Direct enantioselective amination of α-ketoesters catalyzed by an axially chiral guanidine base

Article abstract of DOI:10.1002/chem.201101076

β-functional! Direct enantioselective amination of α-ketoesters with azodicarboxylates was demonstrated using an axially chiral guanidine base catalyst, which enabled efficient access to enantioenriched multifunctionalized ketoesters with an aliphatic substituent at the β-position. Subsequent nucleophilic addition to the β-hydrazinyl-α-ketoester at the reactive ketone yields the corresponding β-hydrazinyl-α-hydroxy esters in high syn diastereo- and enantioselectivities (see scheme).

Full text of DOI:10.1002/chem.201101076

COMMUNICATION
DOI: 10.1002/chem.201101076
Direct Enantioselective Amination of a-Ketoesters Catalyzed by an Axially
Chiral Guanidine Base
Masahiro Terada,*[a, b] Kei Amagai,[a] Kenichi Ando,[a] Eunsang Kwon,[b] and
Hitoshi Ube[c]
Pyruvate esters and related a-ketoesters are extensively
utilized as multifunctional synthons in synthetic organic
chemistry due to the fact that an electron-withdrawing ester
moiety adjacent to a ketone functionality enhances the elec-
trophilicity of the ketone carbonyl carbon. Indeed, a-ke-
toesters have been applied in a diverse array of organic
transformations as an active ketone where the reaction of a
carbon nucleophile affords a tertiary alcohol with an ester
functionality.[1] In this context, the development of catalytic
enantioselective reactions of a-ketoesters using chiral metal
complexes[2] or organocatalysts[3] has stimulated much inter-
est because the method provides an efficient route for the
construction of a quaternary stereogenic center in an enan-
tioenriched fashion. In contrast, the enol tautomer (or eno-
late form) of a-ketoesters have rarely been utilized as a nu-
cleophilic component in catalytic enantioselective reac-
tions,[4,5] despite the fact that these groups function as a
homo-enolate equivalent to afford densely functionalized
products in an optically active form. The lack of investiga-
tion of these reagents is presumably due to their high elec-
trophilicity, which is prone to induce homo-aldol reactions.
In fact, enantioselective homo-aldol reactions of pyruvate
esters have been reported using chiral catalysts.[4c,6] Hence,
the development of cross reactions of a-ketoesters as the
pro-nucleophile is a challenging and attractive topic in
asymmetric synthesis. Several excellent studies have been
reported to date on enantioselective reactions of a-ketoest-
ers using chiral metal complexes,[4] however organocatalytic
approaches employing a-ketoesters as the pro-nucleophile
in cross reactions have received little attention,[5] despite the
tremendous growth in asymmetric organocatalysis during
the past decade.[7] We therefore aimed to expand the syn-
thetic potential of a-ketoesters 1 by means of organocata-
lysts. Herein, we report the enantioselective b-functionaliza-
tion of a-ketoesters 1 with azodicarboxylates 2[8] to prepare
b-hydrazinyl-a-ketoesters 4 in high enantioselectivity using
axially chiral guanidine 3, which was developed by our
group as a chiral Brønsted base catalyst[9,10] (Scheme 1). The
enantioselective process thus developed is the first organo-
catalytic approach to the electrophilic amination of a-ke-
toesters 1.[4b]
Scheme 1. Enantioselective amination of a-ketoesters catalyzed by axially
chiral guanidine base 3.
An initial investigation was conducted by exploring the
appropriate ester substituents of both a-ketoesters 1 (R2)
and azodicarboxylates 2 (R3) as well as the substituents Ar
and G of guanidine catalyst 3 (Table 1). The screening of
these substituents was performed using 3 (5 mol%) in THF
at 08C, and the enantioselectivity of the amination products,
b-amino-a-ketoesters 4, was determined by chiral stationary
phase HPLC analysis after reduction of the a-ketone to a
hydroxy group using L-selectride, exclusively affording syn
products 5.[4b,11] Introduction of bulky tert-butyl moieties to
the azodicarboxylate 2b, led to an increase in the enantiose-
lectivity without a detrimental effect on the reaction rate as
compared to that obtained with the sterically less hindered
ethyl-substituted azodicarboxylate 2a (Table 1, entry 1 vs.
2). In contrast, the ester substituents of a-ketoesters did not
display a significant effect on the enantioselectivity but did
[a] Prof. Dr. M. Terada, K. Amagai, K. Ando
Department of Chemistry
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
Fax : (+81)22-795-6602
E-mail: mterada@m.tohoku.ac.jp
Homepage: http://www.orgreact.sakura.ne.jp/index.html
[b] Prof. Dr. M. Terada, Dr. E. Kwon
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
[c] Dr. H. Ube
Department of Chemistry
Graduate School of Science, The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101076.
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9037

