Key words organocatalysis - bifunctional catalyst - noncovalent interaction - asymmetric cyclization
- chiral oxazoline
Nitrogen-containing heterocycles are important in pharmaceutical investigations, especially
for small-molecule drug design.[1 ] Aimed at target skeletons of this sort, α-isocyanoacetate has been frequently used
as versatile synthon providing dipolar reactivity in a [3+2] cyclization process.[2 ] Mediated by organocatalysis, several prominent manipulations have been used for
the construction of analogues of pyrrole[3 ] and imidazole.[4 ] However, the straightforward assembly of optically active oxazolines, which act
as ligands for transition metals and are the core framework in numerous natural products,
is highly dependent on chiral metal complexes. In 1986, Ito and Hayashi reported the
first asymmetric aldol-type reaction for α-isocyanoacetate using a chiral Au(I) complex.[5 ] Subsequent investigations focused on disparate transition metal catalyst systems
and often led to the formation of trans -substituted oxazolines.[6 ] In 2011 Dixon et al. utilized a chiral amino phosphine Ag(I) complex to obtain oxazolines
with excellent cis selectivity.[7 ] In sharp contrast, the organocatalytic variant for such conversions has been studied
and only a single example was presented by Gong et al.[8 ] There has been no report of the combination involving a ketone group, which would
afford direct access to oxazolines bearing one or two quaternary asymmetric centers.
In this paper, we describe the first asymmetric aldol-type transformation of α-keto
esters with α-isocyanoacetate catalyzed by a thiourea/amine bifunctional catalyst
and leading to a precursor of β-hydroxy-α-amino acids.[5a ]
[b ]
[c ]
,
[7 ]
[9 ]
We began by evaluating the efficiency of the bifunctional catalyst system.[10 ] Progress in noncovalent catalysis furnishes findings, abundant and well-documented,
concerning versatile methodologies and selectivities.[11 ] With thiourea/amine-type bifunctional catalysts, the Brønsted basicity of a tertiary
amine affords the activation energy for reaction with nucleophilic compounds and simultaneously
the thiourea moiety acts as a hydrogen donor to interact with the corresponding electrophile.[12 ] This cooperative mode takes advantage of both the substrate proximity effect and
a sterically well-defined transition state rendering high synergy to the catalysis.
We hypothesized that the dual carbonyl groups of α-keto esters would permit a well-organized
cyclic interaction with the thiourea moiety of the bifunctional catalyst, as shown
in Scheme [1 ]. Simultaneously, the acidic C–H bond of α-isocyanoacetate spontaneously enters into
a noncovalent interaction with the alkaline site and interacts intramolecularly with
the keto group of the α-keto ester.
Scheme 1 α-Keto ester for chiral oxazoline skeleton
The inception of the aldol-cyclization cascade is initiated by the reaction of ethyl
phenylglyoxylate (1a ) with methyl isocyanoacetate (2a ) which is promoted by various thiourea amines. Takemoto’s catalyst (3a ; Table [1 ], entry 1), the simplest bifunctional analogue of chiral 1,2-diaminocyclohexane,
delivers fair asymmetric induction along with moderate differentiation of diastereoisomers.
The results indicate that thioureas containing a strong basic tertiary amine two carbon
atoms removed from the thiocarbonyl group could lead to activation and the resulting
stereochemistry. The comparable structure in the cinchona alkaloids (3c –g ) was systematically investigated in the reaction and the essential role of the thiourea
moiety was also evaluated (3b ). Catalysts lacking thiourea can nevertheless catalyze the oxazoline synthesis, but
with noticeably diminished enantioselectivity and yield (Table [1 ], entry 2, 48% yield, 33% ee). The aryl substituents of the thiourea group demonstrate
no obvious discrepancy and promote the cyclization with moderate efficiency and enantioselectivity
(entries 3 and 4, Table [1, 68 ]% ee vs. 76% ee). In a brief screening of the solvent system, toluene was identified
as a suitable solvent, delivering acceptable reactivity and selectivity (Table [1 ], entries 8 and 9).
The substituent effect was evaluated by modifying the R1 , R2 and R3 groups in the starting materials. The substituent in the α-position of the isocyanoacetate
(R3 ) triggered selectivity which might result from excessive crowding in the transition
state (entry 10, Table [1 ]; methyl substituent for 53% ee). When manipulating the steric size of ester groups
in the isocyanoacetates, a proportional increase of enantioselectivity indicates that
the bulky tert -butyl ester could enhance the facial discrimination and generate an appreciable ee
value (entries 9, 11, and 12 in Table [1 ]; 79% ee vs. 84% ee vs. 94% ee, respectively). On the other hand, the α-keto esters
can tolerate alkyl groups (R1 ) of various sizes with no effect on the enantioselectivity (Table [1 ], entries 13 and 14). The absolute configurations of the thiourea and quinuclidine
moieties were found to control the steric orientation of the transition state and
the reaction furnished the desired product with determinable conformation. The same
reactions for cinchonidine (3e ), quinidine (3f ) and cinchonine (3g ) showed no significant difference in both catalytic ability and steric discrimination
(Table [1 ], entries 15–17). Catalysts 3f and 3g generated the desired product with a structure which is the mirror image of that
in 3c . In view of the experimental data and the demonstrated catalytic model, the absolute
configuration of the title product was assigned and is shown in Scheme [2 ].
