Enantioselective syn-selective scandium-catalyzed ene reactions

Article abstract of DOI:10.1021/ja0522130

An enantio- and diastereoselective carbonyl-ene reaction catalyzed by chiral scandium pyridyl bis(oxazoline) (pybox) complexes has been developed. Uniformly high enantiomeric excesses and good yields were observed. Use of trisubstituted olefins generated

Full text of DOI:10.1021/ja0522130

Published on Web 05/14/2005
Enantioselective Syn-Selective Scandium-Catalyzed Ene Reactions
David A. Evans* and Jimmy Wu
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received April 6, 2005; E-mail: evans@chemistry.harvard.edu
The carbonyl-ene reaction continues to be a powerful C-C bond
forming reaction. The first catalytic enantioselective variant using
Table 1. Ene Reaction with 1,1-Disubstituted Olefins (eq 3)
1
a chiral aluminum BINOL complex was reported by Yamamoto.2
Subsequently, Mikami and others have reported the use of titanium-
based BINOL complexes as efficient catalysts for the carbonyl-
ene reaction.3 Other metal cations that have also been used to
effectively catalyze the asymmetric carbonyl-ene reaction include
,4
complexes derived from Co, Pd, Pt, Cr, Cu,9 and several
lanthanides.10 The purpose of this Communication is to report that
chiral scandium(III) complexes 4 and 5 are effective carbonyl-
ene catalysts that afford excellent diastereoselectivities with trisub-
stituted olefins (eq 1). While there have been isolated reports in
the literature of diastereoselective, carbonyl-ene reactions, these
transformations have not been systematically explored.3
5
6
7
8
c,d,8a,11
a Enantiomeric excesses were determined by HPLC using Chiracel OD-H
or AD-H columns. b Absolute stereochemistry was determined by Mosher
ester analysis. Remaining product configurations were assigned by analogy.
Next, we were able to demonstrate that the catalyst was capable
of regioselective discrimination of substituents found on unsym-
metrical, 1,1-disubstituted olefins (eq 4). Steric considerations seem
to be the dominant factor in determining selectivity since the use
of bulkier substituents led to increased regioselectivities. In each
of these three cases, the product containing a terminal olefin was
preferentially formed over the more highly substituted alkene.
We have previously documented the utility of chiral scandium-
pybox12 complexes as effective Lewis acids exhibiting good
13
chelating potential. More recently, the application of these
complexes to the catalysis of the Nazarov reaction has been
reported.14 These results suggested that trivalent scandium-pybox
complexes might be effective promoters of the asymmetric,
carbonyl-ene reaction. Accordingly, a survey of these complexes
was conducted to evaluate the reaction between R-methylstyrene
Trisubstituted olefinic substrates introduce the possibility of
simultaneously incorporating a second vicinal stereogenic center
(eq 1). We were initially disappointed that the reaction of 2-methyl-
2-butene (12), under standard conditions with complex 4, yielded
a 5:1 syn:anti mixture of diastereomers (97% ee). However, we
were pleased to discover that the related [Sc(S,S)Phpybox)](OTf)3
complex 5, in the reaction of 12 with 2b, afforded the ene product
in high diastereoselectivity while simultaneously maintaining excel-
lent enantiomeric excesses (13:1 syn:anti, 94% ee, Table 2).
Similarly, the reactions of 3-ethyl-2-pentene, ethylidene cyclohex-
ane, ethylidene cyclopentane, and 2-methyl-2-pentene with 2b,
catalyzed by complex 5, afforded products with good syn selectivi-
ties and high enantiomeric excesses. Once again, all products were
isolated as crystalline solids. This present methodology is comple-
mentary to the anti-selective, Cu(II)-catalyzed glyoxylate-ene reac-
(
(
1) with either ethyl glyoxylate (2a) or N-phenyl glyoxamide (2b)
eq 2).15 From this screen, complexes 4 and 5 surfaced as attractive
catalysts for reactions with olefins and glyoxamide 2b. A benefit
of using phenyl glyoxamide as the carbonyl component is that the
desired products are routinely isolated as crystalline solids, a
desirable attribute for large-scale reactions. This is the principal
motivation for using this substrate in the present study.
Under optimized reaction conditions, a representative number
of 1,1-disubstituted olefins were evaluated (Table 1). Good yields
and high enantiomeric excesses (92-94% ee) were observed for
each of the products formed when using R-methylstyrene, isobu-
tylene, methylenecyclohexane, and methylenecyclopentane as nu-
cleophiles. All products were isolated as crystalline solids.
9
tion previously reported by our group. This represents one of a
8006
9
J. AM. CHEM. SOC. 2005, 127, 8006-8007
10.1021/ja0522130 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Ene Reaction with Trisubstituted Olefins (eq 5)
obtained in the Sc(III)-catalyzed reaction between 2b and acyclic
allylsilanes. This transformation affords the anti diastereomers in
good yields and selectivities (eq 9). Further studies on both of these
processes are ongoing.
The N-phenylcarboxamides employed in this study may be
readily activated for either hydrolysis or transesterification through
18
their derived N-Boc imide analogues or through amide nitrosation.
Acknowledgment. Support is provided by the NIH (GM-33328-
20), the NSF (CHE-9907094), and Merck Research Laboratories.
We gratefully acknowledge Dr. Andr e´ Beauchemin for providing
an efficient synthesis of N-phenyl glyoxamide (2b). J.W. thanks
the ASEE for an NDSEG predoctoral fellowship.
a
Enantiomeric excesses were determined by HPLC using Chiracel OD-H
b
or AD-H columns. Absolute stereochemistry was determined by Mosher
ester analysis. The remaining product configurations were assigned by
analogy. Syn stereochemistry was determined by single-crystal X-ray
analysis. The remaining product configurations were assigned by analogy.
c
Supporting Information Available: Experimental details and
characterization data for all new compounds (PDF). Crystallographic
data for 12b, 15b-18b and stereochemical proofs. This material is
available free of charge via the Internet at http://pubs.acs.org.
limited number of examples of enantioselective, syn-selective, ene
reactions between glyoxylate derivatives and unactivated olefins.16
Finally, we were interested in determining if this catalyst was
capable of simultaneously providing both regio- and diastereose-
lectivity. When olefin 17 was subjected to the standard reaction
conditions with catalyst 5, 17b was produced in excellent enantio-
and diastereoselectivity (eq 6). When the same reaction was carried
out with its geometric isomer 18, 18b was also generated in
excellent enantio- and diastereoselectivity (eq 7). In both of these
experiments, we did not detect the presence of any regioisomeric
products. The major product produced in both cases corresponds
to proton transfer from the â-cis substituent through an exo
transition state17 (eq 8). The fact that regioselectivities are
significantly enhanced when unsymmetrical trisubstituted olefins
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(
In our previous study of the glyoxylate ene reaction with the
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6 2
cationic [Cu(t-BuBox)](SbF ) complexes, a general preference for
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9
endo transition states was observed. It is thus significant that a
predisposition for exo transition states has been observed with
scandium complex 5.
As a complement to the present study, we have also found that
convenient access to the anti glyoxylate ene-type adducts may be
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