Table 1. Optimization of enantioselective amination of a-ketoesters 1
catalyzed by (R)-3.[a]
Table 2. Optimization of guanidine catalysts 3.[a]
Entry
3
Ar1
t
Yield
[%][b]
ee
[h]
[%][c]
Entry
1
R2
2
R3
3
t
5
Yield
[%][b]
ee
1
2
3
4
5
6
3a
3e
3 f
3g
3h
3i
Ph
5
24
5
2
4
2
2
4
79
53
>99
88
86
59
83
88
91
93
95
96
[h]
[%][c]
3,5-(CF3)2C6H3
3,5-(CH3)2C6H3
4-MeOC6H4
3,5-(MeO)2C6H3
3,4,5-(MeO)3C6H2
1
2
3
4
5
6
7
1a
1a
1b
1c
1a
1a
1a
Et
Et
Me
tBu
Et
2a
2b
2b
2b
2b
2b
2b
Et
3a
3a
3a
3a
3b
3c
3d
7
6
4
22
26
26
24
5a
5b
5c
5d
5b
5b
5b
76
72
85
68
74
37
61
67
84
78
83
43
59
70
tBu
tBu
tBu
tBu
tBu
tBu
80
>99
>99
>99
7[d]
8[d,e]
3i
3i
Et
Et
[a] Unless otherwise noted, all reactions were carried out using (R)-3
(0.005 mmol, 5 mol%), compound 1a (0.11 mmol, 1.1 equiv), and 2b
(0.10 mmol) in THF (1.0 mL) at À108C. [b] Yield of isolated product 5b.
[c] Determined by chiral stationary phase HPLC analysis after reduction
of 4b to 5b. [d] Carried out using 1a (0.10 mmol) and 2b (0.15 mmol,
1.5 equiv) in THF (0.2 mL). [e] At À208C.
[a] Unless otherwise noted, all reactions were carried out using (R)-3
(0.005 mmol, 5 mol%), 1 (0.11 mmol, 1.1 equiv), and 2 (0.10 mmol) in
THF (1.0 mL) at 08C. [b] Yield of isolated product 5. [c] Determined by
chiral stationary phase HPLC analysis after reduction of 4 to 5 (exclusive
formation of syn isomer).
induce a marked change in the reaction rate (Table 1, en-
tries 2–4), in which the sterically hindered tert-butyl ester 1c
retarded the reaction considerably (Table 1, entry 4). The
highest enantioselectivity was achieved in the reaction of
ethyl ester 1a with di-tert-butyl azodicarboxylate (2b) with-
out compromising the reaction rate (Table 1, entry 2).
Screening of the catalyst was thus performed in the reaction
of 1a with 2b by changing the substituents Ar and G intro-
duced at the 3,3’-position of the binaphthyl backbone and at
the nitrogen atom of the guanidine moiety, respectively
(Table 1, entries 5–7). The substituent effects of Ar and G
are notable in the efficient enantioselective catalysis. An in-
crease in steric bulkiness of the Ar group by substituting the
3,5-di-tert-butylphenyl moiety resulted in a considerable loss
of both catalytic activity and enantioselectivity (Table 1,
entry 5). Further, substitution of G by methyl or benzyl in-
stead of benzhydryl also exhibited a negative effect on cata-
lytic performance (Table 1, entry 2 vs. entries 6 and 7).
As shown in Table 1, introduction of a benzhydryl moiety
as the substituent G in the catalyst 3 is the key to gaining
good catalytic performance. We therefore next focused our
attention on modification of the benzhydryl substituent
(Table 2). Further optimization of catalyst 3 was conducted
using the reaction of 1a with 2b in THF by lowering the re-
action temperature to À108C. As shown in Table 2, the elec-
tronic effect of the aromatic rings (Ar1) of the benzhydryl
substituents exhibited a marked influence not only on enan-
tioselectivity but also on catalytic activity (Table 2, en-
tries 1–6). The catalyst bearing electron-withdrawing tri-
fluoromethyl substituents, 3e, exhibited low catalytic activity
and significant loss of enantioselectivity (Table 2, entry 2).
In contrast, the enantiomeric excess was improved when cat-
alysts 3g–3i having electron-donating methoxy groups were
employed (Table 2, entries 4–6). Furthermore, the enantio-
meric excess of 5b was enhanced in accordance with the
number of methoxy groups introduced. Further optimization
of the reaction conditions by increasing the equivalents of
2b (1.5 equiv) and lowering the reaction temperature to
À208C enhanced the enantioselectivity to 96% enantiomer-
ic excess (ee)(Table 2, entry 8).
Having identified the optimal guanidine catalyst and reac-
tion conditions, the scope of the present amination reaction
was investigated with a series of a-ketoesters having aliphat-
ic substituents using 3i as the catalyst in THF at À208C. As
shown in Table 3, the amination reaction is well suited for a
range of a-ketoesters, giving rise to products 5 in uniformly
high enantioselectivities, although chemical yields were
strongly dependent on the substituent employed. The reac-
tion of a-ketoesters having primary substituents proceeded
smoothly to afford products 5 in good yields (Table 3, en-
tries 1–4) with the exception of a-ketoester 1e bearing a
methyl substituent, in which the homo-aldol reaction of 1e
occurred simultaneously (Table 3, entry 2). Secondary alkyl
substituents (isopropyl) retarded the reaction with a consid-
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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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www.chemeurj.org
9039

