Catalytic asymmetric hydroxylation of α-alkoxycarbonyl amides with a Pr(OiPr)3/amide-based ligand catalyst

Article abstract of DOI:10.1016/j.tetlet.2010.11.064

A catalytic asymmetric hydroxylation of N-nonsubstituted α-alkoxycarbonyl amides is described. A new effective catalyst comprising Pr(OⁱPr)₃ and a fluoro-substituted amide-based ligand was identified using oxaziridine as the oxidizin

Full text of DOI:10.1016/j.tetlet.2010.11.064

Tetrahedron Letters 52 (2011) 2140–2143
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Catalytic asymmetric hydroxylation of
a
-alkoxycarbonyl amides
with a Pr(OiPr)3/amide-based ligand catalyst
a,
⇑
Sho Takechi a,b, Naoya Kumagai a, , Masakatsu Shibasaki
*
a Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
b Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 18 November 2010
A catalytic asymmetric hydroxylation of N-nonsubstituted a-alkoxycarbonyl amides is described. A new
effective catalyst comprising Pr(OiPr)3 and a fluoro-substituted amide-based ligand was identified using
oxaziridine as the oxidizing reagent. The catalyst components were in dynamic equilibrium in the reac-
tion mixture, which assembled to form the associated transition state through metal coordination and
hydrogen bonding.
This work is dedicated to Professor
Wasserman to express our sincere
appreciation of his 38 years of service as
Editor of Tetrahedron Letters
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Asymmetric hydroxylation
Rare earth metal
Tetrasubstituted stereogenic centers
Amide-based ligand
a-Substituted a-alkoxycarbonyl amides constitute an intriguing
class of pronucleophiles providing densely and differently func-
tionalized chemical entities at the tetrasubstituted carbon center.1
In contrast to the widespread use of b-keto esters as related 1,3-
dicarbonyl-type pronucleophiles in asymmetric catalysis,
oxycarbonyl amides have received little attention presumably be-
cause (1) the higher pKa of -hydrogen retards efficient in situ
a-alk-
a
generation of active nucleophiles; and (2) the highly coordinative
nature and multiple coordination pattern of these functionalities
make it difficult to control the stereochemical course of the reac-
tion, particularly for N-nonsubstituted
a-alkoxycarbonyl amides
1.2,3 These pronucleophiles attracted our attention as substrates
for catalytic asymmetric amination to furnish densely functional-
ized polar head groups of optically pure sphingosines,4 a class of
compounds that elicit a wide variety of biological activities
Figure 1. Catalytic asymmetric amination of N-nonsubstituted
amides 1 for a concise asymmetric synthesis of sphingosines.
a-alkoxycarbonyl
( Fig. 1).5 N-Nonsubstituted
a-alkoxycarbonyl amides 1 allowed
for direct access to enantioenriched tetrasubstituted carbon bear-
ing distinct carboxylate-type substituents with ester and amide
functionality, amenable to further manipulation of the product in
a chemoselective manner. In our continuing efforts to develop cat-
enantioselective installation of a hydroxyl group to provide an
optically enriched tertiary alcohol. Although significant advances
have been made in the field of catalytic asymmetric
a-hydroxyl-
alytic asymmetric reactions utilizing N-nonsubstituted
a-alkoxy-
ation of carbonyl compounds,6 there are limited number of reports
of this important transformation using 1,3-dicarbonyl com-
pounds.7 Herein, we report a catalytic asymmetric hydroxylation
carbonyl amides 1,4 we expanded this methodology for
⇑
Corresponding authors. Tel.: +81 3 3441 8133; fax: +81 3 3441 7589 (N.K.); tel.:
of N-nonsubstituted
a-alkoxycarbonyl amides 1 promoted by a
+81 3 3447 7779; fax: +81 3 3441 7589 (M.S.).
