Direct Enantioselective Amination of a-Ketoesters
COMMUNICATION
Table 3. Substrate scope for the enantioselective amination catalyzed by
(R)-3i.[a]
Scheme 3. Transformation of amination product 4b to b-hydrazinyl-a-hy-
droxy ester 8 (93% ee). Reagents and conditions: a) (R)-3i (5 mol%),
THF, À208C, 4 h; b) MeMgCl (4 equiv), ZnMe2 (4 equiv), THF, À788C,
6 h (93% from 1a).
Entry
1
R1
t
5
Yield
[%][b]
ee
[h]
[%][c]
center at the a-position, was obtained with high syn diaste-
reoselectivity without considerable loss of enantiomeric
purity.
The absolute stereochemistry of (+)-5b was determined
after the transformation to stereochemically known N-tert-
butoxycarbonyl (N-Boc)-protected b-amino-a-hydroxy ester
9 by a four step transformation (Scheme 4). Derivatization
1
2
3
4
5
1d
1e
1 f
1g
1h
nPr
Me
allyl
iBu
iPr
5
13
4
4
13
5e
5 f
5g
5h
5i
76
31
73
90
36
96
93
96
96
94
[a] Unless otherwise noted, all reactions were carried out using (R)-3i
(0.005 mmol, 5 mol%), 1 (0.10 mmol), and 2b (0.15 mmol, 1.5 equiv) in
THF (0.2 mL) at À208C. [b] Yield of isolated product 5. [c] Determined
by chiral stationary phase HPLC analysis after reduction of 4 to 5.
erable amount of starting a-ketoester 1h recovered under
the optimal reaction conditions (Table 3, entry 5).
We next applied the present method to the construction
of a quaternary stereogenic center with a nitrogen function-
ality by using unsymmetrically substituted a-ketoester 6.
The reaction of 2b with 6 (phenyl and methyl substituents
at the b-position) was conducted using (R)-3 (5 mol%) in
1,4-dioxane at room temperature.[12] As shown in Scheme 2,
Scheme 4. Transformation of b-hydrazinyl-a-hydroxy ester (+)-5b
(98% ee) to b-amino-a-hydroxy ester (À)-9 (98% ee). Reagents and con-
ditions: a) CF3COOH, CH2Cl2, RT, 10 min; b) Raney-Ni (W-2), H2,
EtOH, RT, 12 h; c) Boc2O, 4-(dimethylamino)pyridine, EtOH, 408C,
12 h; d) MeONa, MeOH, RT, 12 h (39% from 5b).
of recrystallized (+)-5b (98% ee) was achieved by deprotec-
tion of the Boc groups under acidic conditions followed by
hydrogenolysis of the hydrazine moiety using Raney-Ni (W-
2). The amino group thus generated was protected by a Boc
group, and subsequent transesterification yielded methyl
ester 9. The absolute stereochemistry of 9 was determined
to be the (2S,3R)-configuration by comparison of the mea-
sured optical rotation with the literature value.[4b] Thus it
was confirmed that the electrophilic amination catalyzed by
(R)-3i gave (3R)-4 as the major product.
Scheme 2. Enantioselective amination of unsymmetrically substituted a-
ketoester 6.
catalyst 3a accelerated the reaction efficiently to give the
corresponding amination product 7 in fairly good yield with
moderate enantioselectivity. The use of dimethoxy-substitut-
ed catalyst 3h, however, resulted in a considerable decrease
in the enantioselectivity.
To demonstrate the synthetic potential of the present
methodology, we further investigated the nucleophilic addi-
tion of an alkylation reagent such as a trialkylzinc(II) ate
complex to b-hydrazinyl-a-ketoester 4b at the reactive
ketone functionality (Scheme 3). The nucleophilic addition
to 4b was conducted in a one-pot sequential manner. After
the amination reaction of 1a with 2b was complete, the re-
action mixture was directly introduced to a preformed solu-
tion of Me3ZnMgCl prepared from a methyl Grignard re-
agent and dimethylzinc.[13] The corresponding b-hydrazinyl-
a-hydroxy ester 8, possessing a quaternary stereogenic
We further attempted the X-ray crystallographic analysis
of the guanidine catalyst (R)-3i. To our delight, an X-ray
À
grade single crystal of the HBF4 salt, [(R)-3i·H]+BF4 , was
successfully obtained (Figure 1a).[14] In the crystalline state,
À
the guanidinium salt exists as contact ion pairs. The BF4
anion occupies the bottom side of the basal plane defined
by the guanidinium moiety to avoid steric repulsion of both
the modified benzhydryl moiety and one of the two phenyl
rings attached to the binaphthyl backbone. Furthermore,
electrostatic potential analysis of the crystal structure con-
formation of [(R)-3i·H]+ indicated that both of the NH
groups at positions 1 and 2 have a partial positive charge
(blue in the electrostatic potential map) (Figure 1b). Of par-
ticular interest is the fact that position 1 is more positive
than position 2, as clearly indicated in Figure 1b.[15] These
Chem. Eur. J. 2011, 17, 9037 – 9041
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