Chiral NHC-catalyzed oxodiene Diels-Alder reactions with α-chloroaldehyde bisulfite salts

Article abstract of DOI:10.1021/ol801502h

(Chemical Equation Presented) α-Chloroaldehyde bisulfite adducts were successfully employed in chiral NHC-catalyzed hetero-Diels-Alder reactions with various oxodienes under biphasic reaction conditions with high levels of enantioselectivity. This new pro

Full text of DOI:10.1021/ol801502h

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3817-3820
Chiral NHC-Catalyzed Oxodiene
Diels-Alder Reactions with
r-Chloroaldehyde Bisulfite Salts
Ming He, Brendan J. Beahm, and Jeffrey W. Bode*,†
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara,
California 93106-9510
bode@sas.upenn.edu
Received July 2, 2008
ABSTRACT
r-Chloroaldehyde bisulfite adducts were successfully employed in chiral NHC-catalyzed hetero-Diels-Alder reactions with various oxodienes
under biphasic reaction conditions with high levels of enantioselectivity. This new protocol makes possible enantioselective additions from
commercially available chloroacetaldehyde sodium bisulfite and demonstrates that this unique class of catalysts readily tolerates aqueous
conditions.
Enantioselective hetero-Diels-Alder reactions provide a
versatile and convergent approach to the construction of
chiral heterocycles.1 In recent years, significant progress
has been achieved in the development of efficient chiral
metal and organic catalysts for enantioselective hetero-
Diels-Alder reactions.2,3 Their great synthetic utility
Scheme 1
.
NHC-Catalyzed Hetero-Diels-Alder Reactions with
Chloroaldehyde Sodium Bisulfite 2
† Current address: Department of Chemistry, University of Pennsylvania.
(1) For recent reviews, see: (a) Boger, D. L.; Weinreb, S. M. Hetero
Diels-Alder Methodology in Organic Synthesis; Academic Press: San
Diego, 1987; Chapter 2. (b) Evans, D. A.; Johnson, J. S. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: New York, 1994; Vol. 3, p 1177. (c) Corey, E. J. Angew. Chem.,
Int. Ed. 2002, 41, 1650–1667. (d) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668–1698. (e) Jørgensen, K. A. Eur. J. Org. Chem. 2004, 2093–2102.
(2) For selected references of metal-catalyzed, enantioselective hetero-
Diels-Alder reactions, see: (a) Evans, D. A.; Miller, S. J.; Lectka, T. J. Am.
Chem. Soc. 1993, 115, 6460–6461. (b) Evans, D. A.; Olhava, E. J.; Johnson,
J. S.; Janey, J. M. Angew. Chem., Int. Ed. 1998, 37, 3372–3375. (c) Jarvo,
E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44,
6043–6046. (d) Abraham, C. J.; Paull, D. H.; Scerba, M. T.; Grebinski,
J. W.; Lectka, T. J. Am. Chem. Soc. 2006, 128, 13370–13371. (e) Kawasaki,
M.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 16482–16483. (f)
Esquivias, J.; Arrayas, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2007,
129, 1480–1481. (g) Yu, Z.-P.; Liu, X.-H.; Dong, Z.-H.; Xie, M.-S.; Feng,
continues to drive further interest in improved protocols and
expanded substrate scope. Of particular need are reactions
in which the starting materials are readily accessible, and
X.-M. Angew. Chem., Int. Ed. 2008, 47, 1308–1311
.
10.1021/ol801502h CCC: $40.75
Published on Web 07/26/2008
2008 American Chemical Society

