Discovery of exceptionally efficient catalysts for solvent-free enantioselective hetero-Diels-Alder reaction

Article abstract of DOI:10.1021/ja0172518

Combinatorial coordination chemistry strategy combined with high-throughput screening techniques has been successfully applied to engineering practical enantioselective catalysts for asymmetric hetero-Diels-Alder reaction. The reaction of Danishefsky's di

Full text of DOI:10.1021/ja0172518

Published on Web 12/06/2001
Discovery of Exceptionally Efficient Catalysts for Solvent-Free
Enantioselective Hetero-Diels-Alder Reaction
Jiang Long, Jieyu Hu, Xiaoqiang Shen, Baoming Ji, and Kuiling Ding*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
Received October 6, 2001
Scheme 1
Asymmetric catalysis of organic reactions to provide enantio-
merically enriched products is of central importance to modern syn-
thetic and pharmaceutical chemistry1 as many currently accessible
methods remain impractical in terms of the efficiency, environ-
mental consideration, and other respects.2 Therefore the need for
truly efficient and practical asymmetric synthesis has been one of
the greatest challenges for synthetic chemists. Here we describe
the development of highly efficient enantioselective catalysts for
hetero-Diels-Alder reaction by high-throughput screening of a
combinatorial library of chiral titanium complexes. The reaction
of Danishefsky’s diene with a variety of aldehydes, a powerful
approach for achieving dihydropyrone heterocycles with extensive
synthetic application in natural or unnatural products,3,4 can be car-
ried out with 0.1-0.005 mol % of L5/Ti/L5 or L5/Ti/L6 at room
temperature under solvent- and MS-free conditions to afford dihy-
dropyrones derivatives with up to quantitative yield and 99.8% ee.
To achieve efficient catalyst for asymmetric reaction, tuning the
catalyst to make the perfect match among chiral ligand, metallic
ion, additive, substrate and so on is a key point. High-throughput
screening is essential for tuning a variety of modifications in lead
optimizations and has been found to be an effective technique for
finding the most efficient catalysts for asymmetric reactions as well.5
Therefore, the generation of a combinatorial library of chiral metal-
lic complexes and the expression of the set of constituents of the
library in the target model reaction should be a potentially powerful
approach to finding the highly efficient enantioselective catalysts.
A combinatorial library of chiral metallic complexes was
generated by combining a diol ligand (Lm) with Ti(OiPr)4 and an
alternative diol ligand (Ln) in parallel style as shown in Scheme
1. Every member of the Lm/Ti/Ln library is actually a mixture of
titanium complexes because of ligand diversity and the aggregation
feature of titanium complexes.6,7 These molecular assemblies form
spontaneously,8 and the composition of the mixtures depends on
thermodynamic factors. Therefore, the in situ selection of a highly
reactive (and selective) metallic complex from a variety of
thermodynamically dictated assemblies by substrate will lead to
the highly enantioselective asymmetric catalysis.9
Scheme 2
With the aim of screening the practical catalysts in mind, the
catalyst loading was first set up at the 1 mol % level and the reaction
was run in 0.1 mmol scale of substrate in diethyl ether at room
temperature. The reaction was quenched with trifluroacetic acid
after 24 h. In the primary screening,10 L4, L5, L6, and L7 modified
catalysts were found to be outstanding in terms of both enantiose-
lectivities (76.7-95.7% ee) and yields (63-100%). The steric
hindrance at the 3,3′-positions were proved to be disadvantageous
for the reaction. With these leading results in hand, the catalyst
loading of Lm/Ti/Ln (m, n ) 4-7) was further decreased to the
0.1 mol % level. The reaction only gave a trace amount of product
under the same experimental conditions. We then examined the
solvent effect on the reaction in both catalyst preparation and the
reaction process. It was found that the catalyst prepared in toluene
is superior to that obtained in diethyl ether. The most important
point is that the reaction under solVent-free conditions gaVe
quantitatiVe yield and much higher enantioselectiVity (up to 99%
The diol ligands (Scheme 2) employed for catalyst preparation
include commercially available or easily prepared tartaric acid deriv-
atives (L1, L2), BINOL (L4), 6,6′-Br2-BINOL (L7), and others (L3,
L9). Considering the backbone effect and steric hindrance around
coordinating oxygen atoms, H4-BINOL (L5), H8-BINOL (L6), 3,3′-
Br2-BINOL (L8), 3,3′-Br2-H8-BINOL (L10), 3,3′-Ph2-BINOL (L11),
3,3′-Ph2-H8-BINOL (L12), and 3,3′-(SPh)2-H8-BINOL (L13) were
also examined. Therefore, a catalyst library containing 104 members
could be generated from a library of 13 chiral ligands, which were
then evaluated for the reaction of Danishesky’s diene with benz-
aldehyde by using the high-throughput chiral HPLC technique.