E-mail addresses: nkumagai@bikaken.or.jp (N. Kumagai), mshibasa@bikake-
n.or.jp (M. Shibasaki).
praseodymium/amide-based-ligand catalytic system, where cata-
lyst components and substrates are in dynamic equilibrium.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.064

S. Takechi et al. / Tetrahedron Letters 52 (2011) 2140–2143
2141
Table 2
We recently identified
amide-based ligand (R)-2a, La(NO3)3Á6H2O, and H-
exhibited high catalytic efficiency and stereocontrol in catalytic
asymmetric amination of N-nonsubstituted -alkoxycarbonyl
amides using azodicarboxylates as an electrophilic aminating
reagent.4a,8 Mechanistic investigation suggested that metal coordi-
nation and hydrogen bonding worked cooperatively to define the
stereochemical course of the reaction. We initially attempted cat-
a
catalytic system comprising an
Effect of the halogen atom installation in the amide-based-ligand on enantioselectivitya
D
-Val-OtBu that
RE(OiPr)3
ligand
3
10 mol %
20 mol %
1.5 equiv
O
O
O
O
a
H2N
H2N
OEt
OEt
HO Ph
THF, 0 ºC, 24 h
Ph
1a
4a
Entry
RE
Ligand
Yieldb (%)
ee (%)
alytic asymmetric hydroxylation using a-phenyl N-nonsubstituted
1c
2
La
Pr
La
Pr
La
Pr
La
Pr
Pr
Pr
Pr
(S)-2b
(S)-2b
(S)-2c
(S)-2c
(S)-2d
(S)-2d
(S)-2e
(S)-2e
(S)-2f
(S)-2g
(S)-2h
70
88
81
84
87
86
78
87
34
82
80
79
91
80
75
81
91
69
87
13
88
70
a
-alkoxycarbonyl amide 1a as a model substrate with a catalyst
prepared by combining rare earth metal (RE) alkoxides9 and
3c
4
amide-based ligand (S)-2a in a ratio of 1 to 2.10,11 Davis’oxaziridine
3
12 was selected as the oxidizing agent because we anticipated that
5
6
a sulfonamide functionality in proximity to the liberating oxygen
atom would activate and control the stereochemical course of
the reaction through both metal coordination and hydrogen bond-
ing. As summarized in Table 1, the RE/(S)-2a catalyst promoted
asymmetric hydroxylation at 0 °C in THF to afford tertiary alcohol
4a in moderate to excellent yield after 24 h. Among the RE alkox-
ides investigated, the catalysts prepared from La and Pr performed
best in terms of enantioselectivity (entries 3 and 4). Solvent
screening indicated that THF was optimum for this specific trans-
formation. Because only marginal differences in catalytic perfor-
mance between La and Pr catalysts were detected, subsequent
studies on the structure of the amide-based ligand were conducted
using these two REs (Table 2). Installation of halogen atoms on the
salicylic acid part of the parent ligand (S)-2a affected the enanti-
oselectivity of the desired hydroxylation product 4a.
7c
8
9
10
11
O
OH
H
N
Ar
N
H
O
OH
OH
OH
OH
Ar =
F
Cl
(S)-2c
Br
(S)-2d
I
Substitution of the para-position of the hydroxyl group slightly
increased the enantioselectivity in most cases (entries 1–8); in par-
ticular, Pr catalysts with ligands having either a fluoro- or bromo-
substituent provided 4a in 91% ee (entries 2 and 6). Fluoro substi-
tution next to the hydroxyl resulted in a significantly lower yield
and enantioselectivity (entry 9). None of the ligands with other
substitution patterns were superior to (S)-2b (entries 10 and 11)
in combination with Pr(OiPr)3, which was identified as the best
amide-based ligand for the present asymmetric hydroxylation.
The absolute configuration was unequivocally determined by
X-ray crystallographic analysis (Fig. 2).
(S)-2b
(S)-2e
OH
OH
OH
F
F
F
(S)-2f
(S)-2g
(S)-2h
a
b
c
0.2 mmol scale.
Determined by 1H NMR analysis.
1.2 equiv of 3 were used.
