Highly enantioselective synthesis of tertiary alcohols: C 2-symmetric N,N′-dioxide-Sc(iii) complex promoted direct aldol reaction of α-ketoesters and diazoacetate esters

Article abstract of DOI:10.1039/b913520k

A C₂-symmetric N,N′-dioxide-Sc(iii) complex has been developed to promote the asymmetric catalytic aldol reaction of α-ketoesters and diazoacetate esters to afford tertiary alcohols in good yields with excellent enantioselectivities.

Full text of DOI:10.1039/b913520k

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Highly enantioselective synthesis of tertiary alcohols: C2-symmetric
N,N0-dioxide-Sc(III) complex promoted direct aldol reaction
of a-ketoesters and diazoacetate estersw
Fei Wang, Xiaohua Liu, Yulong Zhang, Lili Lin and Xiaoming Feng*
Received (in Cambridge, UK) 7th July 2009, Accepted 16th October 2009
First published as an Advance Article on the web 2nd November 2009
DOI: 10.1039/b913520k
A
C2-symmetric N,N0-dioxide-Sc(III) complex has been
enantioselectivity of the reaction, the steric and electronic
effects of the ligand were examined (Table 1, entries 2–6). As
shown in Table 1, ligand L4, with a bulkier group at the ortho
position of aniline, such as isopropyl, could be used to obtain
the aldol adduct with higher enantioselectivity (up to 92% ee;
Table 1, entry 4 vs. entries 2 and 3). As for the chiral backbone
moiety, the (S)-pipecolic acid derived N,N0-dioxide exhibited
its superiority in both yield and enantioselectivity toward this
reaction compared with the L-proline and (S)-ramipril derived
ones (Table 1, entry 4 vs. entries 5 and 6). Moreover, when
amide ligand L5 was employed, the reaction did not take
place, which revealed that the N-oxide group was essential for
the reaction (Table 1, entry 9).
developed to promote the asymmetric catalytic aldol reaction
of a-ketoesters and diazoacetate esters to afford tertiary
alcohols in good yields with excellent enantioselectivities.
Asymmetric synthesis, especially the synthesis of certain
classes of chiral compounds, has attracted growing attention
over the past half century. Chiral tertiary alcohols are
important building blocks of naturally occurring and
pharmaceutical drugs.1 Till now, many synthetic methodologies
towards chiral tertiary alcohols have been developed through
the asymmetric catalytic nucleophilic addition reactions of
ketones and their derivatives, such as the addition of organo-
metallics on ketones,2 alkylation and arylation reactions,3
Henry-type reactions,4 carbonyl-ene reactions,5 Mukaiyama-
type aldol reactions6 and direct aldol reactions of ketones and
functional ketones.7 Despite these impressive contributions,
the development of new and efficient synthetic methodologies
is still challenging and in high demand.
Using the L4-Sc(III) complex as catalyst, the reaction
conditions were further optimized. Solvent screening did not
give any improvement in both enantioselectivity and
yield, CH2Cl2 was still the best solvent for this reaction
(Table 1, entry 4 vs. entries 7 and 8). When the molar ratio
of ligand to central metal was changed to 1.5 : 1, the reactivity
was increased and enantioselectivity was maintained
(Table 1, entry 10). Remarkable progress in reactivity was
As aldol donors, the higher pKa values of a-protons of
diazoacetate esters relative to aldehydes or ketones makes
them less reactive substrates. Despite the significant progress
made in the development of the direct aldol reaction of
aldehydes and diazoacetate esters,8 there are no reports of
catalytic enantioselective aldol reactions between a diazoacetate
ester as a nucleophile and an a-ketoester as an electrophile. In
this communication, we focus on the enantioselective synthesis
of tertiary alcohols by the reaction of a-ketoesters and
diazoacetate esters using a C2-symmetric N,N0-dioxide-Sc(III)
complex catalyst.
Table 1 Optimization of the reaction conditions
Entrya
Ligand
Solvent
Yieldb (%)
Eec (%)
Owing to their tunable electronic and steric chiral
environments, N,N0-dioxide complexes have emerged as a
new class of effective catalysts for many asymmetric
reactions.4f,9 Encouraged by our previous study, we initially
examined the aldol reaction of phenylglyoxylate 1a and ethyl
diazoacetate 2a, promoted by N,N0-dioxide-Sc(III) complexes
(Table 1) in 1 mL CH2Cl2 at 30 1C. N,N0-Dioxide L3 (Fig. 1),
derived from an aromatic amine, exhibited a superior result to
L1, based on an aliphatic amine, with moderate enantio-
selectivity (Table 1, entry 1 vs. 3). To further improve the
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L6
L7
L4
L4
L5
L4
L4
L4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
32
45
52
54
54
