Lewis base activation of Lewis acids: Catalytic enantioselective glycolate aldol reactions

Article abstract of DOI:10.1002/anie.200705499

(Chemical Equation Presented) Both syn- and anti-1,2-diols can be obtained with high diastereoselectivity and enantioselectivity from the properly substituted glycolate-derived silyl ketene acetals in the presence of SiCl ₄ and a chiral bisphos

Full text of DOI:10.1002/anie.200705499

Communications
DOI: 10.1002/anie.200705499
Asymmetric Catalysis
Lewis Base Activation of Lewis Acids: Catalytic Enantioselective
Glycolate Aldol Reactions**
Scott E. Denmark* and Won-jin Chung
Chiral 1,2-diols are ubiquitous subunits in natural products
and in chiral ligands used for asymmetric catalysis. In
addition, a variety of useful structures can be accessed by
chemical transformations of 1,2-diols. Whereas syn-1,2-diols
can be prepared with high enantioselectivities by Sharpless
asymmetric dihydroxylation of olefins,[1] anti-1,2-diols can be
synthesized by asymmetric epoxidation and ring opening.[2]
These oxidation reactions represent powerful methods for
vicinal functionalization of geometrically defined alkenes
because of the highly stereospecific nature of these methods.
The glycolate aldol reaction is a conceptually distinct
route to the preparation of stereodefined 1,2-diol units in
which the bond between the vicinal diol and both stereogenic
centers are formed as part of the process concomitantly
(Scheme 1). In principle, the selective formation of either
diastereomer by this type of reaction is possible. Moreover, it
is not necessary to control the geometry of the double bonds
because of the stereoconvergent nature of Mukaiyama-type
aldol reactions.[3]
amine ligands, it is necessary to employ an excess of tin
reagents and a stoichiometric amount of the chiral amine in
some cases. Moreover, slow addition of the tin reagents over
several hours with a syringe pump is required. Thus, an
efficient and practical catalytic enantioselective glycolate
aldol reaction remains a challenge.
Previous studies from our group have demonstrated the
utility of Lewis base catalyzed, Lewis acid mediated, enan-
tioselective Mukaiyama-type aldol reactions utilizing SiCl4
and bisphosphoramide catalyst (R,R)-1 (Figure 1).[7] This
catalyst system is effective for the addition of aldehyde-,
ketone-, acetate-, or propanoate-derived enoxysilanes. Inter-
estingly, the aldol additions of substituted silyl ketene acetals
are highly anti-selective, although the rate and selectivity are
sensitive to the size of the a-carbon substituent and the ester
group. Herein, we describe the first diastereodivergent,
catalytic, enantioselective glycolate aldol reaction.
Scheme 1. Glycolate aldol reaction.
Stereoselective glycolate aldol reactions are most com-
monly performed with chiral oxazolidinone derivatives of
glycolate esters.[4] In general, syn-1,2-diols are obtained as the
major diastereomers through boron-mediated aldolizations.
Recently, a few systematic studies of auxiliary-directed syn- or
anti-selective glycolate aldol reactions have been described.[5]
However, catalytic stereoselective glycolate aldol reactions
are very rare. The only successful examples have been
reported by Kobayashi et al.[6] Although highly selective
formation of both diastereomers is achieved by changing both
the geometry of ketene acetals and the structure of chiral
Figure 1. Structures of catalyst and aldehydes.
An extensive survey of hydroxy protecting groups, ester
moieties, and silyl derivatives revealed that trimethylsilyl
(TMS) ketene acetal 3a, prepared from a methyl glycolate
that is affixed with a large (cumyl) protecting group on the a-
oxygen atom, leads to high syn selectivity in the glycolate
aldol reaction. For example, 3a reacted with benzaldehyde
(2a) in the presence of SiCl4 (1.1 equiv) and (R,R)-1
(1 mol%) to afford the syn-aldol product 4aa after
0.5 hours in high diastereoselectivity and enantioselectivity
(Table 1, entry 1). The syn-selective glycolate aldol reaction is
general for a range of structurally and electronically diverse
aromatic aldehydes. Excellent chemical yields and stereose-
lectivities were consistently obtained from electron-rich 4-
[*] Prof. S. E. Denmark, W.-j. Chung
Department of Chemistry
University of Illinois
Urbana, IL, 61801 (USA)
Fax: (+1)217-333-3984
E-mail: denmark@scs.uiuc.edu
Homepage: http://www.scs.uiuc.edu/denmark/
[**] We are grateful to the National Science Foundation for generous
financial support (NSF CHE 0414440 and CHE0717989).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: syn-Selective glycolate aldol reactions with aromatic aldehydes.[a]
Unfortunately, neither 3a nor 3b underwent aldol reac-
tions with hydrocinnamaldehyde (2 f) even after 20 hours in
the presence of 5 mol% of (R,R)-1 at À508C and a concen-
tration of 0.4m. The attenuated reactivity of aliphatic
aldehydes has been a persistent problem in the Lewis base
catalyzed, SiCl4-promoted carbonyl addition reactions.[7]
