Copper-catalyzed asymmetric [4+1] cycloadditions of enones with diazo compounds to form dihydrofurans

Article abstract of DOI:10.1021/ja068344y

This report describes the use of a planar-chiral bipyridine ligand to achieve the first diastereo- and enantioselective copper-catalyzed [4+1] cycloadditions of enones with diazo compounds to produce highly substituted 2,3-dihydrofurans. The method is app

Full text of DOI:10.1021/ja068344y

Published on Web 01/11/2007
Copper-Catalyzed Asymmetric [4+1] Cycloadditions of Enones with Diazo
Compounds To Form Dihydrofurans
Sunghee Son and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received November 21, 2006; E-mail: gcf@mit.edu
Table 1. Copper-Catalyzed Asymmetric [4+1] Cycloadditions:
2,3-Dihydrofurans are subunits of a range of biologically active
compounds (e.g., aflatoxin B1 and clerodin);1 furthermore, they
serve as extremely useful synthetic intermediates, since they can
be transformed with good stereoselectivity into an array of highly
functionalized tetrahydrofurans.2 Although many strategies for the
synthesis of 2,3-dihydrofurans have been described, virtually no
catalytic asymmetric processes have been developed.3
Survey of Ligandsa
entry
ligand
yield (%)b
dr
ee (%)
In 1967, Spencer reported that CuSO4 catalyzes the [4+1]
cycloaddition of â-methoxy-R,â-unsaturated ketones with ethyl
diazoacetate, leading to furans upon elimination of methanol from
the presumed 2,3-dihydrofuran intermediate.4 Since this pioneering
work, there have been several other studies of copper-catalyzed
reactions of enones with diazo compounds, but none of these
investigations has explored the possibility of accessing 2,3-
dihydrofurans with control of relative or absolute stereochemistry.5
We recently decided to address this challenge, and in this report
we describe our progress to date. Specifically, we have established
that, through the use of planar-chiral bipyridine ligand bpy*,6
copper-catalyzed [4+1] cycloadditions of R,â-unsaturated ketones
with diazoacetates can produce highly substituted 2,3-dihydrofurans
in good yield, dr, and ee (eq 1).7,8
1
2
3
4
5
6
bis(oxazoline) 1
semicorrin 2
bis(azaferrocene) 3
(-)-bpy*
no ligand
12
<2
6
45
10
<2
>20:1
-20c
>20:1
>20:1
>20:1
34
60
no CuOTf, no ligand
a All data are the average of two runs. b Isolated yield of the trans
diastereomer. c The opposite enantiomer is produced.
Table 2. Copper-Catalyzed Asymmetric [4+1] Cycloadditions:
Impact of the Structure of the Diazoestera
entry
R
yield (%)b
dr
ee (%)
1
2
3
4
5
6
t-Bu
Et
Ph
45
43
44
63
79
47
>20:1
>20:1
>20:1
7:1
13:1
16:1
60
37
37
83
85
85
2,6-dimethylphenyl
2,6-diisopropylphenyl
2,6-di-t-butyl-4-methylphenyl
a All data are the average of two runs. b Isolated yield of the trans
diastereomer.
higher enantioselectivities (entries 4-6), with the 2,6-diisopropyl-
phenyl ester providing the best combination of yield, dr, and ee
(entry 5).
In initial studies, we explored cycloadditions of enones with diazo
compounds in the presence of a variety of chiral ligands that have
proved useful in other copper-catalyzed processes. Unfortunately,
for the reaction of chalcone with t-butyl diazoacetate, a bis-
(oxazoline),9 a semicorrin,10 and a bis(azaferrocene)11 were not
effective (Table 1, entries 1-3). On the other hand, a planar-chiral
2,2′-bipyridine (bpy*)12 provided promising yield, dr, and ee
(entry 4).
To improve upon our preliminary lead (Table 1, entry 4), we
investigated the dependence of these Cu/bpy*-catalyzed asymmetric
[4+1] cycloadditions on the steric demand of the diazoester (Table
2). Use of a small alkyl or aryl group led to lower ee (entries 2 and
3 versus entry 1). On the other hand, hindered aryl esters furnished
We have examined the scope of this copper-catalyzed asymmetric
synthesis of 2,3-dihydrofurans (Table 3). The enantiomeric excesses
are highest when the enone substituents are unsaturated. Thus,
regardless of whether R or R1 is an electron-poor or an electron-
rich aromatic group, good ee is typically observed (entries 2-6).
Furthermore, the reaction proceeds with useful enantioselectivity
when a heteroaromatic substituent is present (entries 7 and 8).
Finally, an enone that bears an alkenyl group undergoes cycload-
dition with high efficiency (entry 9).
This Cu/bpy*-catalyzed method for the synthesis of 2,3-dihy-
drofurans may also be applied to alkyl-substituted enones, although
such cycloadditions proceed with more modest enantiomeric excess
9
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J. AM. CHEM. SOC. 2007, 129, 1046-1047
