Quasi Solvent-Free Enantioselective Carbonyl-Ene Reaction with Extremely Low Catalyst Loading

Article abstract of DOI:10.1002/anie.200352535

Simply mixing the neat substrates and a small amount of the chiral catalyst (0.1-0.01 mol%) under nearly solvent-free conditions makes the enantioselective carbonyl-ene reaction of glyoxylate ester with a variety of olefins proceed smoothly to afford the

Full text of DOI:10.1002/anie.200352535

Communications
Catalytic Carbonyl-Ene Reaction
version has been achieved with various chiral Lewis acids
including Al, Ti, Ni, Pt, Pd, Yb, and Cu complexes.[6,7] The
catalyst loadings employed in most cases were in the range
from 1 to 10 mol%. In our experiments we employed
binolate-Ti, which was prepared in situ by the reaction of
(R)-binol (2,2’-dihydroxy-1,1’-biphenyl) and titanium iso-
propoxide (2:1 molar ratio in dichloromethane/toluene).
Under nearly solvent-free conditions (the solvent volume
from the catalyst was about 13% of the whole system) and
with a catalyst loading of 0.1 mol%, a-methylstyrene (1a)
reacted with ethyl glyoxylate (2) [Eq. (1)] efficiently at room
temperature to give a-hydroxy ester (R)-3a in quantitative
yields and good enantioselectivity (90% ee). The practical
advantages of this strategy—the easy preparation of the
catalyst, the nearly solvent-free conditions, the high yield and
enantiopurity of the product, and the extremely low catalyst
loading—make this protocol attractive for the preparation of
enantiomerically enriched a-hydroxy esters of biological and
synthetic importance.
Tuning the sterics and electronics of the diol ligands in
their metal complexes is essential to achieving highly efficient
catalysts for asymmetric reactions, and the combinatorial-
chemistry approach may be a powerful strategy for this
purpose.[8] We searched for more efficient catalysts for the
reaction of 1a with 2 by high-throughput screening of a
catalyst library generated from the parallel combination of
any two of the ligands shown in Scheme 1 with titanium
Quasi Solvent-Free Enantioselective Carbonyl-
Ene Reaction with Extremely Low Catalyst
Loading**
Yu Yuan, Xue Zhang, and Kuiling Ding*
Asymmetric catalysis of organic reactions to provide enan-
tiomerically enriched products is of central importance to
modern synthetic and pharmaceutical chemistry.[1] The devel-
opment of chiral catalysts for the enantioselective carbon–
carbon bond-forming reactions is a fundamental topic in
asymmetric catalysis.[1] However, many currently accessible
methods are impractical, for example, in terms of efficiency
and environmental considerations.[2] Therefore the develop-
ment of truly efficient and practical synthesis has been one of
the greatest challenges for synthetic chemists. As part of our
continuing effort in this area,[3] we report in this communi-
cation the first quasi solvent-free enantioselective carbonyl-
ene reaction. The reaction of ethyl glyoxylate with a variety of
olefins could be carried out with 0.1–0.01 mol% of catalysts to
give a-hydroxy esters in good to excellent yields and up to
99% ee [Eq. (1)].
For practical synthesis, solvent-free processes are ideal in
terms of volumetric productivities and environmental
safety.[4] Although most catalytic asymmetric processes are
highly sensitive to the polarity of solvent and the concen-
tration of substrates, a solvent-free procedure might be
suitable for an asymmetric reaction with a concerted mech-
anism[3] because its transition state is less influenced by the
polarity of the solvents. The thermal pericyclic ene reaction
represents a typical concerted pathway involving sixelectrons
with a suprafacial orbital interaction,[5] and its asymmetric
Scheme 1. Chiral ligands employed for asymmetric induction.
[*] Prof. Dr. K. Ding, Dr. Y. Yuan, X. Zhang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
isopropoxide. We found that both the electronic effect and the
steric bulk of the substituents of these binol derivatives have
significant impact on the catalytic activity and enantioselec-
tivity of the binol-Ti catalysts (see the Supporting Informa-
tion). The serious steric hindrance of the substituents (e.g.