However, the effect of substituents on the rate and selectivity
allowed a suitable reaction partner to be found. Silyl ketene
acetal 3c[8] was sufficiently reactive to undergo aldol reaction
with 2 f in a considerably improved yield (Scheme 2); accept-
able syn diastereoselectivity and enantioselectivity were also
obtained.
Entry
RCHO
t [h]
Product
Yield [%][b]
d.r.[c]
99:1
99:1
99:1
e.r.[d]
1
2
3
4
5
2a
2b
2c
2d
2e
0.5
1.5
0.5
9.0
0.5
4aa
4ab
4ac
4ad
4ae
87
98
99
93
94
96.6:3.4
97.7:2.3
98.0:2.0
96.8:3.2
98.5:1.5
98:2
>99:1
[a] Reaction conditions: silyl ketene acetal (1.2 equiv), SiCl4 (1.1 equiv),
and iPr2NEt (0.1 equiv) at 0.1m concentration. The silyl ketene acetal was
added as a 0.24m solution over 15 min. [b] Yields of analytically pure
material. [c] Determined by 1H NMR analysis of HC2 or HC3. [d] Deter-
mined by chiral stationary phase-supercritical fluid chromatography
(CSP-SFC).
methoxybenzaldehyde (2b), electron-poor 4-trifluoromethyl-
benzaldehyde (2c), sterically hindered 2-tolualdehyde (2d),
and bicyclic 2-naphthaldehyde (2e) (Table 1, entries 2–5).
However, the reactivity was significantly influenced by steric
encumbrance in the aromatic aldehyde as demonstrated by
the reduced reactivity of 2d.
Scheme 2. syn-Selective glycolate aldol reaction with an aliphatic alde-
hyde.
In the anti-selective reaction manifold, the reactivity of
the silyl ketene acetal could be enhanced by replacing the
bulky tertiary ester with a bulky secondary ester. Silyl ketene
acetal 3d reacted smoothly with 2 f to afford the correspond-
ing anti-aldol product 4df in high yield and stereoselectivity
(Scheme 3). In this case, the more synthetically useful benzyl
group, as opposed to the methyl group, could be employed to
protect the a-oxygen atom. Another primary aliphatic
aldehyde, 6-benzyloxyhexanal (2g), was also a suitable
substrate which provided anti-aldol product 4dg in high
yield and excellent stereoselectivity.
Remarkably, the stereochemical course of this reaction
could be completely reversed by changing the size of the
substituents on the silyl ketene acetal. tert-Butyldimethylsilyl
(TBS) ketene acetal 3b, derived from the 3-methyl-3-pentyl
ester of a-methoxyacetic acid, reacted with benzaldehyde
(2a) to give the anti-aldol product 4ba in high diastereose-
lectivity and enantioselectivity (Table 2, entry 1). The gen-
erality of anti-selective glycolate aldol reaction was also
shown for a series of aromatic aldehydes. Electron-rich 4-
methoxybenzaldehyde (2b), electron-poor 4-trifluoromethyl-
benzaldehyde (2c), o-substituted 2-tolualdehyde (2d), as well
as bicyclic 2-naphthaldehyde (2e) provided products in high
yields and stereoselectivities (Table 2, entries 2–5). Again, the
decreased reactivity of 2d was observed. All attempts to
replace the methyl group on the a-oxygen atom to more
readily removable groups were unsuccessful.
Table 2: anti-Selective glycolate aldol reactions with aromatic alde-
hydes.[a]
Scheme 3. anti-Selective glycolate aldol reactions with aliphatic alde-
hydes; Bn=benzyl.
Entry
RCHO
t [h]
Product
Yield [%][b]
d.r.[c]
e.r.[d]
1
2
3
4
5
2a
2b
2c
2d
2e
0.5
3.0
0.5
18.0
0.5
4ba
4bb
4bc
4bd
4be
91
93
96
91
93
>99:1
>99:1
>99:1
98:2
95.1:4.9
98.3:1.7
98.3:1.7
93.1:6.9
97.4:2.6
Silyl ketene acetals 3c and 3d also underwent aldol
addition with an alkenyl aldehyde (Scheme 4). The reactions
of 3c and 3d with E-cinnamaldehyde (2h) afforded the syn-
and anti-aldol products, respectively, in high yields with
excellent diastereo- and enantioselectivities.
The absolute and relative configurations of 4aa and 4ba
were established by chemical correlations to known com-
pounds 5[9] and 6[10] (Scheme 5). The S configurations at C3
imply a Re face attack on the aldehyde. This sense of
>99:1
[a] Reaction conditions: silyl ketene acetal (1.2 equiv), SiCl4 (1.1 equiv),
and iPr2NEt (0.1 equiv) at 0.1m concentration. The silyl ketene acetal was
added as a 0.24m solution over 15 min. [b] Yields of analytically pure
material. [c] Determined by 1H NMR analysis of HC2 or HC3. [d] Deter-
mined by CSP-SFC methods.
Angew. Chem. Int. Ed. 2008, 47, 1890 –1892
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Communications
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asymmetric induction is in agreement with previous results
from the same catalytic system.[7]
In conclusion, an efficient, Lewis base catalyzed, stereo-
selective glycolate aldol reaction has been developed for a
wide range of aldehydes. Remarkably, both syn- and anti-1,2-
diols can be obtained under the same catalytic system by
modulating the size of the substituents on the silyl ketene
acetal. Additional studies are underway to elucidate the
origin of the remarkable switch of diastereoselectivity.
Received: December 2, 2007
Published online: January 31, 2008
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Keywords: 1,2-diols · aldol reaction · diastereoselectivity ·
.
enantioselectivity · Lewis base catalysis
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