Table 1. Effect of Inorganic Bases and Organic Solvents on Epimerizationa
entry
X
R
aqueous base
organic solvent
time/h
yield/%b
ee/%c
1
2
3
4
5
6
7
5
5
5
5
5
5
1
Me
Me
Me
Me
Me
Me
Et
1.6 equiv of 1.0 M K2CO3
1.6 equiv of 1.0 M NaHCO3
1.6 equiv of 1.5 M NaHCO3
1.6 equiv of 1.0 M K2CO3
1.6 equiv of 1.0 M K2CO3
1.6 equiv of 1.0 M K2CO3
3.2 equiv of 1.0 M K2CO3
0.2 M EtOAc
0.2 M EtOAc
0.2 M toluene
0.2 M toluene
0.2 M toluene
0.2 M toluene
0.16 M toluene
2.5
76
78
48
40
55
62
84
31
65
75
99
93
86
90
23.0
23.0
2.5
4.0
6.0
6.0
a All reactions were performed with 1.6 equiv of 2 and 1.0 equiv of oxodiene. b Isolated yield after chromatography. c Determined by HPLC analysis.
low catalyst loadings can be employed while still maintaining
high levels of enantioselectivity.
biphasic conditions (eq 1). This new protocol both extends
the scope and operational simplicity of NHC-catalyzed
enantioselective hetero-Diels-Alder reactions and demon-
strates that this unique class of catalysts readily tolerates
aqueous conditions.10
We have recently reported the first chiral N-heterocyclic
carbene (NHC) catalyzed hetero-Diels-Alder reaction, via
the catalytic generation of chiral enolates that serve as
dienophiles.4,5 We have also extended the dienophile precur-
sors from electron-deficient enals to R-chloroaldehydes,6
which can be readily prepared from the corresponding
aldehydes.7 However, R-chloroaldehydes are sensitive to
moisture and oxygen,8a and their preparation and storage
require precautions. Furthermore, R-chloroacetaldehyde,
which would provide entry into challenging but synthetically
important enantioselective acetate additions,9 is difficult and
unsafe to obtain in pure form.8b In this communication, we
document efficient solutions to both of these challenges
through the use of R-chloroaldehyde bisulfite salts under
At the outset of our studies, we investigated a number of
R-chloroaldehyde surrogates, including hemiacetals, bro-
mopyruvic acid, and the R-chloroaldehyde bisulfite adducts.
Among these starting materials, the R-chloroaldehyde bisulfite
adducts were particularly attractive as they were bench-stable
solids that could be readily prepared by the addition of
aqueous sodium bisulfite to a solution of the appropriate
aldehydes.11b Their use as substrates, however, would
necessitate the use of aqueous conditions to decompose the
bisulfite adducts to the corresponding aldehydes in the
presence of the NHC catalyst.11,12
(3) For selected references of enantioselective hetero-Diels-Alder
reactions catalyzed by organic catalysts, see: (a) Itoh, J.; Fuchibe, K.;
Akiyama, T. Angew. Chem., Int. Ed. 2006, 45, 4796–4798. (b) Akiyama,
T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006, 128, 13070–13071.
(c) Wang, Y.; Li, H.; Wang, Y.-Q.; Liu, Y.; Foxman, B. M.; Deng, L.
J. Am. Chem. Soc. 2007, 129, 6364–6365. (d) Singh, R. P.; Bartelson, K.;
Wang, Y.; Su, H.; Lu, X.-J.; Deng, L. J. Am. Chem. Soc. 2008, 130, 2422–
2423.
(4) (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418–8420. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc.
2006, 128, 15088–15089. For an intramolecular example of this reaction,
see: (c) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 3107–3110
.
(9) (a) Hayashi, Y.; Itoh, T.; Aratake, S.; Ishikawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 2082–2084. (b) Yang, J. W.; Chandler, C.; Stadler, M.;
Kampen, D. B. Nature 2008, 452, 453–455. (c) Alcaide, B.; Almendros, P.
Angew. Chem., Int. Ed. 2008, 47, 4632–4634. (d) Garc´ıa-Garc´ıa, P.;
Lade´peˆche, A.; Halder, R. B. List. Angew. Chem., Int. Ed. 2008, 47, 4719–
4721. (e) Hayashi, Y.; Itoh, T.; Ohkubo, M.; Ishikawa, H. Angew. Chem.,
Int. Ed. 2008, 47, 4722–4724.
(5) For other recent work on enantioselective NHC-catalysis, see: (a)
Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129,
3520–3521. (b) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 418–
419. (c) Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc.
2008, 130, 2416–2417. (d) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye,
S. Org. Lett. 2008, 10, 277–280.
(6) For the use of R-functionalized aldehydes in NHC-catalysis, see:
(a) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126–
8127. (b) Reynolds, N. T.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 9518–9519. (c) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc.
2005, 127, 16406–16407.
(10) For a recent survey of organic reactions under aqueous conditions:
Li, C.-J. Chem. ReV. 2005, 105, 3095–3165.
(11) For recent references of use of aldehyde bisulfite adducts, see: (a)
Wuts, P. G. M.; Bergh, C. L. Tetrahedron Lett. 1986, 27, 3995–3998. (b)
Seki, M.; Hatsuda, M.; Yoshida, S. Tetrahedron Lett. 2004, 45, 6579–6581.
(c) Seki, M.; Hatsuda, M.; Mori, Y.; Yoshida, S.; Yamada, S.; Shimizu, T.
(7) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen,
K. A. J. Am. Chem. Soc. 2004, 126, 4790–4791.
Chem.-Eur. J. 2004, 10, 6102–6110
.
(8) (a) De Kimpe, N.; Verhe´, R. The Chemistry of R-Haloketones,
R-Haloaldehydes, and R-Haloimines; John Wiley & Sons: New York, 1988;
Chapter 3. (b) House, H. O.; Jones, V. K.; Frank, G. A. J. Org. Chem.
1964, 29, 3327–3333. (c) Kraus, G. A.; Gottschalk, P. J. Org. Chem. 1983,
48, 2111–2112.
(12) We have previously shown that achiral, imidazolium-derived NHC
catalysts can be employed for a different class of annulation reactions in
the presence of protic solvents: (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W.
J. Am. Chem. Soc. 2004, 126, 14370–14371. (b) He, M.; Bode, J. W. Org.
Lett. 2005, 7, 3131–3134
.
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Org. Lett., Vol. 10, No. 17, 2008