CH3, Ph, Br) at the 3,3’-positions of binol proved to be
disadvantageous for the reaction. The partially reduced
binaphthyl ligands L3 and L4 were inferior to the parent
ligand L1. The modification of diol ligand at the 6,6’-positions
of binol with Br (L2) is quite effective for enhancing both the
reactivity and the enantioselectivity of the reaction.
354 Fenglin Road, Shanghai 200032 (P.R. China)
Fax: (+86)21-6416-6128
E-mail: kding@mail.sioc.ac.cn
[**] Financial support from the NSFC, the CAS, the Major Basic
Research Development Program of China (grant no. G2000077506),
and the Ministry of Science and Technology of Shanghai Munici-
pality is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
5478
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DOI: 10.1002/anie.200352535
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Angewandte
Chemie
All these results demonstrated that enhancing the Lewis
acidity of the titanium complexes might be a key point for
achieving high efficiency and enantioselectivity in the car-
bonyl-ene reaction. Therefore, we decided to set up a second-
generation library of chiral binol ligands with various
electron-withdrawing groups (X = Br, I, CF3) at the 6,6’-
positions (Scheme 2). As we expected, the catalyst library
lectivities [Eq. (2)]. Incidentally, product 3e is a key inter-
mediate in the synthesis of the collagenase-selective inhibitor
Trocade.[9] In the case of benzocyclic olefin substrate 1g, the
corresponding a-hydroxy ester 3g could be obtained in 94–
97% yields with 92.6–96.3% ee.
Scheme 2. Second-generation chiral binol ligands employed for asym-
metric induction.
generated by either homocombination or heterocombination
of these chiral ligands with titanium isopropoxide showed
excellent enantioselectivity (> 94.9% ee) (see the Supporting
Information) under nearly solvent-free conditions even
though the catalyst loading was reduced to 0.01 mol%. (The
solvent volume of the catalyst system was only ca. 1.3% of the
whole system in these cases!) The catalysts formed by
homocombination of L11 or heterocombination of L11 and
L12 with titanium isopropoxide were found to be superior to
other catalysts, affording a-hydroxy ester 3a in 97.1% yield
and 97.7% ee.
The reactions promoted by the optimized catalysts (L11/
Ti/L11 and L11/Ti/L12) were then carried out on a gram scale
with catalyst loadings of 0.1–0.01 mol% at 08C. We found that
both L11/Ti/L11 and L11/Ti/L12 are highly efficient catalysts
for the reactions of a variety of 2-arylpropenes (1a–d),
including derivatives with electron-withdrawing or electron-
donating substituents (Table 1). The olefin substrates could
be also extended to cyclic systems (1e,f). The reactions of
ethyl glyoxylate with methylenecyclopentane (1e) and meth-
ylenecyclohexane (1 f) proceeded with excellent enantiose-
To demonstrate the preparative utility of this method-
ology, we conducted the reaction of ethyl glyoxylate with a-
methylstyrene at 08C on
a 0.1-mole scale employing
0.05 mol% L11/Ti/L12; the desired adduct 3a was generated
in > 99% yield and 95% ee. To the best of our knowledge,
this is the lowest catalyst loading for a Lewis acid catalyzed
asymmetric carbonyl-ene reaction.[6h] The resulting product
3a could be converted stereoselectively into functionalized g-
butyrolactone 4a by iodolactionization in excellent yield with
the (R,S) isomer as the major product (Scheme 3).[10] This is a
powerful approach for the synthesis of biologically important
products.
Scheme 3. Preparation of g-butyrolactone 4a. Conditions: a) 20%
aq KOH, CH3OH, 408C, 4 h; b) I2, NaHCO3, CH3CN, room
temperature, 16 h.
Table 1: Enantioselective ene reactions between ethyl glyoxylate and
representative olefins under nearly solvent-free conditions.
