one of the most powerful and reliable tools
for the enantioselective synthesis of five-membered hetero-
cyclic systems.[3] The asymmetric [3+2] cycloaddition of
azomethine ylides and alkenes is of particular interest
because it allows the preparation of enantiomerically
enriched pyrrolidine structures,[4] which are constituents of
many natural products and pharmaceuticals. However,
despite intensive efforts in recent years by several research
groups, who have developed a number of very efficient
protocols for performing this reaction with chiral metal
complexes as catalysts,[5] an organocatalytic asymmetric
version of this important transformation remains elusive.[6]
We designed the transformation depicted in Scheme 1. It
is known that a-amino acid imines can undergo thermal 1,2-
prototropy to produce azomethine ylides in a kinetically
controlled process;[7] the acidity of the a hydrogen atom is a
key parameter in terms of whether or not this process
occurs.[8] We envisaged that imines 1 would undergo this 1,2-
prototropy process very readily to afford a stabilized azome-
thine ylide, which would react with an a,b-unsaturated
aldehyde under organocatalytic conditions upon the activa-
tion of the aldehyde as an iminium ion. Differentiation of the
enantiotopic faces of the dienophile as a result of the chirality
of the secondary amine catalyst would lead to the formation
of an enantiomerically enriched pyrrolidine 2.
We started our investigation with a set of experiments
directed at the identification of the most efficient amine
catalyst for the cycloaddition of imine 1a and crotonaldehyde
as a model reaction (Table 1).[9] We found that proline (3)
catalyzed the reaction very efficiently to afford 2a in good
yield as a single endo isomer but with moderate enantiose-
lectivity (Table 1, entry 1), while the use of modified proline
compounds, such as 4 and 5, did not lead to a significant
improvement (Table 1, entries 2 and 3). The pyrrolidine
catalyst 6 furnished 2a in excellent yield but with almost no
stereoselectivity (Table 1, entry 4), and imidazolidinone 7,
which performs well in the [3+2] cycloaddition of a,b-
unsaturated aldehydes with nitrones,[6a] was inactive in this
transformation (entry 5). However, when we carried out the
reaction with commercially available a,a-diphenylprolinol (8)
as the catalyst, the cycloaddition product was obtained as a
single endo isomer and with excellent enantioselectivity
(Table 1, entry 6). The necessity of the free OH group in the
catalyst structure was verified by the lack of catalytic activity
of the protected derivative 9 (Table 1, entry 7). The use of the
modified diaryl prolinol 10 led to a similar yield and similar
stereoselectivity to those observed with 8 (Table 1, entry 8).
We found that an increase in the temperature to 48C had a
positive influence on the yield of the product. At this
temperature, the high stereoselectivity of the reaction with
catalyst 8 was maintained (Table 1, entry 9). Furthermore, we
were able to carry out the reaction in THF with no loss of
efficiency (Table 1, entry 10) and, remarkably, observed that
the inclusion of water as an additive resulted in a significant
acceleration of the reaction to furnish the cycloadduct 2a in
better yield in the same reaction time (entry 11). The
incorporation of acid additives to assist the formation of the
activated iminium intermediate was also surveyed, but upon
all attempts the yield of 2a was found to be significantly lower
[*] Prof. J. L. Vicario, S. Reboredo, Prof. Dr. D. Badía, Prof. L. Carrillo
Departamento de Química Orgµnica II
Facultad de Ciencia y Tecnología
Universidad del País Vasco
P.O. Box 644, 48080 Bilbao (Spain)
Fax: (+34)94-601-2748
E-mail: joseluis.vicario@ehu.es
Homepage: http://www.ehu.es/GSA
[**] This research was supported by the University of the Basque
Country (Subvención General a Grupos de Investigación and
UNESCO06/06) and the Spanish Ministerio de Educación y Ciencia
(CTQ2005-02131/BQU).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angewandte
Chemie
Table 1: [3+2] cycloaddition reaction of 1a and crotonaldehyde.[a]
Table 2: Scope of the cycloaddition reaction.[a]
Entry Pro- R1
duct
R2
Yield endo/exo[c] ee
[%][b]
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2a
2b
2c
2d
2e
2 f
2g
2h
2i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Et
nPr
iPr
nBu
Ph
89
91
87
85
88
82
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
92:8
>95:5
93:7
>95:5
>95:5
91:9
98
97
97
95
99
>99
94
>99
99
85
>99
94
93
98
93
99
98
97
Entry Catalyst Solvent T [8C] Yield [%][b] endo/exo[c] ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
3
4
5
6
7
8
9
10
8
8
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
À30
À30
À30
À30
À30
À30
À30
À30
4
77
60
44
86
<5
58
<5
56
67
65
89
55
79
>95:5
>95:5
90:10
60:40
n.d.