Table 1
Catalytic asymmetric hydroxylation of 1a promoted by RE(OiPr)3/(S)-2a catalysta
We next focused our investigation on the substrate scope of the
Pr/(S)-2b catalytic system (Table 3).13,14 The reaction of
-aryl
alkoxycarbonyl amide afforded the desired product with moderate
to high enantioselectivity irrespective of the electronic nature of
the substituents on the aromatic ring (entries 1–8).
Yield of some products are low to moderate due to difficulty in
isolation (entries 1, 2, and 8). The substrate bearing heteroaromatic
thiophene ring was also applicable to give the corresponding prod-
a
a-
RE(OiPr)3
(S)-2a
3
10 mol %
20 mol %
1.2 equiv
O
O
O
O
H2N
H2N
OEt
OEt
HO Ph
THF, 0 ºC, 24 h
Ph
1a
4a
Entry
RE
Yieldb (%)
ee (%)
uct with high enantioselectivity (entry 9). In the case of
-alkoxycarbonyl amide 1j, the reaction mixture became compli-
cated by an undesired Mannich reaction pathway with aldimine
a-methyl
1
2
3
4
5
6
7
8
9
Sc
y
La
Pr
Nd
Sm
Gd
Dy
Er
32
82
88
85
81
65
84
76
86
9
48
76
75
51
30
19
51
35
a
O
O
Ph
N
OH
O
OH
H
O
O
H2N
OEt
S
N
HO Ph
N
H
O
4a
O
Ph
Davis' oxaziridine 3
(S)-2a
a
0.2 mmol scale.
Determined by 1H NMR analysis.
b
Figure 2. X-ray crystallographic analysis of 4a.

2142
S. Takechi et al. / Tetrahedron Letters 52 (2011) 2140–2143
Table 3
protons remained and the chemical shift of each peak was almost
Substrate scope of catalytic asymmetric hydroxylationa
identical to that of (S)-2b with slight broadening, indicating that
the complexation of Pr(OiPr)3 and (S)-2b was in rapid equilibrium
with the dissociated form being dominant.18 This observation is
consistent with CD analysis, in which the spectrum of catalyst mix-
ture and (S)-2b was superimposed.18 In contrast, the peak derived
Pr(OiPr)3
(S)-2b
3
x mol %
2x mol %
1.5 equiv
O
O
O
O
OR2
OR2
H2N
H2N
HO R1
THF, 0 ºC, 24 h
R1
from the
a-proton of a-alkoxycarbonyl amide 1d instantly disap-
1
4
peared upon the addition of Pr(OiPr)3 and substantial line broaden-
ing was detected. Given the lack of an effect of the concentration of
1d on the reaction rate as well as the 0.9th and 0.7th order depen-
dency of the Pr/(S)-2b catalyst and oxaziridine 3, respectively,18
the likely scenario of the present asymmetric hydroxylation is as
Entry
x
a
R1
-Alkoxycarbonyl amide
R2
Product
Yieldb (%)
ee (%)
1c
10
10
10
10
10
5
10
10
10
10
Ph
Et
Me
Et
Me
Et
Me
Me
Et
1a
1b
1c
1d
1e
1f
1g
1h
1i
4a
4b
4c
4d
4e
4f
4g
4h
4i
58 (88)
51 (63)
85
91
79
85
84
90
85
84
89
86
68
2c,d
3
4-MeC6H4
2-Naph
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-MeOC6H4
3-Thienyl
Me
follows. Pr(OiPr)3 and
a-alkoxycarbonyl amide predominantly
4d
5
94
92
82
96
formed a complex, with which the amide-based ligand (S)-2b
and 3 assembled through metal coordination and hydrogen bond-
ing to form the associated transition state. The trans amide N–H
proton would be essential to form a crucial assembled transition
state to promote the reaction in a highly enantioselective manner.
The effect of the fluoro substituent on the amide-based ligand can
be attributed to the enhanced acidity of the phenolic proton, which
facilitated the formation of the assembly, whereas substitution
next to phenolic OH disturbed the complexation, resulting in poor
yield and enantioselectivity.
