.
Angewandte
Communications
(
Table 1). In the presence of trifluoroacetic acid (TFA) as
a Brønsted acid catalyst, the reaction between the N-Boc-
aminal 2a and b-keto ester 6 in CH Cl proceeded to give the
2
2
Mannich-type product 7a in good yield, albeit without
[10]
diastereoselectivity (entry 1).
In contrast, the chiral
Brønsted acids (R)-3 and (R)-4 gave only trace amounts of
product (entries 2 and 3). Since the chiral phosphoric acid
catalyst (R)-5a was also effective for this reaction (entry 4),
we then investigated various chiral phosphoric acid catalysts
[7]
(
entries 5–10). Aromatic substituents on the 3,3’-positions
of the catalyst significantly affected both diastereo- and
enantioselectivity, and the catalyst (S)-5e having sterically
demanding terphenyls was found to be the optimal catalyst in
terms of both reactivity and stereoselectivity (entry 8).
Among the solvents tested, CH Cl gave the best result with
Figure 1. X-ray crystal structure of 8 with ellipsoids set at 50%
probability.
[
11]
2
2
respect to yield and selectivity (entry 8 versus entries 11–15).
With the optimized reaction conditions in hand, we turned
our attention to the effect of substitution on the aminal
substrate (Table 2). A variety of C-alkynyl aminals were
[
a]
Table 2: Asymmetric Mannich reaction of 2 with 6.
Scheme 2. Asymmetric Mannich reaction of the aminal 2a with the
keto ester 9. Boc=tert-butoxycarbonyl.
reaction of the acyclic b-keto esters 11a,b was also carried out
at 408C, thus giving the Mannich adducts 12a,b with
a quaternary carbon center in good enantioselectivity, albeit
with low diastereoselectivity (Scheme 3). This tandem reac-
tion methodology was also applicable to the reaction between
[
b]
[c]
[d]
Entry
R
Yield [%]
anti/syn
ee [%]
1
2
Ph
4-BrC H4
4-MeC H4
1-cyclohexenyl
(E)-styryl
pentyl
PhCH CH2
Cy
94
86
93
95
93
98
95
89
97
92
9.1:1
9.1:1
5.9:1
6.1:1
10:1
6.3:1
7.7:1
6.3:1
6.7:1
10:1
94
94
93
94
90
92
91
95
93
95
6
[9]
a C-aryl imine precursor, 13, and 6 (Scheme 4).
[
e]
f
3
4
5
6
7
8
9
1
6
[
[
e]
2
cyclopropyl
tBu
0
[a] The reaction of 2 (0.10 mmol) with 6 (0.30 mmol) was carried out in
the presence of (S)-5e (0.010 mmol) and molecular sieves 5 ꢀ (50 mg) in
CH Cl (1.0 mL) at room temperature for 36 h. [b] Yield of the isolated
product. [c] Determined by H NMR spectroscopy. [d] Determined by
2
2
1
Scheme 3. Asymmetric Mannich reaction of the aminal 2a with the
keto ester 11.
HPLC on a chiral stationary phase. [e] CHCl used as the solvent.
3
[f] Toluene used as the solvent.
investigated for the generality of this reaction. All of these
aminals 2 were found to react with 6 in the presence of the
catalyst (S)-5e, thus giving the corresponding Mannich-type
products 7 in satisfactory yields with good to excellent
stereoselectivities. The relative and absolute configuration
of the product was unambiguously confirmed by X-ray
crystallographic analysis after conversion into the corre-
sponding 3,5-dinitrobenzoate ester 8 (Figure 1).
Scheme 4. Asymmetric Mannich reaction of the aminal 13 with the
keto ester 6.
The reactions with other b-keto esters were also inves-
tigated. We observed that the b-keto ester 9 was significantly
less reactive than 6 at room temperature (Scheme 2). When
the reaction of 2a with 9 was performed in higher temper-
ature (408C), the desired Mannich adduct 10 was obtained in
good yield with high diastereo- and enantioselectivity. The
The alkynyl substituent on the obtained Mannich adduct
was readily converted into the corresponding Z-alkenyl and
alkyl groups by hydrogenation (Scheme 5). Treatment of the
Mannich adduct 7a (anti/syn = 9.1:1) with the Lindlar catalyst
under a hydrogen atmosphere for 2 hours led cleanly to the Z-
2
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!
Kano, Taichi
