Enantioselective α-hydroxylation of -ketoamides

Article abstract of DOI:10.1039/c2ob27283k

The first enantioselective α-hydroxylation reaction of α-substituted -ketoamides has been developed by using the commercially available hydroquinine/TBHP system. The tertiary alcohols are obtained in good to high yield and up to 83% ee, which can be improved by a single crystallization.

Full text of DOI:10.1039/c2ob27283k

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COMMUNICATION
Enantioselective α-hydroxylation of β-ketoamides
Claudia De Fusco, Sara Meninno, Consiglia Tedesco and Alessandra Lattanzi*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
human tumor cell lines.16 In this study, we illustrate the first
50 enantioselective α-hydroxylation reaction of β-ketoamides
mediated by the commercially available hydroquinine/tert-butyl
hydroperoxide (TBHP) system (Scheme 1). The products have
been isolated in generally high yield and moderate to good
enantioselectivity.
5
The first enantioselective α-hydroxylation reaction of α-
substituted β-ketoamides has been developed by using the
commercially available hydroquinine/TBHP system. The
tertiary alcohols are obtained in good to high yield and up to
83% ee, which can be improved by a single crystallization.
10 The asymmetric α-hydroxylation of α-substituted-1,3-dicarbonyl
compounds is an important transformation which allows to
O
O
O
O
HQN/TBHP
R2
R2
H
H
directly install
a
carbon-oxygen bond. These densely
N
R1
N
()n
()n
OH
functionalised molecules bearing a quaternary stereocentre1 are
useful synthetic intermediates and the structural motif is found in
15 a variety of natural products and insecticides as the Indoxacarb
R1
55
Scheme 1 Enantioselective organocatalytic α-hydroxylation of β-
ketoamides.
produced by Dupont.2
A
limited number of direct
Our initial screening focused on model β-ketoamide 1a, using
a variety of easily accessible bifunctional organocatalysts of
different nature (Scheme 2), employed at 20 mol% loading with
60 TBHP as the oxygen source in toluene at room temperature
(Table 1).
enantioselective α-hydroxylation reactions has been developed,
predominantly focused on β-ketoesters, by using Ti-,3 Ni-,4 Pd-,5
Cu-,6 Zn-chiral ligand complexes7 and different oxidants. In most
20 cases, the hydroxylation reactions proceeded with good to
excellent enantiocontrol. Cinchona alkaloids,8 chiral β-amino
alcohols9 and phase transfer catalysts10 have recently
demonstrated to promote the α-hydroxylation of α-substituted β-
ketoesters with alkyl hydroperoxides to afford the products in
25 moderate to good level of enantioselectivity. Chiral phosphoric
acids were also successfully employed to catalyze the
enantioselective aminoxylation of β-ketoesters with nitroso
compounds as the oxygen source.11
OH
OH
Ph
N
H
Ph
2a
NH2
NH CH2OH
Bn
2c
2b
65
S
S
OH
Ar
N
Ar
HN
N
N
H
N
H
N
N
+
H
N
Br
N
Surprisingly, investigations on the enantioselective α-
30 hydroxylation of different 1,3-dicarbonyl compounds such as α-
substituted β-ketoamides received poor attention,12 although the
amido group is amenable of further manipulations.13 β-
Ketoamides are challenging substrates for this process due to the
lower acidity of the α-hydrogen and the requirement of more
35 basic reaction conditions to generate the enolate. Very recently,
Shibasaki developed the first asymmetric α-hydroxylation of N-
unsubstituted α-alkoxycarbonyl amides with Pr(OiPr)3 and chiral
fluoro-substituted amide-based ligands using oxaziridines as the
oxidant.14 The corresponding synthetically useful tertiary
40 alcohols were isolated in moderate to good yield and fairly good
level of enantioselectivity.
Considering our long-standing interest in the development of
enantioselective oxidation reactions,15 we embarked in a study
aimed to synthesize functionalised tertiary alcohols via
45 asymmetric hydroxylation of α-substituted β-ketoamides. These
substrates, in racemic form, have been recently demonstrated to
be key-intermediates to access Brazilin-type compounds,
showing promising antiproliferative activity against different
70
CF3
2d
R
2e
Ar = 3,5-(CF3)2C6H3
eHQNT, R = OMe
QN QD
HQN
HQD
= hydroquinidine
= quinine,
= quinidine,
= hydroquinine,
Scheme 2 Organocatalysts screened in the α-hydroxylation of β-
ketoamide 1a.
