Figure 1. Stereochemical rationale for enolsilane additions to ethyl glyoxylate catalyzed by Sc complexes 1a and 1b.10
glyoxylate. In additions of these enolsilane nucleophiles, the
use of 2.0 equiv of chlorotrimethylsilane was essential to
facilitate catalyst turnover. The use of a para-substituted
isobutyrophenone-derived enolsilane (entry 2) as well as
cyclic variants of the disubstituted enolsilanes (entries 3 and
4) performed equally well in terms of both yield and
enantioselection. Initial attempts with enolsilanes derived
from acetophenone provided low levels of induction in the
aldol reaction with catalyst 1b, presumably due to the more
planar nature of the enolsilane nucleophile.9 In an attempt
to test this hypothesis and expand the methodology to include
acetophenone-derived enolsilanes, ortho-substituted enolsi-
lanes (entries 5 and 6) were surveyed.
It was anticipated that ortho substitution would expand
the dihedral angle between the aryl ring and the olefinic
moiety, thereby effectively increasing the steric bulk of the
nucleophile and affording a more selective aldol addition.
Gratifyingly, these ortho-substituted enolsilanes afford the
R-hydroxy-γ-ketoesters with high levels of enantioselectivity
(entries 5 and 6) comparable to the values observed with
the isobutyrophenone-derived enolsilanes. An X-ray crystal-
lographic analysis of adduct 6e confirmed the (S) configu-
ration of the glyoxylate adduct (see Supporting Information).
Of particular note, the enolsilane additions mediated by
catalyst 1b afforded the opposite sense of induction from
that obtained with catalyst 1a using the thiosilylketene acetal
nucleophiles (Table 1). In all cases examined in Table 2,
the arylenolsilane additions to ethyl glyoxylate afford the
complementary (S)-R-hydroxy-γ-ketoesters with high levels
of enantiocontrol.
The stereochemical course of both the thiosilylketene
acetal and arylenolsilane additions to ethyl glyoxylate can
be rationalized by the model10 shown in Figure 1. Models
A and B represent the minimized transition state structures
of complexes 1a and 1b docked with ethyl glyoxylate,
respectively.11 In model A, the aldehyde functionality is
bound in the apical position, thereby favoring addition to
the re-face of the aldehyde carbonyl as the si-face is
effectively shielded by a phenyl group of the pybox ligand.
In model B, the aldehyde moiety is bound in the equatorial
position, thereby favoring addition to the si-face of the
aldehyde carbonyl as the re-face is effectively blocked by
the tert-butyl group of the pybox ligand. In each of these
representations, the binding of the aldehyde carbonyl in a
single position (i.e., apical in model A, equatorial in model
B) during the addition of the nucleophile is necessary to
explain the high levels of enantioselectivity observed for each
of the glyoxylate additions. Steric factors within the chiral
pocket of the scandium-catalyst may explain the preference
for the location of the aldehyde carbonyl in the complex.
Specifically, the reversal of binding preference for the
aldehyde moiety in complexes 1a and 1b may be a result of
the steric environment of the ligand architecture, which
(1) Evans, D. A.; Rovis, T.; Johnson, J. S. Pure Appl. Chem. 1999, 71,
1407-1415.
(2) Evans, D. A.; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett.
1996, 37, 7481-7484.
(3) Evans, D. A.; MacMillan, D. W. C.; Campos, K. R. J. Am. Chem.
Soc. 1997, 119, 10859-10860.
(4) For a comprehensive review of catalytic enantioselective aldol
reactions: see Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-389.
(5) Evans, D. A.; Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem.
Soc. 2001, 123, 12095-12096. For a syn-aldol, cf.: Mikami, K.; Mat-
sukawa, S. J. Am. Chem. Soc. 1994, 116, 4077-4078.
(10) This model was generated from the pentagonal-bipyramidal crystal
structure of the Sc[Ph-pybox(H2O)](OTf)3 complex (ref 5) by the following
procedure. Coordinates for the Sc[Ph-pybox(H2O)](OTf)3 complex were
input into Chem 3D Pro; the vicinal triflates were removed and replaced
with chloride ions, and the remaining triflate and bound water were replaced
with ethyl glyoxylate, which was docked onto the Sc-center. The ligand-
Sc bond lengths were held constant and the molecular energy of the structure
minimized.
(11) These structures were subjected to a MM2 transition state minimiza-
tion using Chem 3D Pro (Version 5.0). In each model, an apical or equatorial
binding of the aldehyde carbonyl was minimized separately with the lower
energy structure shown.
(6) (a) Evans, D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc.
1996, 118, 5814-5815. (b) Evans, D. A.; Kozlowski, M. C.; Burgey, C.
S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7893-7894.
(7) Enantioselectivities obtained with other [ScCl2(pybox)]SbF6 com-
plexes: 1b (11% ee), 1c (50% ee), 1d (40% ee).
(8) For the addition to ethyl glyoxylate catalyzed by 1a, the corresponding
(E)-thiosilylketene acetals led to the formation of the malate products in
lower yields and syn selectivity. For example, the reaction of (E)-2b afforded
3b (80% ee, dr 1.4:1) and (E)-2c afforded 3c (78% ee, dr 1:1).
(9) The trimethylsilyl enolsilane derived from acetophenone afforded the
aldol product in 11% ee using the conditions in Table 2.
Org. Lett., Vol. 4, No. 20, 2002
3377