9
10 VOL. 124, NO. 1, 2002 J. AM. CHEM. SOC.
10.1021/ja0172518 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Solvent-Free Asymmetric HDA Reaction of Aldehydes with Danishefsky’s Dienea
L5/Ti/L5
L5/Ti/L6
time (h)
aldehyde
benzaldehyde
p-anisylaldehyde
m-anisylaldehyde
o-anisylaldehyde
3-phenylpropionaldehyde
trans-cinnamaldehyde
furfural
loading (%)
time (h)
yield (%)b
e.e. (%)c
loading (%)
yield (%)b
e.e. (%)c
0.05
0.05
0.05
0.05
0.05
0.1
24
48
48
48
96
96
48
96
>99
>99
81
95
>99
82
99.3
90.8
96.6
75.1
97.9
98.4
99.2
94.7
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.005
0.05
0.05
0.05
0.05
0.05
0.05
0.05
24
48
48
48
96
96
48
96
144
48
48
48
48
48
48
24
82
>99
82.6
>99
>99
56.6
>99
>99
63
99.4
98.0
99.8
95.1
98.3
96.6
99.7
97.7
96.2
99.5
98.5
97.9
97.6
98.4
99.1
99.4
0.05
0.01
>99
37
furfural
furfural
m-tolyl aldehyde
R-naphthyl aldehyde
p-cyanobenzaldehyde
m-bromobenzaldehyde
p-bromobenzaldehyde
p-chlorobenzaldehyde
p-nitrobenzaldehyde
0.1
0.05
0.1
48
48
48
48
48
48
48
95
55
98.5
85.6
92.9
97.4
98.0
91.2
97.3
92
65
>99
>99
>99
>99
>99
98.4
98.3
>99
>99
>99
0.1
0.05
0.05
0.05
a Reactions carried out at room temp (20 °C). b Isolated yields. c Enantiomeric excesses determined by HPLC on Chiralcel OD or Chiralpak AD column.
ee) of the product. For practical synthesis, solvent-free condition
is the ideal process in terms of volumetric productivities and
environmental safety.11 However, asymmetric catalytic processes
are usually highly sensitive to solvent and concentration of
substrates. Our finding promoted us to further optimize the leading
catalysts under solvent-free conditions by decreasing the catalyst
loading to 0.05 mol %. Under the experimental conditions, L5/Ti/
L5 and L5/Ti/L6 were found to be the best catalysts. The reactions
proceeded efficiently at room temperature to give the product in
99% and 82% yields, respectively, with up to 99% ee.
Major Basic Research Development Program of China (Grant no.
G2000077506), and the Science and Technology Commission of
Shanghai Municipality is gratefully acknowledged.
Supporting Information Available: Experimental details and the
results of high-throughput evalution of the catalyst library (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For comprehensive reviews on asymmetric catalysis, see: (a) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; Wiley-Interscience: New
York, 1993. (b) AdVances in Catalytic Processes: Asymmetric Chemical
Transformations; Doyle, M., Ed.; JAI: Greenwich, CT, 1995; Vol. 1. (c)
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; Vols. I-III. (d) Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
2000; Chapter 8A.
