Enantioselective assembly of substituted dihydropyrones via organocatalytic reaction in water media

Article abstract of DOI:10.1021/ol800835m

(Chemical Equation Presented) The diarylprolinol ether/HOAc-catalyzed cascade Michael addition and cyclization of aldehydes and α-keto-α, β-unsaturated esters proceeds smoothly in water to afford cyclic hemiacetals, which are oxidized to furnish highly fu

Full text of DOI:10.1021/ol800835m

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2561-2564
Enantioselective Assembly of
Substituted Dihydropyrones via
Organocatalytic Reaction in Water Media
Jing Wang,† Fang Yu,‡ Xiaojing Zhang,‡ and Dawei Ma*,†
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China, and Shenyang Pharmaceutical UniVersity, 103 Wenhua Lu,
Shenyang 110016, China
madw@mail.sioc.ac.cn
Received April 11, 2008
ABSTRACT
The diarylprolinol ether/HOAc-catalyzed cascade Michael addition and cyclization of aldehydes and r-keto-r,ꢀ-unsaturated esters proceeds
smoothly in water to afford cyclic hemiacetals, which are oxidized to furnish highly functionalized 3,4,5,6-tetrasubstituted dihydropyrones with
excellent enantioselectivities.
In recent years more and more examples have demonstrated
the broad applicability and great efficiency of diarylprolinol
ethers 1 as amine-based catalysts for reactions involving
aldehydes. They normally give rise to an excellent asym-
metric induction via enamine or iminium ion intermediates
by a steric control approach.1 The scope of reactions includes
Michael addition of aldehydes to electron-deficient olefins,2
R-functionalization of aldehydes,3 epoxidation of R,ꢀ-
unsaturated aldehydes,4 and conjugate addition of nucleo-
philes to R,ꢀ-unsaturated aldehydes.5 Recently, we found that
the combination of diarylprolinol ether/Brønsted acid as a
catalyst and water as solvent is a highly efficient system for
(3) For recent leading references, see:(a) Fraze´n, J.; Marigo, M.;
Fielenbach, D.; Wabnitz, T. C.; Kjaersgard, A.; Jørgensen, K. A. J. Am.
Chem. Soc. 2005, 127, 18296. (b) Chi, Y.; Gellman, S. H. J. Am. Chem.
Soc. 2006, 128, 6804. (c) Ibrahem, I.; Co´rdova, A. Chem. Commun. 2006,
1760. (d) Palomo, C.; Vera, S.; Velilla, I.; Mielgo, A.; Go´mez-Bengoa, E.
Angew. Chem., Int. Ed. 2007, 46, 8054.
(4) (a) Marigo, M.; Franze´n, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen,
K. A. J. Am. Chem. Soc. 2005, 127, 6964. (b) Sunde´n, H.; Ibrahem, I.;
Co´rdova, A. Tetrahedron Lett. 2006, 47, 99.
† Chinese Academy of Sciences.
‡ Shenyang Pharmaceutical University.
(1) For a review, see: Paloma, C.; Mielgo, A. Angew. Chem., Int. Ed.
2006, 45, 7876.
(5) For selected examples, see: (a) Marigo, M.; Bertelsen, S.; Landa,
A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 5475. (b) Marigo, M.;
Schulte, T.; Franze´n, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127,
15710. (c) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006,
128, 10354. (d) Brandau, S.; Maerten, E.; Jørgensen, K. A. J. Am. Chem.
Soc. 2006, 128, 14986. (e) Rios, R.; Sunde´n, H.; Vesely, J.; Zhao, G.-L.;
Dziedzic, P.; Co´rdova, A. AdV. Synth. Catal. 2007, 349, 1028. (f) Cabrera,
S.; Alema´n, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed 2008, 47, 121. (g) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.;
Tang, Y.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 3732. (h) Palomo,
(2) (a) Hayashi, Y.; Gotoh, H.; Hayasi, T.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212. (b) Chi, Y.; Gellmann, S. H. Org. Lett. 2005, 7,
4253. (c) Brandau, S.; Landa, A.; Franze´n, J.; Marigo, M.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2006, 45, 4305. (d) Ender, D.; Hu¨ttl, M. R. M.;
Grondal, C.; Raabe, G. Nature 2006, 441, 861. (e) Ender, D.; Hu¨ttl,
M. R. M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem., Int. Ed. 2007,
46, 467. (f) Hayashi, Y.; Okano, T.; Aratake, S.; Hazelard, D. Angew. Chem.,
Int. Ed. 2007, 46, 4922. (g) Zhu, S.; Yu, S.; Ma, D. Angew. Chem., Int. Ed.
2008, 47, 545. (h) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 404.
´
C.; Landa, A.; Mielgo, A.; Oiarbide, M.; Puenta, A.; Vera, S. Angew. Chem.,
Int. Ed 2007, 46, 8431.
10.1021/ol800835m CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society