Table 2. NHC-Catalyzed Biphasic Diels-Alder Reactions of 2
Table 3. NHC-Catalyzed Biphasic Diels-Alder Reactions of
with Different Oxodienesa
Chloroaldehyde Bisulfite Saltsa
a All reactions were performed at 0.16 M in toluene with 1.6 equiv of
chloroacetaldehyde sodium bisulfite 2, 1.0 equiv of oxodiene, 1 mol % of
1, and 3.2 equiv of 1.0 M aq K2CO3. b Isolated yield after chromatography.
c Determined by HPLC or SFC analysis. d 5 mol % of 1 was employed.
To test the feasibility of our approach, we selected
inexpensive, commercially available chloroacetaldehyde
sodium bisulfite 2 as a precursor of chloroacetaldehyde for
the NHC-promoted reactions with two representative oxo-
dienes: 4-oxoenoate 3a and ꢀ,γ-unsaturated R-ketoester 4a
(Scheme 1). We screened a number of reaction conditions
before selecting biphasic conditions employing 1.0 M K2CO3
as the inorganic base and EtOAc as the organic solvent for
further development. These studies established the feasibility
of using the bisulfite adducts as starting materials but
confirmed our fears of epimerization. The use of 3a as the
oxodiene provided product 5a only in 31% ee, while the use
of 4a afforded adduct 6a in >99% ee.4b
a All reactions were performed at 0.16 M in toluene with 1.6 equiv of
chloroaldehyde bisulfite adduct, 1.0 equiv of oxodiene, 1 mol % of 1, and
3.2 equiv of 1.0 M aq K2CO3. In all cases, only one diastereomer was
detected in unpurified reaction mixtures. b Isolated yield after chromatography.
c Determined by HPLC or SFC analysis.
had been present in all of the examples from our prior
work. To improve the enantiomeric excess of the product
5a, we investigated the effect of reaction conditions
including inorganic bases and organic solvents (Table 1).
Although the use of either a weaker base (NaHCO3, entries
1 and 2) or a nonpolar solvent (entry 3) suppressed
epimerization, the combination of NaHCO3 and toluene
afforded the product only in 75% ee. In contrast, those of
1.0 M K2CO3 and toluene minimized the epimerization
(entries 4 and 5) at the expense of diminished yields. Some
of the product loss was traced to hydrolysis, and improved
yields could be obtained simply by employing the more
We reasoned from these results that the low enantiose-
lectivity observed for 5a was due to epimerization of the
annulation product. Notably, this product contains a
readily epimerizable stereocenter by virtue of the ꢀ,γ-
unsaturated ester and lacks adjacent substitution, which
Org. Lett., Vol. 10, No. 17, 2008
3819