The reactions promoted by the optimized catalysts (L5/Ti/L5
and L5/Ti/L6) were then carried out in gram scale at the catalyst
loading of 0.1-0.005 mol %. It was found that both L5/Ti/L5 and
L5/Ti/L6 were highly efficient for the reactions of a variety of
aldehydes, including aromatic, olefinic, and aliphatic derivatives
(Table 1). Particularly, in the cycloaddition of furfural to Dan-
ishefsky’s diene, 0.005 mol % of L5/Ti/L6 could promote the
reaction smoothly to give the corresponding cycloadduct in 63%
yield with 96.3% ee. To the best of our knowledge, this is the lowest
catalyst loading in Lewis acid-catalyzed asymmetric reactions.12
In conclusion, combinatorial coordination chemistry strategy
combined with high-throughput screening techniques has been suc-
cessfully applied to engineering practical enantioselective catalysts
for asymmetric hetero-Diels-Alder reaction. The present catalytic
system provides an attractive protocol to various optically active
dihydropyrones in terms of the following features: (i) the chemicals
are all inexpensive and easily available; (ii) the protocol has a broad
scope of substrates; (iii) the reaction shows enhanced enantioselec-
tivity when the amount of catalyst is reduced; (iv) the reaction is
environmentally benign and energy-saving because of solvent-free
and room-temperature reaction conditions; and (v) exceptionally
low catalyst loading (0.1-0.005 mol %) is sufficient to achieve
high yield and optical purity of the products. We hope our findings
in this research will stimulate further work on practical asymmetric
catalysis to achieve more efficient chemical reactions for modern
synthetic chemistry. Further insight into the mechanism and
application of the combinatorial catalyst libraries to other solvent-
free asymmetric reactions is currently under investigation.
(2) Noyori, R. AdV. Synth. Catal. 2001, 343, 1.
(3) For comprehensive reviews on asymmetric HDA, see e.g.: (a) Danishef-
sky, S. J.; De Ninno, M. P. Angew. Chem., Int. Ed. Engl. 1987, 26, 15.
(b) Jo¨rgensen, K. A. Angew. Chem., Int. Ed. Engl. 2000, 39, 3558.
(4) (a) Boger, D. L.; Weinreb, S. N. In Hetero Diels-Alder Methodology in
Organic Synthesis; Wasserman, H. H., Ed.; Academic Press: San Diego,
CA, 1987; Vol. 47. (b) Tietze, L. F.; Kettschau, G. In StereoselectiVe
Heterocyclic Synthesis; Metz, I. P., Ed.; Springer-Verlag: Berlin, 1997;
Vol. 189.
(5) For comprehensive reviews on combinatorial catalysis, see: (a) Shimizu
K. D.; Snapper, M. L.; Hoveyda, A. H. Chem. Eur. J. 1998, 4, 1885. (b)
Francis, M. B.; Jamison, T. F.; Jacobsen, E. N. Curr. Opin. Chem. Biol.
1998, 2, 422. (c) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 2001, 40,
284. (d) Kagan, H. B. J. Organomet. Chem. 1998, 567, 3.
(6) Chiral titanium complexes promoted HDA, see: (a) Keck, G. E.; Li, X.;
Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998. (b) Wang, B.; Feng,
X.; Cui, X.; Liu, H.; Jiang, Y. Chem. Commun. 2000, 1605.
(7) For aggregation of BINOL-titanium complexes, see e.g.: (a) Pandiaraju,
S.; Chen, G.; Lough, A.; Yudin, A. K. J. Am. Chem. Soc. 2001, 123,
3850. (b) Terada, M.; Matsumoto, Y.; Nakamura, Y.; Mikami, K. Inorg.
Chim. Acta 1999, 296, 267.
(8) For examples, see: (a) Mikami, K.; Matsukawa, S.; Volk, T.; Terada, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2768. (b) Hill, C. L.; Zhang, X.
Nature 1995, 373, 342.
(9) For examples, see: (a) Berrisford, D. J.; Bolm, C.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1059. (b) Mikami, K.; Matsukawa, Nature
1997, 385, 613. (c) Ding, K.; Ishii, A.; Mikami, K. Angew. Chem., Int.
Ed. Engl. 1999, 38, 497.
(10) See Supporting Information.
(11) For solvent-free asymmetric catalysis, see e.g.: Tokunaga, M.; Larrow,
J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936
(12) (a) Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH:
New York, 2001. (b) Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.;
Jo¨rgensen, K. A. J. Am. Chem. Soc. 1998, 120, 8599, where 0.05 mol %
of catalyst was used. (c) Doyle, M. P.; Phillips, I. M.; Hu, W. H. J. Am.
Chem. Soc. 2001, 123, 5366, where 0.01 mol % of catalyst was used and
up to 80% ee obtained.
Acknowledgment. Financial support from the National Natural
Science Foundation of China, Chinese Academy of Sciences, the
JA0172518
9
J. AM. CHEM. SOC. VOL. 124, NO. 1, 2002 11