promoting Michael addition of aldehydes to nitroalkenes.2g
When this system was used in Michael addition of aldehydes
2 and R-keto-R,ꢀ-unsaturated esters 3,6 cyclic hemiacetals
4 were isolated, which were oxidized with PCC or
Dess-Martin periodinane to afford highly functionalized
3,4,5,6-tetrasubstituted dihydropyrones 57 with excellent
consumption of 3a, cyclic hemiacetal 4a was isolated in 73%
yield as a 1:1 diastereomeric mixture, which was treated with
PCC to afford 5a with greater than 99% ee (entry 1).
Switching the additive to acetic acid gave an improved yield
(entry 2), while NaOAc or no additive gave poor yields
(entries 3 and 4). The use of catalyst 1b gave rise to poor
yields (entry 5), which probably resulted from the additional
steric hindrance caused by two bulkier aromatic groups.
Additionally, increasing the aldehyde and additive loadings
could further improve the yield (entry 6). Searching for
practical usage, we gave up these conditions in late inves-
tigation.
Scheme 1
The optimized 1a/HOAc combination was then applied
to a variety of aldehydes and olefins. In general, the desired
trans-dihydropyrones were obtained in good yields and with
excellent enantioselectivities. In either case the corresponding
cis-isomers were isolated in 3-4% yield, illustrating a
diastereomeric ratio of around 94:6. Two functionalized
aldehydes were compatible with this process (Table 2, entries
1 and 2), thereby providing an access to more complex
dihydropyrones. When 3-methylbutanal was utilized, the
cycloaddition turned out to be sluggish and the catalyst
loading had to be increased to ensure good conversion (Table
2, entry 3), which demonstrates that the steric bulk of the
aldehydes greatly affects the cycloaddition step. Switching
from ethyl esters to tert-butyl esters had only little influence
on this process (compare entries 1 and 4, 2 and 5, Table 2).
This advantage provides an opportunity for the acid-induced
cleavage of the ester moiety in the examined dihydropyrones.
Variation of the 4-position of 5 is possible, as evident from
the fact that tert-butyl 2-acyl-6-benzoxyhexenoate furnished
the corresponding dihydropyrones 5g-i in good yields (Table
2, entries 6-8). The slight drop in ee value for 5i illustrates
that the steric hindrance of the aldehydes might impair
asymmetric induction. Interestingly, better results were
obtained when diethyl 2-acetylfumarate was employed (Table
2, entries 9 and 10). In these cases the first step turned out
to be significantly faster, and only 10 mol % of catalyst 1
was required even for sterically hindered 3-methylbutanal
(compare entries 3 and 10, Table 2). This result demonstrates
that the additional ester group, which renders the R,ꢀ-
unsaturated ketone more electron deficient, greatly facilitates
the addition reaction.
enantioselectivities (Scheme 1). Herein we wish to detail our
results.
Table 1. The Effect of Additive on the Addition Reaction of
n-Pentanal to Ethyl 2-Acyl-2-heptenoate Catalyzed by Amines 1a
entry catalyst acid/mol % time (h) yield (%)b ee [%]c
1
2
3
4
5
6
1a
1a
1a
1a
1b
1a
PhCO2H/50
AcOH/50
AcONa
none
AcOH/50
AcOH/100
36
24
72
48
72
24
73
83
33
44
<5
86
>99
>99
>99
>99
98d
a Reaction conditions for first step: 1 (0.025 mmol), n-pentanal (0.5
mmol), 3a (0.25 mmol), additive, water (0.25 mL), 0 °C for 1 h, then rt for
the indicated time. b Isolated yield for addition step. c Determined by HPLC
analysis of 5a on a chiral stationary phase. d 1 mmol of n-pentanal was
used.
In our studies the required R-keto-R,ꢀ-unsaturated esters
3 were synthesized via TiCl4-catalyzed Knoevenagel con-
densation of aldehydes and ꢀ-keto esters.8 In the case of
aliphatic aldehydes, only Z-olefins were isolated in good
yields. However, a chromatographically separable mixture
of E- and Z-olefins (2:1 ratio) was obtained when aromatic
aldehydes were used, which provided an opportunity to
examine the influence of the double bond geometry of the
R-keto-R,ꢀ-unsaturated esters on the cycloaddition. Much
to our surprise, both 6a and its Z-isomer 3e gave rise to 5m
as the major product (entries 1 and 2, Table 3). Careful
As indicated in Table 1, we conducted our initial experi-
ment by stirring a mixture of n-pentanal (0.5 mmol), ethyl
2-acyl-2-heptenoate 3a (0.25 mmol), 1a (0.025 mmol), and
benzoic acid (0.125 mmol) in water. Upon the complete
(6) For organocatalytic Michael addition to various electron-deficient
olefins, see ref 2 and the following: (a) Hechavarria, M. T.; Fonseca, B.;
List, B. Angew. Chem., Int. Ed. 2004, 43, 3958. (b) Hayashi, Y.; Gotoh,
H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. J. Am. Chem. Soc.
2005, 127, 16028. (c) Mosse´, S.; Alexakis, A. Org. Lett. 2005, 7, 4361. (d)
Palomo, C.; Vera, S.; Mielgo, A.; Gomez-Bengoa, E. Angew. Chem., Int.
Ed. 2006, 45, 5984. (e) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 4966. (f) Zhao,
G.-L.; Xu, Y.; Sunde´n, H.; Eriksson, L.; Sayah, M.; Co´rdova, A. Chem.
Commun. 2007, 734. (g) Cao, C.; Sun, X.; Zhou, J.; Tang, Y. J. Org. Chem.
2007, 72, 4073.
(7) For other approaches to enantiopure dihydropyrones, see: (a) Evans,
D. A.; Thomson, R. J.; Franco, F. J. Am. Chem. Soc. 2005, 127, 10816. (b)
Fehr, M. J.; Consiglio, G.; Scalone, M.; Schmid, R. J. Org. Chem. 1999,
64, 5768.
(8) Lehnert, W. Tetrahedron 1972, 28, 663.
2562
Org. Lett., Vol. 10, No. 12, 2008