6d
7d
8c,d
9
39 (80)
89
— (40)
Et
Et
10d,e
1j
4j
O
O
O
N
S
Ph
N
S
O
5
O
6
Ph
In summary, we developed a catalytic asymmetric hydroxyl-
ation reaction of N-nonsubstituted a-alkoxycarbonyl amide 1
a
b
c
0.2 mmol scale.
Isolated yield. Yield determined by 1H NMR is shown in parenthesis.
The product was isolated via TMS protection/deprotection sequence.
0.1 mmol scale.
and oxaziridine promoted by a Pr/amide-based ligand (S)-2b cata-
lyst, affording enantioenriched tertiary alcohols with a densely
functionalized tetrasubstituted stereogenic carbon. It is intriguing
that the catalyst components are in dynamic equilibrium while
exhibiting high enantioselectivity. Application of the present
hydroxylation protocol to enantioselective synthesis of biologically
active chemical entities is in progress.
d
e
2 equiv of 6 were used instead of 3. Reaction time was 48 h.
5 derived from oxaziridine 3. Employment of oxaziridine 612b de-
rived from ketoimine avoided formation of the Mannich product
to give the desired product 4j, albeit with only moderate yield
and enantioselectivity (entry 10).15
Acknowledgments
As previously observed for the La ternary catalyst,4a the present
This work was financially supported by a Grant-in-Aid for Sci-
entific Research (S) from MEXT. Dr. Motoo Shiro at Rigaku Corpo-
ration is gratefully acknowledged for technical assistance for X-
ray crystallographic analysis of product 4a.
Pr/amide-based ligand catalyst recognized the
amide motif including a trans amide proton as a privileged sub-
structure. When the optimized asymmetric hydroxylation condi-
tions were applied to N-methyl
a-alkoxycarbonyl
a-ethoxycarbonyl amide 1k, the
reaction outcome was poor, presumably because the lack of a trans
amide N–H proton resulted in insufficient activation/stereocontrol
through hydrogen bonding (Scheme 1).16 The use of DMF as a sol-
vent to disrupt the hydrogen bond control in the reaction with 1a
had negative effects.17 The reaction with N,N-dimethyl substrate 1l
failed to promote the reaction at all. These results are consistent
with the dynamic equilibrium of the catalyst components in the
present catalysis. In the 1H NMR spectrum of the catalyst solution
in THF-d8 comprising Pr(OiPr)3 and (S)-2b in a 1:2 ratio, phenolic
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.11.064.
References and notes
1. (a) Purwono, B.; Smally, R. K.; Porter, T. C. Synlett 1992, 231; (b) Poschenrieder,
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2. For catalytic asymmetric fluorination of N-unsubstituted
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Sodeoka, M. J. Org. Chem. 2007, 72, 246; For partially successful 1,4-
a-tert-
Pr(OiPr)3
10 mol %
20 mol %
1.5 equiv
O
O
O
O
a
(S)-2b
Me
Me
reduction of unsaturated primary amide and the following enantioselective
protonation by asymmetric catalysts (1 example, 50% ee), see: (b) Ohtsuka, Y.;
Ikeno, T.; Yamada, T. Tetrahedron: Asymmetry 2003, 14, 967.
3
MeHN
Me2N
N
H
OEt
OEt
OEt
OEt
HO Ph
THF, 0 ºC, 24 h
yield 31%
6% ee
Ph
3. Diastereoselective reactions using N-nonsubstituted
a-alkoxycarbonylamides
1k
4k
as substrates, see: (a) Kozlowski, M. C.; DiVirgilio, E. S.; Malolanarasimhan, K.;
Mulrooney, C. A. Tetrahedron: Asymmetry 2005, 16, 3599; Catalytic
transformation utilizing N-nonsubstituted
a-alkoxycarbonyl amides, see: (b)
Pr(OiPr)3
Zhang, J.; Sarma, K. D.; Curran, T. T.; Belmont, D. T.; Davidson, J. G. J. Org. Chem.
2005, 70, 5890.
10 mol %
20 mol %
1.5 equiv
O
O
O
O
(S)-2b
4. (a) Mashiko, T.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 14990;
(b) Berhal, F.; Takechi, S.; Kumagai, N.; Shibasaki, M. Chem. Eur. J., in press.