Scheme 2 Proposed transition sate for cis -oxazoline
Under the optimized reaction conditions, diverse aromatic α-keto esters were examined
and the corresponding oxazolines were synthesized in good yields and with excellent
ee values.[13 ] As shown in Table [2 ], ethyl phenylglyoxylate structures containing electron-donating substituents (Me,
OMe) or electron-withdrawing groups (F, Cl, Br) gave the corresponding products with
appreciable enantioselectivity (Table [2 ], entries 2–9). Different patterns of substituents (m - and p -) of substituents with different electronic characteristics are tolerated in the
reaction. Compounds with a multisubstituted aryl group also performed well giving
an excellent ee value for the title oxazoline (entry 10). Furthermore, α-keto esters
with a heteroaromatic ring and a fused ring can also be converted smoothly into the
desired products with appropriate selectivity (Table [2 ], entries 11 and 12).
Table 1 Reaction Optimizationa
Entry
Cat.
R1 , R2 , R3
Solvent
Yield (%)b
drc
ee (%)d
1
3a
Et, Me, H (2a )
CH2 Cl2
53
1.8:1
–70
2
3b
Et, Me, H (2a )
CH2 Cl2
48
1.2:1
33
3
3c
Et, Me, H (2a )
CH2 Cl2
53
1.3:1
68
4
3d
Et, Me, H (2a )
CH2 Cl2
58
1.4:1
76
5
3d
Et, Me, H (2a )
Et2 O
56
1.4:1
56
6
3d
Et, Me, H (2a )
THF
trace
n.d.
n.d.
7
3d
Et, Me, H (2a )
EtOAc
36
1.5:1
76
8
3d
Et, Me, H (2a )
toluene
65
2:1
84
9
3c
Et, Me, H (2a )
toluene
70
2:1
79
10
3c
Et, Me, Me (2b )
toluene
62
2:1
53
11
3c
Et, Et , H (2c )
toluene
46
1.7:1
84
12
3c
Et,
t -Bu , H (2d )
toluene
75
2:1
94
13
3c
Me , t -Bu, H (2e )
toluene
67
2:1
93
14
3c
Bn , t -Bu, H (2f )
toluene
60
1:1
94
15
3e
Et, t -Bu, H (2d )
toluene
75
2:1
91
16
3f
Et, t -Bu, H (2d )
toluene
75
2:1
–91
17
3g
Et, t -Bu, H (2d )
toluene
75
2:1
–89
a Unless otherwise noted, all reactions were carried out using 1a (0.1 mmol), 2a (0.12 mmol) and the catalyst (10 mol%) in solvent (0.5 mL) at 26 °C for 12 h.
b Isolated yield after silica gel chromatography.
c The dr was determined by 1 H NMR analysis of the crude mixture.
d Determined by chiral HPLC.
Table 2 Scope of the α-Keto Estersa
Entry
R
Yield (%)b
drc
ee (%)d
1
Ph (1a )
75
2:1
94 (81e )
2
4-MeC6 H4 (1b )
73
2:1
94
3
3-MeC6 H4 (1c )
67
2:1
91
4
4-MeOC6 H4 (1d )
78
2:1
97
5
3-MeOC6 H4 (1e )
72
2:1
94
6
4-FC6 H4 (1f )
70
2:1
92
7
3-FC6 H4 (1g )
76
2:1
91
8
4-ClC6 H4 (1h )
73
2:1
93
9
4-BrC6 H4 (1i )
77
2:1
91
10
3-F-6-MeC6 H3 (1j )
75
2:1
97
11
2-naphthyl (1k )
84
2:1
90
12
2-thienyl (1l )
80
2:1
89
a Unless otherwise noted, all reactions were carried out using 1a –l (0.1 mmol), 2d (0.12 mmol) and 3c (10 mol%) in toluene (0.5 mL) at 26 °C for 24 h.
b Isolated yield after silica gel chromatography.
c The dr was determined by 1 H NMR analysis.
d Determined by chiral HPLC.
e The ee value for minor diastereomer.
Derived from Nuclear Overhauser Effect Spectroscopy (NOESY) analysis (cis product)[14 ] and the well-understood interaction pattern between the thiourea moiety and α-keto
ester,[15 ] a proposed transition state is shown in Scheme [2 ]. The ester carbonyl group of the α-keto ester enjoys an H-bonding interaction with
the N atom bearing an aryl group and the ketone carbonyl interacts with the residual
N atom of the thiourea. The nucleophilic α-isocyanoacetate is activated by the quinuclidine
moiety and attacks from above the rigid ring system. As a consequence, the substituent
effect is consistent with the experimental data and the diastereoselectivity indicates
a stepwise approach for the cyclization.
In summary, an asymmetric isocyanoacetate aldol reaction of α-keto esters was realized
by a bifunctional catalytic strategy.[16 ] Aromatic and heteroaromatic α-keto esters are converted into oxazolines in good
yield (up to 84%) and with high enantioselectivity (up to 97% ee). This provides practical
synthetic access to chiral oxazolines which can be precursors to β-hydroxy-α-amino
acids. Further efforts are aimed at improving the diastereoselectivity and elucidating
the synthetic utility of the reaction in pharmaceutical chemistry.