Table 2. Synthesis of 3,4,5,6-Tetrasubstituted Dihydropyrones 5a
Table 3. Synthesis of 6-Methyl Dihydropyrones 5m-q (R′′′ )
Me) from ꢀ-Aryl Enones 6 and 3ea
entry
aldehyde
enone product/yield (%)b ee [%]c
1
2
3
4
5
6
n-pentanal
n-pentanal
2-methylbutanal 6a
n-pentanal
n-pentanal
n-pentanal
6a
3e
5m/64 (3)
5m/62 (3)
5n/56 (2)d
5o/45 (6)
5p/44 (10)
5q/51 (4)
>99
>99
>99
>99
98
6b
6c
6d
>99
a Reaction conditions for cycloaddition: 1a (0.025 mmol), aldehyde (1.0
mmol), enone (0.25 mmol), HOAc (0.25 mmol), water (0.25 mL), 0 °C for
1 h, then rt for 48 h. b Isolated yields for two steps, the yield for the
corresponding cis-isomer is indicated in parentheses. c Determined by HPLC
on a chiral stationary phase. d 0.05 mmol 1a and 0.25 mmol HOAc were
used.
To explore the variability of the 6-position of the dihy-
dropyrones 5, enones 3f and 3g were synthesized from the
corresponding ꢀ-keto esters. We were pleased that these two
substrates gave the desired products 5r and 5s, although an
increased catalyst loading was required to obtain complete
conversion in the cycloaddition (Scheme 2). Importantly,
Scheme 2
compound 5r had been synthesized by Evans and co-
workers,7a and by comparing the analytical data we could
establish the stereochemistry of our reaction products as
3R,4R.
a Reaction conditions for cycloaddition: 1a (0.025 mmol), aldehyde 2
(0.5 mmol), olefin 3 (0.25 mmol), HOAc (0.125 mmol), water (0.25 mL),
0 °C for 1 h, then rt for the indicated time. b For the addition step. c Isolated
yield. d Determined by chiral-phase HPLC analysis. e 0.05 mmol 1a and
0.25 mmol HOAc were used.
The present cyclic semiacetal formation might proceed via
a stepwise Michael addition/cyclization process as depicted
in Scheme 3. After the initial attack of enamines 7 that
formed from amine 1a and aldehydes on R-keto-R,ꢀ-
unsaturated esters from its Re face to afford syn-adducts 8,
intramolecular attack of enol anion on iminium ion might
occur to provide cyclization products 9, which might undergo
hydrolysis to afford cyclic semiacetals 4. This mechanism
could be used for rationalizing the established stereochem-
istry of the dihydropyrones 5. However, it is also possible
monitoring of the reaction process by TLC revealed that
isomerization of 6a to 3e occurred first, and the latter was
the actual reactant in the cycloaddition. Similar results were
observed when functionalized ꢀ-aryl enones were utilized
(Table 3, entries 3-6).
Org. Lett., Vol. 10, No. 12, 2008
2563