M. Terada et al.
Figure 2. Plausible transition-state model for enantioselective amination
catalyzed by (R)-3i.
the phenyl ring (Figure 1a, c). According to this proposed
TS model, the re face of the enolate form of 1a is exposed
to the electrophilic addition of azodicarboxylate 2b, giving
(3R)-4b, which is consistent with the major stereoisomer ob-
tained experimentally.
In conclusion, we have demonstrated the direct enantiose-
lective amination of a-ketoesters catalyzed by an axially
chiral guanidine base. The present method enables an effi-
cient access to enantioenriched multifunctionalized ketoest-
ers, which can be readily derivatized to b-amino-a-hydroxy
esters with an aliphatic substituent at the b-position with
high syn diastereo- and enantioselectivities. Further studies
of direct transformations through activation of a-ketoesters
by chiral guanidine catalysts are currently underway in our
laboratory.
À
Figure 1. a) X-ray crystallographic analysis of the [(R)-3i·H]+BF4 salt
(N=blue, O=red, C=gray, B=yellow, F=green). Hydrogen atoms of
aromatic rings and methyl groups have been omitted for clarity.
b) B3LYP/6-311+gACHTUNGTRENNUNG(d,p) 0.002 au isodensity surface with superimposed
electrostatic potential using the crystal structure conformation of [(R)-
3i·H]+. c) A space-filling representation of the crystal structure of [(R)-
3i·H]+.
Experimental Section
Representative procedure: To a solution of di-tert-butyl azodicarboxylate
2b (34.5 mg, 0.15 mmol) and a-ketoester 1a (20.6 mg, 0.10 mmol) in
THF (200 mL) at À208C was added (R)-3i (4.18 mg, 0.005 mmol). After
stirring at that temperature for 4 h, the reaction mixture was cooled to
À788C and a 1.0m solution of L-selectride in THF (200 mL) was added.
The mixture was stirred for 1 h and then quenched with an aqueous
NH4Cl solution, followed by extraction with ethyl acetate. The organic
phase was dried over Na2SO4 and filtered. After removal of solvents, the
residue was purified by flash column chromatography (hexane/EtOAc=
10:1 to 2:1 as eluent) to afford the corresponding product 5b (>99%
yield, 96% ee).
electronic properties suggest that anionic species are prone
to interact with H1 rather than H2.
The structural and electronic properties of [(R)-3i·H]+
coupled with the determination of the absolute stereochem-
istry of 4b prompted us to propose a plausible transition-
state (TS) model (Figure 2). Deprotonation of a-ketoester 1
by the chiral guanidine catalyst generates ion pairs of the
guanidinium ion [(R)-3i·H]+ and the enolate of 1a, which
would interact at H1 rather than H2 through hydrogen
bonding as speculated based on the electrostatic potential
analysis of [(R)-3i·H]+. Because of the equilibrium condi-
tions it seems likely that the geometry of the generated eno-
late is the thermodynamically stable Z form as an exclusive
isomer.[16] Meanwhile, the H2 proton of the guanidinium ion
would interact with the Lewis basic nitrogen atom of the
azodicarboxylate 2b through hydrogen bonding and thus ac-
tivate 2b.[9d,17] As illustrated in Figure 2, the transient struc-
ture would be located at the sterically less hindered side of
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research on
Priority Areas “Advanced Molecular Transformation of Carbon Resour-
ces” (Grant No. 19020006) from MEXT, Japan. We also acknowledge the
JSPS Research Fellowship for Young Scientists (H.U.) from the Japan
Society for the Promotion of Science.
À
the guanidinium moiety, as observed for BF4 , to avoid
Keywords: amino alcohols
·
asymmetric catalysis
·
steric repulsion of both the modified benzhydryl moiety and
enantioselectivity · guanidine · organocatalysis
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Direct Enantioselective Amination of a-Ketoesters
COMMUNICATION
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[11] Epimerization of 4 was observed during purification by silica-gel
column chromatography.
[12] When the reaction was performed using 5 mol% of (R)-3h in THF
at 08C for 23 h, the corresponding product 7 was obtained in moder-
ate yield (50%) with low enantioselectivity (27% ee).
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[14] CCDC-722240 ([(R)-3i·H]+BF4À) contains the supplementary crys-
tallographic data for this paper. This data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[15] An essentially identical result was obtained from the Mulliken pop-
ulation analysis, which indicates that the N1 atom is more positive
than the N2 atom. See the Supporting Information for details.
[16] The relative stabilities of the enol forms of 1 were evaluated by
DFT calculations at the B3LYP/6-311+gACTHNUTRGNEU(GN d,p) level. The Z isomer is
more stable than the E isomer by 3.98 kcalmolÀ1. See the Support-
ing Information for details of the computational studies.
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Received: April 8, 2011
Published online: July 12, 2011
Chem. Eur. J. 2011, 17, 9037 – 9041
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9041