stable ethyl ester (entries 6 and 7). Notably, these
conditions also allowed us to lower the catalyst loading
to 1 mol % of chiral triazolium precatalyst 1.
by X-ray analysis of an enantiomerically pure sample of
(3S,4S)-ethyl 3-benzyl-6-(4-bromophenyl)-2-oxo-3,4-dihy-
dro-2H-pyran-4-carboxylate (Table 3, entry 2, see Supporting
Information).15
The scope of these conditions for NHC-catalyzed Diels-
Alder reactions with chloroacetaldehyde bisulfite salt 2 with
various oxodiene substrates is shown in Table 2. This survey
demonstrated that this biphasic process accommodated
various substrates 3b-e (entries 1-4) including aromatic
and aliphatic substitution. Except for entry 2, all of the
substrates screened afforded the desired 4,6-disubstituted
dihydropyran-2-ones with good enantioselectivity, albeit
slightly diminished by epimerization. As expected, the ꢀ,γ-
unsaturated R-ketoesters 4a and 4b furnished the correspond-
ing products in good yields and with excellent enantiose-
lectivity. The absolute configuration of the products was
determined by single-crystal X-ray analysis of the product
(R)-ethyl 6-(4-bromophenyl)-2-oxo-3,4-dihydro-2H-pyran-
4-carboxylate (Table 2, entry 2).13 Interestingly, the sterically
hindered 4-oxoenolate 7, which did not react with any
R-chloroaldehydes in our previous investigations, afforded
bicyclic product 8 with excellent enantioselectivity when
catalyzed by 5 mol % of 1.
In addition to allowing direct use of the commercially
available chloroacetaldehyde bisulfite adduct, we also sought
to utilize these conditions to simplify the preparation,
handling, and reactions of substituted R-chloroaldehydes.
After some experimentation, we identified reliable conditions
for the conversion of common R-chloroaldehydes to the
bench-stable, solid bisulfite adducts (see Supporting
Information).11b We were pleased to find that the reaction
conditions optimized for the chloroacetaldehyde bisulfite salt
were directly applicable to these substrates. Biphasic reac-
tions with either substituted 4-oxoenolates (entries 1-7) or
ꢀ,γ-unsaturated R-ketoesters (entry 8 and 9) provided the
Diels-Alder products in good chemical yields and excellent
enantioselectivity.14
In summary, we have developed a catalytic enantioselec-
tive method for hetero-Diels-Alder reactions that employs
easily available, bench-stable R-chloroaldehyde bisulfite salts
as starting materials. This enantioselective, biphasic hetero-
Diels-Alder reaction represents the first enantioselective
NHC-catalyzed reaction that is demonstrably water-tolerant.
It provides an innovative solution to enantioselective addi-
tions of acetate equivalents using the inexpensive, com-
mercially available bisulfite adduct of chloroacetaldehyde,
thereby interfacing with ongoing efforts to employ com-
modity chemicals in lieu of preactivated or protected
reactants.16 This approach also extends the scope of enan-
tioselective NHC-catalysis and provides a more convenient
and operationally simple protocol for NHC-catalyzed
Diels-Alder reactions.
Acknowledgment. Partial support for this work was
provided by the National Science Foundation (CHE-
0449587). Support of this research program by Amgen,
AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb,
Eli Lilly, Roche, and the NIH (GM-079339) is gratefully
acknowledged. J.W.B. is a fellow of the Packard Foundation,
the Beckman Foundation, the Sloan Foundation, and a
Cottrell Scholar. We thank Justin Struble (University of
Pennsylvania) for catalyst preparation.
Supporting Information Available: Full experimental
procedures and characterization data and X-ray crystal-
lographic data for 5c. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL801502H
(14) These conditions eliminated epimerization and gave diastereose-
lectivities superior to the conditions in ref 4b.
In all cases, only 1 mol % of chiral triazolium precatalyst
1 was employed. The absolute configuration was determined
(15) CCDC 689208 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(13) A sample with 93% ee was prepared for the X-ray analysis, although
in low yield. CCDC 689207 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(16) (a) Lyothier, I.; Defieber, C.; Carreira, E. M. Angew. Chem., Int.
Ed. 2006, 45, 6204–6207. (b) Defieber, C.; Ariger, M. A.; Moriel, P.;
Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 3139–3143.
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