Scheme 3
Scheme 4
be hydrogenated to afford saturated lactones, and ring-
opening of these compounds followed by decarboxylation
would give highly functionalized δ-keto esters (from 5a to
5s) and 1,2-diesters (from 5j to 5l), this method should find
various applications in organic synthesis. Additionally, the
discovery that our conditions are superior to those reported
by Jørgensen with regard to enantioselectivity in the reaction
of aldehydes and ꢀ,γ-unsaturated-R-ketoesters is remarkable.
These results set another impressive example to illustrate
the efficiency of the diarylprolinol ether/Brønsted acid/water
system11 for reactions involving aldehydes, which may
prompt the further exploration of the applicability of this
system in organocatalytic reactions.
to rationalize all the experimental phenomena by a hetero-
Diels-Alder reaction mechanism as reported by Juhl and
Jørgensen for the reaction of aldehydes and ꢀ,γ-unsaturated-
R-ketoesters.9,10 Additional experiments are required to solve
this problem.
Considering that in Jørgensen’s studies the enantioselec-
tivities (80-94% ee) are not excellent for many substrates,
we tried our conditions for the reaction of ꢀ,γ-unsaturated-
R-ketoester 10 with some aldehydes. Gratifyingly, when 10
mol % 1a and 50 mol % benzoic acid were used as the
catalytic system, this reaction worked well in water, to
provide 3,4,6-trisubstituted dihydropyrones 12 with greater
than 97% ee (Scheme 4).
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (grant 20321202 & 20572119) for their financial
support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra for all
new products. This material is available free of charge via
the Internet at http://pubs.acs.org.
In conclusion, we have developed a convenient and highly
enantioselective method for the assembly of highly func-
tionalized 3,4,5,6-tetrasubstituted dihydropyrones, which
relies on a Michael addition/cyclization process. Considering
the fact that the CdC double bond in dihydropyrones can
OL800835M
(9) (a) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498.
(b) Samanta, S.; Krause, J.; Mandal, T.; Zhao, C.-G. Org. Lett. 2007, 9,
(11) For early studies on organocatalysis-mediated reaction in water
media, see: (a) Mase, N.; Nakai, Y.; Ohara, N.; Yoda, H.; Takabe, K.;
Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2006, 128, 734. (b) Hayashi,
Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M. Angew.
Chem., Int. Ed. 2006, 45, 958.
2745
.
(10) A stoichiometric hetero-Diels-Alder reaction of achiral enamines
with R-keto-R,ꢀ-unsaturated esters has been reported, see: Eiden, F.; Eckle,
A. Arch. Pharm. 1989, 322, 617
.
2564
Org. Lett., Vol. 10, No. 12, 2008