75
We were pleased to observe the formation of the expected
product 3a when using α,α-L-diphenyl prolinol 2a bearing a
secondary amine group, although it was obtained with 18% ee
(entry 1). This result indicated the suitability of bifunctional
80 organocatalysts, bearing a moderately basic site, as promoters for
the oxidation. The employment of cis-1,2-amino alcohol
derivative 2b led to compound 3a in low yield and
enantioselectivity (entry 2). Interestingly, cis-(1R,2S)-amino
indanol 2c, bearing a primary amine moiety, enabled the
85 formation of compound 3a in 62% yield, although without
enantiocontrol (entry 3).17 Surprisingly, both Takemoto thiourea
2d and epi-hydroquinine derived thiourea eHQNT proved to be
less effective catalysts than amino alcohols 2a-c (entries 4-5). We
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Organic & Biomolecular Chemistry
Page 2 of 4
also investigated the feasibility of the process under phase
transfer catalysis by using N-[4-
76% ee (entry 19). The enantioselectivity did not improve when
working at lower temperatures.
(trifluoromethyl)benzyl]cinchoninium bromide 2e, cumyl
hydroperoxide as the oxidant at 0°C under basic conditions (entry
6).
Having established the optimized reaction conditions, an
investigation on the substrate scope was undertaken (Table 2).
View Article Online
5
40 Table 2 Enantioselective α-hydroxylation of β-ketoamides 1a
Table 1 Screening of the reaction conditionsa
Yield (%)b
ee (%)c
45
Entry Catalyst
t/h
1
2
69
51
40
65
70
42
43
72
65
70
48
8
51
38
62
22
13
90
79
57
99
92
81
88
90
82
94
89
97
10m
83
18
2
2a
2b
Entry
R1, R2, R3, n
t/h
Yield (%)b ee (%)c
3
rac
4
2c
1
2
Ph, H, H, 1, a
Ph, H, 4-Br, 1, b
118
115
92
83 (66)
76 (87)
4
2d
88 (66)
83 (96)
5d
6e
4
eHQNT
2e
3
Ph, H, 5-Cl, 1, c
85
79
-30
50
-44
54
-50
45
14
52
52
49
50
56
-
4
Ph, H, 5-Br, 1, d
117
117
64
87
78
7
QN
5
Ph, H, 6-OMe, 1, e
1-Naphthyl, H, H, 1, f
2-ClC6H4, H, H, 1, g
3-CF3C6H4, H, H, 1, h
4-O(n-pentyl)C6H4, H, H, 1, i
Cyclohexyl, H, H, 1, j
Bn, H, H, 1, k
84 (60)
81 (98)
8
QD
6
82
74
9
HQN
HQD
HQN
HQN
HQN
HQN
HQN
HQN
HQN
-
7
111
93
76 (48)
67 (99)
10
11f
12g
13h
14i
15j
16k
17l
18l
19l,n
8
88
89
37
50
-
56
76
40
29
-
9
139
144
142
142
164
160
10d
11d
12d
13d
14d
12
16
16
21
18
22
118
Bn, Me, H, 1, l
Ph, H, H, 2, m
-
-
-
-
1n
a
Reaction conditions: 1a (0.1 mmol), HQN (20 mol%), TBHP (1.2
equiv), CHCl3 (2 mL). b Isolated yield after silica gel chromatography. In
c
parenthesis yield after crystallization. Determined by chiral HPLC
76
HQN
50 analysis. In parenthesis ee after crystallization. d Reaction performed at rt.
a
10 Reaction conditions: 1a (0.1 mmol), cat. (20 mol%), TBHP (1.2 equiv),
Halogen atoms and electron-donating groups on the aromatic ring
of the indane scaffold were tolerated and the products were
obtained in high yield and up to 83% ee (entries 2-5). The 1-
naphthyl substituted compound at the secondary amido moiety 1f,
55 was converted into the product likewise model compound 1a
(entry 6). The substitution pattern of the phenyl ring on the amide
influenced the enantioselectivity with the electron-withdrawing
groups bearing products being obtained with slightly lower ee
values (compare entries 7 and 8 with entries 1 and 9).
60 Compounds 1j-k, with an aliphatic amido group, reacted
sluggishly at room temperature affording the tertiary alcohol in
modest yield and ee values (entries 10 and 11). The presence of
the secondary amido group in the β-ketoamide was found to have
an important role as exemplified by the lack of reactivity
65 observed when reacting compound 1l, bearing a tertiary amide
portion (compare entry 12 with entry 11).