10.1021/ja068344y CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Copper-Catalyzed Asymmetric [4+1] Cycloadditions:
In conclusion, we have described the first examples of diastereo-
and enantioselective copper-catalyzed [4+1] cycloadditions of
enones with diazo compounds. This new method furnishes syntheti-
cally useful, highly substituted 2,3-dihydrofuran derivatives with
good efficiency and stereoselection. Additional studies of asym-
metric copper-catalyzed reactions of diazo compounds are under-
way.
Acknowledgment. We thank Michael M.-C. Lo for preliminary
studies. Support has been provided by the NIH (National Institute
of General Medical Sciences Grant R01-GM66960), Merck Re-
search Laboratories, and Novartis. Funding for the MIT Department
of Chemistry Instrumentation Facility has been furnished in part
by NIH Grant IS10RR13886 and NSF Grant DBI-9729592.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Scopea
entry
R
R1
yield (%)b
dr
ee (%)
1
2
Ph
Ph
Ph
Ph
Ph
79
59
77
84
81
84
68
63
76
92
69
80
13:1
19:1
19:1
>20:1
>20:1
9:1
>20:1
6:1
7:1
85
76
88
92
88
93
93
87
93
78
75
71
4-(F3C)C6H4
4-ClC6H4
4-(MeO)C6H4
Ph
3
4c
5
4-ClC6H4
4-(MeO)C6H4
Ph
3-furyl
CHdCHPh
n-Bu
6
7
8
9
10
11
12
Ph
N-Boc-2-pyrrolyl
Ph
Ph
Ph
n-Hex
n-Hex
>20:1
13:1
>20:1
Ph
Me
References
a All data are the average of two runs. b Isolated yield of the trans
diastereomer. c The product was hydrolyzed and then acetylated prior to
isolation.
(1) For a review and leading references, see: Kilroy, T. G.; O’Sullivan, T.
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Heterocycl. Chem. 2005, 17, 142-171. (b) Elliott, M. C. J. Chem. Soc.,
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1374.
Figure 1. Catalytic asymmetric synthesis of deoxy-C-nucleosides.
than those that bear only unsaturated groups. Nevertheless, the
desired dihydrofurans are generally produced in good yield and
with excellent diastereoselectivity (Table 3, entries 10-12).13
The 2,3-dihydrofuran products can be converted into a variety
of other useful families of compounds without an erosion in dr or
ee. Thus, a primary alcohol can be generated via treatment of the
cycloaddition adduct with LiAlH4 (eq 2). Furthermore, hydrolysis
and then acetylation affords an acyclic ester that bears an R and a
â stereocenter (eq 3).
(8) For leading references to catalytic asymmetric reactions of ylides formed
from diazo compounds, see: Davies, H. M. L. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 2004; pp 83-94. (b) Hodgson, D. M.; Pierard,
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3561-3651.
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G. C. J. Am. Chem. Soc. 2006, 128, 4594-4595.
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Kocovsky, P. Curr. Org. Chem. 2003, 7, 1737-1757. (b) Fletcher, N. C.
J. Chem. Soc., Perkin Trans. 1 2002, 1831-1842.
(13) Under our standard conditions, R,â-unsaturated esters are not suitable
substrates.
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35, 936-943. (b) Loakes, D. Nucleic Acids Res. 2001, 29, 2437-2447.
(c) Watanabe, K. A. In Chemistry of Nucleosides and Nucleotides;
Townsend, L. B., Ed.; Plenum: New York, 1994; Vol. 3, pp 421-535.
(15) To the best of our knowledge, this is the first catalytic asymmetric synthesis
of this deoxy-C-nucleoside (and the first synthesis of the “unnatural”
enantiomer).
(16) For studies of this deoxy-C-nucleoside, see: (a) Initial work: Millican,
T. A.; Mock, G. A.; Chauncey, M. A.; Patel, T. P.; Eaton, M. A. W.;
Gunning, J.; Cutbush, S. D.; Neidle, S.; Mann, J. Nucleic Acids Res. 1984,
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Ren, R. X.-F.; Sheils, C. J.; Tahmassebi, D. C.; Kool, E. T. J. Am. Chem.
Soc. 2000, 122, 2213-2222.
Deoxy-C-nucleosides are of interest in medicinal chemistry as
mimics of naturally occurring nucleosides.14 We have established
that our Cu/bpy*-catalyzed [4+1] cycloaddition can be applied to
the expeditious catalytic asymmetric synthesis of this class of
compounds (Figure 1). Cycloaddition of an R-diazoacetate to the
illustrated vinylogous ester furnishes a 2,3-dihydrofuran, which is
not isolated because of its sensitivity. Hydrogenation of the olefin
and then reduction of the ester affords the desired tetrahydrofuran
in good yield and diastereoselectivity (77% yield for three steps;
>20:1 dr). Deprotection of the trimethylsilylethyl group then
provides the deoxy-C-nucleoside (94% ee).15,16
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