Asymmetric Diels - Alder reactions of 2-pyrones with a bifunctional organic catalyst

Article abstract of DOI:10.1021/ja070859h

The reactions of 2-pyrones with electron-deficient dienophiles constitute a synthetically useful class of Diels-Alder reaction. By exploring cinchona alkaloid-derived organic molecules as acid-base bifunctional catalysts, we successfully developed the first highly enantioselective and diastereoselective catalytic Diels-Alder reaction with 2-pyrones. Furthermore, we demonstrated the possibility of using such catalysts to control the endo/exo selectivity in a Diels-Alder reaction. Copyright

Full text of DOI:10.1021/ja070859h

Published on Web 05/01/2007
Asymmetric Diels-Alder Reactions of 2-Pyrones with a Bifunctional Organic
Catalyst
Yi Wang, Hongming Li, Yong-Qiang Wang, Yan Liu, Bruce M. Foxman, and Li Deng*
Department of Chemistry, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received February 6, 2007; E-mail: deng@brandeis.edu
Table 1. D-A Reaction with Cinchona Alkaloidsa
The Diels-Alder reaction of 2-pyrones provides a direct and
versatile access to synthetically valuable multifunctional bicyclic
chiral building blocks.1,2 However, as electron-deficient dienes of
aromatic character, 2-pyrones are known to be reluctant diene
partners for Diels-Alder reactions.1,3 This presents a distinct
challenge for the development of a catalytic asymmetric variant
for this synthetically useful class of Diels-Alder reactions. Thus,
it comes as no surprise that, in spite of the great strides made on
the development of asymmetric Diels-Alder reactions, a highly
diastereoselective and enantioselective catalytic Diels-Alder reac-
tion with 2-pyrones has not yet been realized.1,4 In fact, to our
knowledge, even for chiral auxiliary-directed asymmetric Diels-
Alder reactions with 2-pyrones, only a single example was
reported.4b Herein, we wish to describe the development of an
efficient asymmetric Diels-Alder reaction of 2-pyrones using
cinchona alkaloid-derived bifunctional organic catalysts.
drb
ee (%)b of
drb
ee (%)b of
entry
catalyst
exo:endo
exo-5aA
entry
catalyst
exo:endo
exo-5aA
1
2
3
4
5
quinidine
cinchonine
66:34
62:38
DHQD-PHN 66:34
5
-5
33
22
57
6
7
8
QD-1c 87:13
QD-1d 85:15
QD-1a 88:12
80
82
88
89
91
â-ICD
QD-1b
94:6
90:10
9c QD-1a 93:7
10d QD-1a 93:7
a See Supporting Information for details. b In crude reaction mixtures.
c Reaction was run in Et2O. d Reaction was run in Et2O; the concentration
of 3a was 0.1 M.
Table 2. D-A Reaction with QD-1a and Q-1a (in Parentheses)a
Nakatani and co-workers explored the use of natural cinchona
alkaloids to promote a Diels-Alder reaction of 3-hydroxy-2-pyrone
(3a) with N-methylmaleimide.4a However, the enantioselectivity
afforded by natural cinchona alkaloids was modest. Nakatani
proposed that the mode of action by natural cinchona alkaloids was
to activate and orient 3a only in the Diels-Alder reaction. We
recently demonstrated that 6′-OH cinchona alkaloids 1 (Figure 1)
are effective organic catalysts for asymmetric conjugate additions,5
aldol reactions,6 and Friedel-Crafts reactions.7 Mechanistic studies
from our laboratories indicate that the hydrogen bond donor and
acceptor motifs in 1 activate and orient the nucleophiles and
electrophiles, respectively, through multiple hydrogen bonding
interactions.5a,b This mechanistic insight in turn implies that 1 might
function as efficient bifunctional catalysts for asymmetric Diels-
Alder of pyrones 3 with electron-deficient dienophiles by simul-
taneously raising the energy of the HOMO of the former and
lowering the energy of the LUMO of the latter while orienting the
two reactants to exert stereochemistry control (Figure 1).8-10
Guided by this hypothesis, we investigated the reaction of
3-hydroxy-2-pyrone 3a and trans-3-benzoylacrylic ester 4A with
various cinchona alkaloids as catalysts. As summarized in Table
1, the reaction readily proceeded to completion with the expected
sense of chemoselectivity to afford cycloadducts endo/exo-5aA as
a mixture of diastereomers (Table 1). Importantly, the 6′-OH
cinchona alkaloids QD-1 afforded significantly better catalytic
efficiency than that by natural cinchona alkaloids, the monofunc-
tional cinchona alkaloid DHQD-PHN, and the conformationally
a See Supporting Information for details. b For major diastereomers.
c Yield of 5. d 10 mol % of catalyst was used instead.
rigid 6′-OH cinchona alkaloid â-ICD (Table 1, entries 5-8 vs 1-4).
These results illustrated that both the structure of the tunable
9-substituent and the bifunctional nature of catalysts 1 are critically
important to their catalytic efficiency for the asymmetric Diels-
Alder reaction. After further optimizations, we achieved a highly
diastereoselective and enantioselective reaction with 5 mol % of
QD-1a to afford exo-5aA in 93:7 dr and 91% ee.
Catalyst QD-1a was found to tolerate a significant degree of alter-
ations in both pyrones 3 and dienophiles 4 (Table 2). The reactions
between pyrone 3a and dienophiles of different substitution patterns
(4A-D) proceeded in 76:24 to 93:7 dr, and the major diastereoiso-
mers were generated mostly in greater than 90% ee. It is note-
worthy that even the relatively unreactive dienophile 4D could be
employed in this reaction, thereby generating optically active chiral
Figure 1. Bifunctional catalysis for D-A reactions of 2-pyrone 3.
9
6364
J. AM. CHEM. SOC. 2007, 129, 6364-6365
10.1021/ja070859h CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. D-A Reactions with 4E,F Catalyzed by QD-2 and Q-2
demonstrated the possibility of using such catalysts to control the
endo/exo selectivity in a Diels-Alder reaction. Studies are under-
way to expand the scope of this reaction and to explore its
application in asymmetric synthesis.
(in Parentheses)a
Acknowledgment. We thank National Institutes of Health (GM-
61591) for financial support. We thank the National Science
Foundation for the partial support of this work through Grant CHE-
0521047 for the purchase of a new X-ray diffractometer.
Supporting Information Available: Experimental procedures and
characterization of the products. X-ray analysis data (CIF) for 5aH
and 5′aH. This material is available free of charge via the Internet at
http://pubs.acs.org.
temp
C)
yieldb
(%)
entry substrate catalyst product solvent
(
°
exo:endo
ee (%)b
1
2
3
4
4E QD-1a 5aE Et2O rt
64:36
97c
15
4E
4F
4G
2
2
2
5aE TBME -20 >97:3 (>97:3) 85c (87)c 92 (85)
5aF TBME -20 93:7 (89:11)
5aG TBME rt 96:4 (93:7)
81 (89) 97 (>98)
91 (87) 94 (93)
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and enantioselectivity for the reaction of 3a with 4A,11 their high
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dienophiles 4E-G. Gratifyingly, QD-2 and Q-2 afforded drastically
improved enantioselectivity and diastereoselectivity, generating the
corresponding exo-adduct in 85 to 98% ee and 89:11 to >97:3 dr
(Table 3, entries 2-4). The results obtained with reactions involving
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JA070859H
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J. AM. CHEM. SOC. VOL. 129, NO. 20, 2007 6365