Highly enantioselective carbonyl-ene reactions catalyzed by In(III)-PyBox complex

Article abstract of DOI:10.1021/ja807501a

A highly enantioselective carbonyl-ene reaction catalyzed by In(III)-pybox is described. Both 1,1-disubstituted alkenes and 1,1,2-trisubstituted alkenes proceeded smoothly to give the ene products in high yields up to 97% and with excellent diastereoselec

Full text of DOI:10.1021/ja807501a

Published on Web 11/13/2008
Highly Enantioselective Carbonyl-ene Reactions Catalyzed by In(III)-PyBox
Complex
Jun-Feng Zhao, Hoi-Yan Tsui, Pei-Jia Wu, Jun Lu, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
Technological UniVersity, Singapore 637371
Received September 22, 2008; E-mail: teckpeng@ntu.edu.sg
The carbonyl-ene reaction has gained tremendous attention1
because it allows the atom-economic construction of homoallylic
alcohols, which are important building blocks for the synthesis of
many natural products and pharmaceutical compounds.2 Accord-
ingly, several research groups have reported the chiral metal
complexes mediated asymmetric carbonyl-ene reaction. Initially,
Yamamoto’s3 aluminum-based and Mikami’s titanium-based4
BINOL complexes were developed. Subsequently, Evans and co-
workers reported that both Cu-Box5 and Sc-PyBox6 are efficient
catalysts for this reaction. Other metal complexes derived from Co,7
Pd,8 Pt,9 Cr,10 and several lanthanides11 had also been used to
mediate the asymmetric carbonyl-ene reaction. Most recently,
Terada12 and Rueping13 have independently reported the organo-
catalyzed enantioselective carbonyl-ene reaction. While extraordi-
nary advances have been achieved, most of them still have
limitations such as high catalyst loading, harsh reaction conditions,
limited substrate scope, or difficult preparation of catalyst. There-
fore, the asymmetric carbonyl-ene reaction remains a challenging
topic. We herein present the In(III)-pybox complex14 catalyzed
highly enantioselective carbonyl-ene reactions.
enantioselective carbonyl-ene reaction in excellent yield and with
satisfactory enantioselectivity (Table 1, entry 1). Next, we evaluated
the effect of solvent, temperature, and amount of catalyst on the
reaction. As shown in Table 1, this reaction was sensitive to solvent,
and 1,2-dichloroethane (DCE) was the optimum choice of solvent
(Table 1, entries 1-6). Importantly, the catalyst loading could be
reduced to 5 mol % with improved enantioselectivity (Table 1, entry
8). We also found that the enantioselectivity could be further improved
by decreasing the concentration of the reaction system (Table 1, entry
10). While room temperature offered good results, the best results were
attained at 0 °C (Table 1, entries 10 and 11).
We then investigated the effect of ester group of glyoxylate. The
carbonyl-ene reactions between R-methyl styrene and representative
glyoxylate esters were carried out under the optimized conditions
(Table 2). All the glyoxylate esters proceeded smoothly to give
Table 2. In(III)-PyBox Complex-Catalyzed Asymmetric
Carbonyl-ene Reactions of R-Methylstyrene with Various
Glyoxylatesa
Preliminary studies15 demonstrated that the chiral indium complex,
formed in situ from commercially availiable In(OTf)3 and pybox 1 in
the presence of 4 Å molecular sieves, did indeed promote the
Table 1. Optimization Studiesa
entry
catalyst (mol %)
solvent
time (day)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
20
20
20
20
20
20
10
5
CH2Cl2
CH3CN
toluene
CHCl3
THF
DCE
DCE
DCE
DCE
1
1
1
1
1
1
2
4
4
4
6
97
trace
45
trace
trace
98
89
95
63
93
83
nd
47
nd
nd
86
89
91
77
94
95
a Reactions were carried out on a 0.5 mmol scale with 2 equiv of
R-methylstyrene in 4.0 mL of DCE, unless noted otherwise. b Isolated
yield. c The ee values were determined by chiral-phase HPLC analysis,
and the absolute configuration of the major products was R, assigned by
comparing HPLC with the literature.
9
2
5
5
10d
11e
DCE
DCE
96
the ene products in good to excellent yields and with high
enantioselectivities.
a Reactions were carried out on a 0.5 mmol scale with 2 equiv of
R-methylstyrene in 2.0 mL of solvent at room temperature, unless noted
otherwise. b Isolated yield. c The ee values were determined by chiral-phase
HPLC analysis, and the absolute configuration of the major products was R,
assigned by comparing HPLC with the literature; nd ) not detected. d This
reaction was carried out in 4.0 mL of solvent at room temperature. e This
reaction was carried out in 4.0 mL of solvent at 0 °C.
To further examine the scope and limitation of the methodology,
carbonyl-ene reactions between the commercially available ethyl
glyoxylate and various 1,1-disubstituted and trisubstituted alkenes
were explored, and the results were summarized in Table 3. Both
the aromatic and aliphatic alkenes afforded the expected homoallylic
9
16492 J. AM. CHEM. SOC. 2008, 130, 16492–16493
10.1021/ja807501a CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 3. In(III)-PyBox Complex-Catalyzed Aymmetric
when the methoxy group was at ortho or para position (Table 3,
entries 8, 10). There was no reaction when 4-nitro-R-methyl styrene
or 4-methylsulfonly-R-methyl styrene was used as substrate. The
reaction of trisubstituted alkene (Table 3, entry 14) is notable:
the regioselectivity, diastereoselectivity, and enantioselectivity were
very high and gave the product almost in optically pure form albeit
in moderate yield. Finally, cyclic and acyclic aliphatic alkenes also
underwent the carbonyl-ene reaction effectively to furnish the
desired products in high yields and with excellent enantioselec-
tivities (Table 3, entries 11-13).
Carbonyl-ene Reactions of Ethyl Glyoxylate with Various Olefinsa
In conclusion, we have developed a highly enantioselective and
efficient indium(III)-pybox complex-promoted carbonyl-ene reaction.
The catalyst is easily prepared from commercially availiable In(OTf)3
and pybox 1. This protocol offers several advantages including
operational simplicity, mild reaction conditions, low catalyst loading,
and high enantioselectivities and yields, which makes it a useful and
attractive strategy for the synthesis of chiral homoallylic alcohols.
Acknowledgment. We gratefully acknowledge the Nanyang
Technological University and Singapore Ministry of Education
AcademicResearchFundTier2(No.T206B1221andT207B1220RS)
for the funding of this research.
Supporting Information Available: Additional experimental proce-
dures, all chromatograms, and spectral data for reactions products. This material
is available free of charge via the Internet at http://pubs.acs.org.
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alcohol products in good to excellent yields and excellent enanti-
oselectivities. Interestingly, it was found that the position and the
electronic property of the substituents on the phenyl ring of ene
have some subtle effects on the reaction efficiency. While weak
electron-donating and withdrawing substituents (Table 3, entries
2-7) were tolerated, strong electron-donating (Table 3, entries
8-10) and withdrawing substituents influenced the reaction sig-
nificantly. The yield or the enantioselectivity or both were sacrificed
(15) For screening of chiral ligands and indium salts, see Supporting Information.
JA807501A
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