5. For reviews, see: (a) Brunner, M.; Koskinen, A. M. P. Curr. Org. Chem. 2004, 8,
1629; (b) Byun, H.-S.; Lu, X.; Bittman, R. Synthesis 2006, 2447.
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2007, 80, 595; (b) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartori, G. Angew.
Chem., Int. Ed. 2008, 47, 6138; (c) Vilaivan, T.; Bhanthumnavin, W. Molecules
2010, 15, 917. and references cited therein.
3
N
HO Ph
THF, 0 ºC, 24 h
No reaction
Ph
Me
1l
4l
Scheme 1. Catalytic asymmetric hydroxylation of
a trans amide N–H proton.
a-alkoxycarbonyl amides lacking

S. Takechi et al. / Tetrahedron Letters 52 (2011) 2140–2143
2143
7. For a catalytic asymmetric hydroxylation of b-keto esters, see: (a) Acocella, M.
R.; Mancheño, O. G.; Bella, M.; Jørgensen, K. A. J. Org. Chem. 2004, 69, 8165; (b)
Bonaccorsi, C.; Althaus, M.; Becker, C.; Togni, A.; Mezzetti, A. Pure Appl. Chem.
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Nakamura, S.; Toru, T.; Kanemasa, S. J. Am. Chem. Soc. 2006, 128, 16488; (e)
Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T. Angew. Chem., Int. Ed.
2009, 48, 803; (f) Lu, M.; Zhu, D.; Lu, Y.; Zeng, X.; Tan, B.; Xu, Z.; Zhong, G. J. Am.
Chem. Soc. 2009, 131, 4562; (g) Smith, A. M. R.; Billen, D.; Hii, K. K. (M). Chem.
Commun. 2009, 3925; Partially successful examples, see: (h) Gong, B.; Meng, Q.;
Su, T.; Lian, M.; Wang, Q.; Gao, Z. Synlett 2009, 2659; (i) Jiang, J.-J.; Huang, J.;
Wang, D.; Zhao, M.-X.; Wang, F.-J.; Shi, M. Tetrahedron: Asymmetry 2010, 21,
794; (j) Smith, A. M. R.; Rzepa, H. S.; White, A. J. P.; Billen, D.; Hii, K. K. (M). J.
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13. The absolute configuration of other products was deduced by analogy.
14. For partially successful catalytic asymmetric hydroxylation of N-protected
a-
alkoxycarbonyl amides, see Ref. 7j.
15. At this stage, the absolute of the product 4j obtained from aliphatic substrate 1j
with oxaziridine is uncertain. The isolation of the product 4j required
8. (a) Mashiko, T.; Hara, K.; Tanaka, D.; Fujiwara, Y.; Kumagai, N.; Shibasaki, M. J.
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6
iterative chromatography.
16. For the comprehensive review of the predominant population of trans isomers
in secondary amides, see: Dugave, C. In cis–trans Isomerization in Biochemistry;
Dugave, C., Ed.; Wiley-VCH: Weinheim, 2006; pp 143–166. Chapter 8.
9. RE alkoxides were purchased from Kojundo Chemical Co. Ltd except for
scandium isopropoxide, which was purchased from Aldrich.
10. The ternary catalytic system comprising La(NO3)3/(R)-2a/H-
D
-Val-OtBu, which
17. Catalytic asymmetric amination of 1a and 3
with La(OiPr)3/(S)-2a (La:
is effective for asymmetric amination of 1a using azodicarboxylate, was not
effective for asymmetric hydroxylation of 1a.
11. For the utility of RE/amide-based ligand catalytic systems in asymmetric
catalysis, see: (a) Nishida, A.; Yamanaka, M.; Nakagawa, M. Tetrahedron Lett.
(S)-2a = 1:2) catalyst (10 mol %) in DMF solvent (0.2 M) delivered 4a in 24%
yield, 5% ee, which is significantly poor result compared with that of entry 2 in
Table 1.
18. See Supplementary data for details.