Olefin Product[a] Cat. (mol%)
t [h] Yield[b] [%] ee [%][c]
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1 f
(R)-3a
(R)-3a
(R)-3a
(R)-3a
L11/Ti/L11 (0.1)
L11/Ti/L12 (0.1)
L11/Ti/L11 (0.01) 72
L11/Ti/L12 (0.01) 72
L11/Ti/L11 (0.1)
L11/Ti/L12 (0.1)
L11/Ti/L11 (0.1)
L11/Ti/L12 (0.1)
L11/Ti/L11 (0.1)
L11/Ti/L12 (0.1)
L11/Ti/L11 (0.1)
48
48
98
85
76
49
89
96
83
96
98.2
97.6
97.2
97.9
99.4
98.2
98.4
98.4
97.1
97.0
91.6
91.8
92.2
96.3
In conclusion, we have first demonstrated that the
enantioselective carbonyl-ene reaction of glyoxylate ester
with a variety of olefins can be carried out under nearly
solvent-free conditions with the catalysis of 6,6’-I2- or 6,6’-
(CF3)2-binol-Ti at very low catalyst loadings (up to
0.01 mol%), affording the corresponding a-hydroxy esters
in high yields and excellent enantioselectivities. The trans-
formation of product 3a into a new type of functionalized g-
butyrolactone 4a was also achieved by stereoselective iodo-
lactonization in excellent yield.
(À)-3b[d]
(À)-3b[d]
(+)-3c[d]
(+)-3c[d]
(À)-3d[d]
(À)-3d[d]
(R)-3e
48
36
48
48
36
36
24
92
>99
>99
42
97
94
1 f
1g
1g
(R)-3 f
(R)-3g
(R)-3g
L11/Ti/L12 (0.01) 42
L11/Ti/L11 (0.1)
L11/Ti/L12 (0.1)
48
48
Experimental Section
General procedure for the quasi solvent-free enantioselective car-
bonyl ene reaction of ethyl glyoxylate with a-methylstyrene. To a
solution of L11 (27 mg, 0.05 mmol) and L12 (21 mg, 0.05 mmol) in
[a] Absolute configurations were assigned by comparing the optical
rotations with literature values. [b] Yields of isolated products. [c] Enan-
tiomeric excesses were determined by GC (Cyclodex B column) or HPLC
(Chiral OJ column). [d] Absolute configuration was not determined.
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Communications
toluene (1 mL) was added 0.5m Ti(OiPr)4 in CH2Cl2 (100 mL,
2768; c) S. Pandiaraju, G. Chen, A. Lough, A. K. Yudin, J. Am.
Chem. Soc. 2001, 123, 3850.
0.05 mmol), and the mixture was stirred for 2 h at room temperature.
The mixture was cooled to 08C, and then a-methylstyrene (1a)
(12.5 mL, 0.1 mol) and ethyl glyoxylate (2) (15 mL, 0.2 mol) were
added. After stirring for 48 h at 08C, the reaction mixture was directly
submitted to flash column separation on silica gel with EtOAc/hexane
(1:4) as eluent to give (R)-3a (22 g, > 99% yield with 95% ee). The
enantiomeric excess of the product was determined by HPLC on a
Chiralcel OJ column; eluent: hexane/2-propanol (97:3); flow rate:
0.7 mLminÀ1; UV detection at l = 254 nm; tR((S)-3a) = 23.3 min
(minor), tR((R)-3a) = 30.7 min (major).
[8] For comprehensive reviews on combinatorial catalysts, see:
a) K. D. Shimizu, M. L. Snapper, A. H. Hoveyda, Chem. Eur. J.
1998, 4, 1885; b) M. B. Francis, T. F. Jamison, E. N. Jacobsen,
Curr. Opin. Chem. Biol. 1998, 2, 422; c) B. Jandeleit, D. J.
Schaefer, T. S. Powers, H. W. Turner, W. H. Weinberg, Angew.
Chem. 1999, 111, 2648; Angew. Chem. Int. Ed. 1999, 38, 2494;
d) M. T. Reetz, K.-E. Jaeger, Chem. Eur. J. 2000, 6, 407; e) M. T.
Reetz, Angew. Chem. 2001, 113, 292; Angew. Chem. Int. Ed.
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Received: August 1, 2003 [Z52535]
[9] P. Brown, H. Hilpert (F. Hoffmann-La Roche AG), EP
Appl96110814.9, 1996.
Keywords: asymmetric catalysis · carbonyl-ene reaction · ligand
effects · titanium
.
[10] The absolute configuration of 4a was determined by X-ray
diffraction analysis, see the Supporting Information. CCDC-
216977 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cam-
bridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
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5480
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