Similarly to data reported in organocatalytic α-hydroxylation
reactions of less reactive tetralone based and acyclic β-ketoesters,
the corresponding β-ketoamides 1m and 1n did not afford the
70 product under usual conditions working at room temperature
(entries 13 and 14). Pleasingly, products 3 could be recovered in
high ee and good yield after a single crystallization (entries 1, 2, 5
and 7).
b
c
solvent (0.5 mL). Isolated yield after silica gel chromatography.
Determined by chiral HPLC analysis. Negative values indicate the
preferential formation of the opposite enantiomer. 10 mol% of catalyst
was used. Reaction conditions: 1a (0.1 mmol), 2e (5 mol%), CHP (1.5
d
e
f
15 equiv), K2HPO3 (50%) (0.5 mL), toluene (1 mL) at 0°C. Cumyl
hydroperoxide was used. g Reaction conditions: 1a (0.1 mmol), HQN (20
h
mol%), H2O2 (50%) (1.2 equiv), MgSO4 (45 mg), toluene (0.5 mL).
CH2Cl2 used as solvent. CH2Br2 used as solvent. Cl(CH2)2Cl used as
i
j
k
l
m
solvent. C6H5Cl used as solvent. CHCl3 used as solvent. Conversion
20 to 3a determined by 1H NMR analysis. n CHCl3 (2 mL) at -20°C.
Compound 3a was obtained in high yield and 30% ee. Cinchona
alkaloids were next tested and proved to be fairly active
promoters (entries 7-10), affording the product in generally high
yield and up to 54% ee when using HQN as the organocatalyst
25 (entry 9). CHP and hydrogen peroxide, tested as alternative
oxygen source in the presence of HQN as promoter, gave inferior
results (entries 11 and 12). In halogenated solvents, the
hydroquinine activity significantly increased (entries 13-17) and
when the reaction was carried out in chloroform the product was
30 isolated in 97% yield and 56% ee after 18 h (entry 17). A control
experiment, performed in CHCl3 without HQN, showed a poor
conversion to the product after a comparable reaction time, which
assured that the racemic oxidative pathway is a negligible process
(entry 18). Performing the reaction at -20°C, under more diluted
35 conditions, led to the isolation of compound 3a in high yield and
Single-crystal X-ray analysis on compound 3b enabled to
75 assign the absolute configuration of the quaternary stereocentre as
2
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Page 3 of 4
Organic & Biomolecular Chemistry
2S (Fig. 1).18
not reveal any particular correlation of the ee values with the
acidity of the amide proton as previously observed in asymmetric
organocatalysed Michael addition reactions of β-ketoamides to β-
60 unsubstituted α,β-unsaturated ketones and acrolein.21a In contrast
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to our findings (see Table 1, entry 4), in the conjugate addition
5
reaction, Takemoto catalyst 2d was found to be the most effective
and the amidic acid form of the β-ketoamide was proposed to be
involved favouring the deprotonation of the methine proton.21a
65
In conclusion,
a
simple methodology for the first
enantioselective α-hydroxylation reaction of α-substituted β-
ketoamides has been developed by using the commercially
available HQN/TBHP system. The functionalized tertiary
alcohols were isolated in good to high yield and up to 83% ee.
10
70 From a practical point of view, products 3 can be eventually
obtained in high ee after a single crystallization.
Financial support from MIUR is gratefully acknowledged. The
authors would like to thank Prof. C. Crescenzi for MS spectra
analyses. The equipment of the X-ray diffraction laboratory was
15 Fig. 1 Molecular structure of S-3b with ellipsoids set at 30% probability
level.
The importance of the secondary amido group was firstly
illustrated with the elegant work of Miller in the asymmetric
epoxidation of functionalized alkenes catalyzed by small peptide
20 organocatalysts and hydrogen peroxide.19
Hoping to get more insight into the nature of interactions
established between HQN and the β-ketoamide, 1H-NMR spectra
of HQN were recordered in CDCl3 at room temperature adding
different amounts of compound 1a (up to 3 equiv) (Fig. 2).
25
75 financially supported by Finanziamento Grandi
Attrezzature 2004.
e Medie
Notes and references
a Dipartimento di Chimica, Università di Salerno, Via Ponte don Melillo,
84084, Fisciano, Italy. Fax:0039-089-9696039; E-mail: lattanzi@unisa.it
80 † Electronic Supplementary Information (ESI) available: [NMR and
HPLC spectra for all the new compounds]. See DOI: 10.1039/b000000x/
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55 compound 1a. Surprisingly, no significant shift of the CONH
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Organic & Biomolecular Chemistry
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Graphical Abstract
4
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