72
82
84
5
n.d.
>99
n.d.
>99
98
98
p-NO2C6H4 80
p-MeOC6H4 91
2-furyl
Me
Ph
90
88
93
91
86
74
72
91
84
57
2j
2k
2l
p-MeOC6H4
(3,4-OCH2O)C6H3 Me
3,5-(MeO)2C6H3
>95:5
n.d.
Me
Me
Me
Me
Me
Me
Me
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
2m o-MeOC6H4
2n
2o
2p
2q
2r
p-FC6H4
o-FC6H4
o-tolyl
2-furyl
(E)-CH3CH CH
>95:5
>95:5
>95:5
>95:5
91:9
4
4
4
4
8
8
8
THF[e]
THF[e,f]
THF[e,g]
98
97
98
=
[a] Reactions were carried out with 1a (0.75 mmol), crotonaldehyde
(0.70 mmol), and the catalyst (0.14 mmol) in the indicated solvent
(6 mL). The reaction mixture was stirred for 72 h at the temperature
[a] Reactions conditions: 1 (0.75 mmol), a,b-unsaturated aldehyde
(0.70 mmol), H2O (50 mL), 8 (0.14 mmol), THF (6 mL), 48C, 72 h.
[b] Yield of the isolated product. [c] Determined by 1H NMR spectro-
scopic analysis of the crude reaction mixture. [d] Determined by HPLC
analysis of the corresponding alcohol on a chiral phase.
1
indicated. [b] Yield of the isolated product. [c] Determined by H NMR
spectroscopic analysis of the crude reaction mixture. [d] Determined by
HPLC analysis of the corresponding alcohol on a chiral phase. [e] H2O
(4.0 equiv) was used as an additive. [f] PhCO2H (0.14 mmol) was used
as an additive. [g] Catalyst: 10 mol%. DMF=N,N-dimethylformamide,
TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl, n.d.=not deter-
mined.
after the same reaction time (Table 1, entry 12).[10] Finally, we
also tried to reduce the amount of the catalyst; however, a
slight decrease in the yield of the product was observed after
the same reaction time (Table 1, entry 13). In all experiments,
the cycloaddition product 2a was obtained as a single
regioisomer.
Scheme 2. Reduction of the adducts 2a–r.
The absolute configuration of the cycloadducts 2 was
determined by chemical correlation (Scheme 3). The [3+2]
cycloaddition of imine 12 and crotonaldehyde under the
optimized conditions, followed by reduction, furnished pyr-
rolidine 13 as a single endo isomer with 98% ee. Next,
diastereoselective monohydrolysis followed by decarboxyla-
tion gave the proline derivative 14 as a single 2,5-syn
diastereomer. Finally, 14 was converted into the known
compound 15[12] by standard procedures. A new stereocenter
was generated with complete selectivity in this sequence,
which should facilitate the future preparation of a wide range
of proline derivatives.
The absolute configuration assigned to adducts 2a–r is in
agreement with the stereochemical outcome reported for
other reactions in which catalyst 8 has been involved through
iminium activation.[6c,13] In this context, we propose that
efficient shielding of the Si face of the chiral iminium
intermediate by the bulky aryl groups of 8 leads to a
stereoselective endo-type approach of the E 1,3-dipole to
the sterically less hindered Re face of the intermediate
E iminium ion. The proposed reaction pathway is illustrated
in Scheme 4.
Having established an optimal protocol for the reaction,
we examined the scope and limitations of the method with
regard to the a,b-unsaturated-aldehyde and imine substrates
(Table 2). In all cases, the reaction proceeded smoothly to
furnish the desired pyrrolidines 2 in excellent yields and with
excellent diastereo- and enantioselectivities. Both linear and
branched aliphatic aldehydes, as well as aldehydes with an
aryl or heteroaryl group in the b position, were found to be
suitable dipolarophiles in the [3+2] cycloaddition reaction
with the azomethine ylide derived from 1a (Table 2,
entries 1–9). Good results were also obtained for a variety
of imine substrates (Table 2, entries 10–18). We verified the
necessity of two electron-withdrawing groups on the imine 1
for the reaction: When we attempted the reaction with the
imine derived from glycine methyl ester and benzaldehyde,
no cycloaddition product was observed at all.[11] Pyrrolidines
2a–r were found to be somewhat unstable compounds.
