.
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active heterocycles.[9,10] Although numerous chiral Lewis acid
catalysts have been developed for the asymmetric inverse
electron demand HDA reaction of a,b-unsaturated carbonyl
compounds, dienophiles are limited to highly electron-rich
alkenes such as vinyl ethers. To the best of our knowledge, this
is the first successful example of the enantioselective inverse
electron demand HDA reaction of b,g-unsaturated a-keto-
esters with allylsilanes.[11–13]
Based on this promising result, we next examined the
reactivities of various allylsilanes for the 1·Cu(NTf2)2-cata-
lyzed reaction of 2a (R3 = Me). As a result, the use of
sterically hindered allylsilanes such as allyltriisopropylsilane,
allyltriphenylsilane, and allyltris(trimethylsilyl)silane sup-
pressed the generation of 4a and improved the yield of 3a,
although the diastereoselectivities were moderate (Table 1,
entries 2–5). Allyltriphenylsilane gave the best result
(entry 4).[14] The major isomer 3a (R = Ph) could be separated
as a single isomer by chromatography on silica gel. Interest-
ingly, the use of sterically hindered allyltris(trimethylsilyl)-
silane preferentially gave the corresponding trans-3a
(entry 5). Notably, in contrast to the 1·Cu(NTf2)2-catalyzed
reaction (entry 4), the use of a conventional bis(oxazoline)·-
copper(II) complex, (S,S)-tBu-bis(oxazoline)·Cu(NTf2)2, as
a catalyst gave 3a in only 51% yield with significant
decomposition of 2a, even after 17 hours at ambient temper-
ature.
LUMO[15,16] (Figure 2a). Indeed, an achiral copper(II) cata-
lyst also preferentially gave cis-3a (ca. 8:2).[8] However, the
steric repulsion between the sulfonamide group and the
triphenylsilyl group decreases the endo/exo selectivity, which
resulted in the moderate cis/trans ratio of the adducts. This
consideration is consistent with the fact that the sterically less
hindered allyltrimethylsilane showed good cis selectivity,
while the sterically hindered allyltris(trimethylsilyl)silane
preferentially gave trans adducts (Table 1).
To improve the cis/trans selectivity of the present HDA
reaction, we next investigated the ester moiety of 2 (Table 2).
Table 2: Effect of the ester moiety on the cis/trans selectivity.[a]
Entry
2 (R3)
Yield [%][b]
cis/trans
ee [%][c]
trans-3
cis-3
1
2
3
4
2a (Me)
2b (iPr)
2c [CH(iPr)2]
2d [CH(tBu)2]
2d [CH(tBu)2]
2e (tBu)
89
89
99
99
99
20[e]
65:35
80:20
89:11
90:10
90:10
97:3[e]
99
95
96
99
97
99
92
99
99
96
5[d]
6
n.d.
[a] Unless otherwise noted, the reaction of 2 (0.4 mmol) and an
We propose here a mechanism for the present inverse
electron demand HDA reaction with allylsilanes based on the
absolute configuration of 3a and our previous studies.[2] The
n–cation interaction would create an efficient asymmetric
environment around the copper(II) cation and preferentially
shield the Cb-Re face of the coordinated 2a (Figure 2b).
Allyltriphenylsilane would approach the Cb-Si face of 2a via
the endo transition state to give cis adducts as major products.
The predominance of endo transition state can be explained
in terms of a secondary orbital interaction between the
allylsilane HOMO and the b,g-unsaturated a-ketoester
allylsilane (2 equiv) was conducted in EtNO2 (2 mL) in the presence of
1·Cu(NTf2)2 (5 mol%) at ambient temperature for 3–17 h. [b] Yield of
isolated product 3. [c] Determined by HPLC analysis on a chiral sta-
tionary phase. [d] The reaction of 2d (4 mmol) and allylsilane (2 equiv)
was conducted in the presence of 1·Cu(NTf2)2 (0.5 mol%) in EtNO2
(4 mL). [e] Yield and cis/trans ratio of the corresponding carboxylic acid
(R3 =H).
As a result, we found that the use of 2 bearing a bulky R3
group improved the cis/trans ratio (entries 2–4). Especially,
the use of a di(tert-butyl)methyl group gave the best results
(entry 4). In contrast, the tert-butyl ester (2e) was unstable
under the reaction conditions and gave the carboxylic acid
derivatives of 3e in low yield (20%), although the diastereo-
selectivity was high (cis/trans 97:3). The improved diastereo-
selectivity can be explained by the structure of the transition-
state assembly (Figure 2c). The sterically hindered di(tert-
butyl)methyl group of 2d would make the sulfonamide group
move toward the left back side. This change in conformation
would release the steric repulsion between the sulfonamide
group and the triphenylsilyl group to improve the diastereo-
selectivity. Only 0.5 mol% of 1·Cu(NTf2)2 efficiently pro-
moted the reaction of 2d (4 mmol) to give the corresponding
adduct 3d in 99% yield with excellent selectivity (entry 5).
The major cis-isomer of 3d could be separated as a single
isomer by chromatography on silica gel.
With the highly diastereo- and enantioselective reaction
conditions in hand, we next explored the generality and scope
of the present HDA reaction with allyltriphenylsilane. The
reactions of the various b,g-unsaturated a-ketoesters 2 were
conducted in the presence of 1·Cu(NTf2)2 (5 mol%) at À208C
to ambient temperature (Table 3). As a result, 2 f–i, bearing
Figure 2. Proposed transition-state assembly for the 1·Cu(NTf2)2-cata-
lyzed HDA reaction of 2.
2
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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