42
50
46
n.r.
60
70
76
36
52
56
92
87
80
90
87
n.d.
93
93
93
9
10d
11e
12f
a
Unless otherwise noted, reactions were carried out with phenyl-
glyoxylate (0.1 mmol) and ethyl diazoacetate (0.2 mmol) in solvent
b
(1.0 mL) at 30 1C for 48 h. Isolated yield; n.r. = no reaction.
Determined by chiral HPLC; n.d. = not determined. Reaction
Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University, Chengdu
610064, P. R. China. E-mail: xmfeng@scu.edu.cn;
Fax: + 86 28 85418249; Tel: +86 28 85418249
w Electronic supplementary information (ESI) available: Experimental
details and product characterization. See DOI: 10.1039/b913520k
c
d
was performed with N,N0-dioxide-Sc(III) (1.5 : 1; 10 mol%) complex.
e
Reaction was carried out by using 0.2 mL of CH2Cl2 as solvent.
Reaction was performed for 72 h.
f
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Table 2 Substrate scope for the catalytic asymmetric aldol reaction
Entrya
R1
R2
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
8
C6H5
C6H5
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
Me
Et
76
78
68
70
70
75
62
68
62
75
66
67
78
85
80
84
64
61
65
35
93
95
96
97
93
92
90
91
94
95
93
95
94
94
90
94
92
91
87
52
3-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-CH3OC6H4
3-FC6H4
3-FC6H4
4-FC6H4
4-FC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
2-Naphthyl
2-Naphthyl
2-Thienyl
Cyclohexyl
Fig. 1 Chiral ligands used in the study.
9
made by enhancing the substrate concentration from 0.1 M to
0.5 M (Table 1, entry 11). Meanwhile, prolonging the reaction
time to 72 h gave the same level of enantioselectivity and
favourable yield (93% ee, 76% yield) (Table 1, entry 12). Thus,
the optimal reaction conditions were 15 mol% L4, 10 mol%
Sc(OTf)3, a-ketoester (0.1 mmol), and diazoacetate ester
(0.2 mmol) in CH2Cl2 (0.2 mL) at 30 1C.
10
11
12
13
14
15
16
17
18
19
20
Me
Et
Me
Me
Et
Under the optimized conditions, the reaction generally
provided the corresponding tertiary alcohol 3 in good yields
with excellent enantioselectivities (Table 2). a-Ketoesters with
both electron-donating and electron-withdrawing groups at
meta or para positions were well tolerated in terms of yields
and enantioselectivities, up to 85% yield and 97% ee were
obtained (Table 2, entries 1–16). A fused ring a-ketoester
was also a suitable substrate for the reaction, giving the
corresponding products with up to 92% ee (Table 2,
entries 17 and 18). Moreover, a heteroaromatic substrate
delivered the aldol adduct in good yield and enantioselectivity
(Table 2, entry 19). Unfortunately, both yield and enantio-
selectivity with an aliphatic a-ketoester10 were inferior to those
with aromatic ones. (Table 2, entry 20).
a
Unless noted otherwise, the reaction was carried out with a-ketoester
(0.1 mmol) and diazoacetate ester (0.2 mmol) in the presence of
Sc(OTf)3 (10 mol%) and L4 (15 mol%) in CH2Cl2 (0.2 mL) at
b
c
30 1C for 72 h. Isolated yield. Determined by chiral HPLC.
In addition, as shown in Scheme 1, when the reaction of
ethyl 2-oxo-2-phenylacetate with ethyl diazoacetate 2a was
performed under the optimal reaction conditions, the desired
product 4 was obtained in 75% yield with 94% ee. Notably,
the absolute configuration of 4 could be determined after
converting to known compound 5 (Scheme 1). The hydro-
genation of 4 following a literature procedure8c did not
result in any loss of enantioselectivity. Thereby, assigning
the absolute configuration of 4 to be S by comparing the
optical rotation of 5 with that given in the literature.11
Scheme 1 Conversion to known compound 5 for assignment of the
absolute configuration.
thank Sichuan University Analytical & Testing Center for
NMR analysis and the State Key Laboratory of Biotherapy
for HRMS analysis.
In conclusion, we have developed
a C2-symmetric
N,N0-dioxide-Sc(III) complex for the asymmetric direct aldol
reaction of a-ketoesters and diazoacetate esters. Aromatic and
heteroaromatic a-ketoesters were converted into the desired
products in good yields (up to 85%) with excellent enantio-
selectivities (up to 97% ee). The operational simplicity,
practicability, and mild reaction conditions rendered it an
efficient approach for the synthesis of optically active tertiary
alcohols. Further efforts are being devoted to elucidate the
reaction mechanism and the application of this catalyst to
other reactions.
Notes and references
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We thank the National Natural Science Foundation of
China (Nos. 20732003 and 20602025) and the Ministry of
Education (No. 20070610019) for financial support. We also
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Chem. Commun., 2009, 7297–7299 | 7299