Therefore, after isolation, we reduced them to the stable
amino alcohols 11a–r (Scheme 2) that could be characterized
and stored for several weeks without decomposition.
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Communications
Keywords: asymmetric catalysis · azomethine ylides ·
.
cycloaddition · organocatalysis · pyrrolidines
[1] For selected recent reviews on asymmetric organocatalysis, see:
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cepts to Applications in Asymmetric Synthesis, Wiley-VCH,
Weinheim, 2005.
[2] a) R. M. Wilson, W. S. Jen, D. W. C. MacMillan, J. Am. Chem.
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Maruoka, Org. Lett. 2006, 8, 2687.
Scheme 3. Determination of the absolute configuration of the cyclo-
addition products. Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl,
DMAP=4-dimethylaminopyridine.
[3] For reviews, see: a) H. Pellissier, Tetrahedron 2007, 63, 3235;
b) I. Coldham, R. Hufton, Chem. Rev. 2005, 105, 2765; c) K. V.
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[4] G. Pandey, P. Banerjee, S. R. Gadre, Chem. Rev. 2006, 106, 4484.
[5] For reviews, see: a) C. Nµjera, J. M. Sansano, Angew. Chem.
2005, 117, 6428; Angew. Chem. Int. Ed. 2005, 44, 6272; b) S.
Husinec, V. Savic, Tetrahedron: Asymmetry 2005, 16, 2047; for
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129, 750; d) O. Dogan, H. Koyuncu, P. Garner, A. Bulut, W. J.
Youngs, M. Panzner, Org. Lett. 2006, 8, 4687; e) B. F. Bonini, F.
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2013; Angew. Chem. Int. Ed. 2006, 45, 1979; g) R. Stohler, F.
Wahl, A. Pfaltz, Synthesis 2005, 1431; h) W. Gao, X. Zhang, M.
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[6] For the first reported organocatalytic asymmetric [3+2] cyclo-
addition, see: a) W. S. Jen, J. J. M. Wiener, D. W. C. MacMillan,
J. Am. Chem. Soc. 2000, 122, 9874; for other examples, see:
b) S. S. Chow, M. Nevalainen, C. A. Evans, C. W. Johannes,
Tetrahedron: Asymmetry 2007, 18, 277; c) W. Chen, X.-H. Yuan,
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Scheme 4. A plausible reaction pathway for the enantioselective [3+2]
cycloaddition of azomethine ylides and a,b-unsaturated aldehydes with
catalyst 8.
[7] R. Grigg, Chem. Rev. 1987, 87, 89.
In summary, we have presented the first organocatalytic
enantioselective [3+2] cycloaddition reaction between a,b-
unsaturated aldehydes and azomethine ylides. The reaction
proceeds with complete regioselectivity and with very high
diastereo- and enantioselectivity to furnish almost stereoiso-
merically pure highly functionalized polysubstituted pyrroli-
dines in excellent yields. The utility of this reaction was
exemplified in the synthesis of a proline derivative in which an
additional stereogenic center was created with complete
stereoselectivity. Further investigations on the application of
this method in total synthesis and additional studies focused
on the use of related dipoles and dipolarophiles are in
progress.
[8] R. Grigg, G. Donegan, H. Q. N. Gunaratne, D. A. Kennedy, J. F.
Malone, V. Sridharan, S. Thianpatanagul, Tetrahedron 1989, 45,
1723.
[9] In a preliminary screening, we found that the reaction proceeded
more efficiently in polar solvents, most probably as a result of
their ability to stabilize the 1,3-dipole formed upon 1,2-proto-
tropy.
[10] We also tested the following acid cocatalysts: trifluoroacetic acid
(13% yield), para-toluenesulfonic acid (31% yield), diphenyl-
acetic acid (60% yield), acetic acid (65% yield).
[11] When l-proline (3) or (S)-a,a-diphenylprolinol (8) were used in
an attempted reaction between methyl benzylideneaminoace-
tate and crotonaldehyde in THF or DMF, we did not observe the
formation of a cycloaddition product.
[12] C. Chen, X. Li, S. L. Schreiber, J. Am. Chem. Soc. 2003, 125,
10174.
[13] X.-W. Xie, L. Yue, D. Xue, X.-L. Ma, Y. C. Chen, Y. Wu, J. Zhu,
J.-G. Deng, Chem. Commun. 2006, 1563.
Received: March 6, 2007
Published online: May 30, 2007
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Angew. Chem. Int. Ed. 2007, 46, 5168 –5170