Cr(III)(salen)Cl catalyzed enantioselective intramolecular addition of tertiary enamides to ketones: A general access to enantioenriched 1H-pyrrol-2(3H)-one derivatives bearing a hydroxylated quaternary carbon atom

Article abstract of DOI:10.1021/ja904534t

(Chemical Equation Presented) Catalyzed by a chiral Cr(III)(salen)Cl complex 3e, tertiary enamides 1 underwent an efficient and enantioselective intramolecular addition reaction to an activated carbonyl moiety to produce in excellent yield highly enantioe

Full text of DOI:10.1021/ja904534t

Published on Web 07/10/2009
Cr(III)(salen)Cl Catalyzed Enantioselective Intramolecular Addition of Tertiary
Enamides to Ketones: A General Access to Enantioenriched 1H-Pyrrol-2(3H)-one
Derivatives Bearing a Hydroxylated Quaternary Carbon Atom
Luo Yang,† De-Xian Wang,† Zhi-Tang Huang,† and Mei-Xiang Wang*,†,‡
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China, and The Key Laboratory of Bioorganic
Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua UniVersity,
Beijing 100084, China
Received June 4, 2009; E-mail: mxwang@iccas.ac.cn
Enamines1 are useful intermediates in organic synthesis oweing to the
pioneering work of Stork in the 1950s.2 The importance of enamine
chemistry is illuminated recently by asymmetric organocatalysis using
chiral amine derivatives.3 As the enamine variant, enamides are, however,
stable and show diminished enaminic reactivity because of the electron-
withdrawing nature of the N-acyl group which alleviates the delocalization
of nitrogen lone-pair electrons into a carbon-carbon double bond.4 The
stability of enamides has been exemplified by the observation of enamides
as naturally occurring products.5 The majority of the synthetic application
of enamides lies therefore on their catalytic hydrogenation reactions to
prepare enantioenriched R-amino acid derivatives.6 Kobayashi7 has shown
recently that secondary enamides, the enamide species bearing an N-H
moiety, are able to react with different electron-deficient reactants in the
present of a Lewis acid catalyst. The reactions proceed via the aza-ene
addition process, and the secondary enamides behave actually as the aza-
ene components.7,8 The enaminic (nucleophilic) reactions of tertiary
enamides are very rare,4,9 and it has been noted7a that tertiary enamides,
not like their secondary enamide homologues, are not able to react with
electrophiles. In the synthesis of clausena alkaloids, however, we10 found
tertiary enamides can act as good nucleophiles to react with epoxide to
form homoclausenamide alkaloids. This has encouraged us to explore the
enaminic reactions of enamides. We report herein the first catalytic
asymmetric intramolecular nucleophilic addition of tertiary enamides to a
carbonyl group to give in excellent yield and enantiomeric excess highly
functionalized 1H-pyrrol-2(3H)-one derivatives bearing a hydroxylated
quaternary carbon center.
that the presence of a small amount of base gave both high yield and
high ee of product 2a (entries 7-10, Table 1). The combination of catalyst
3e (5 mol % loading) and Na2CO3 (0.2 equiv) in benzene at room
temperature was found most efficient for intramolecular enantioselective
enamide addition to the carbonyl (entry 10, Table 1).
Table 1. Optimization of Catalytic Enantioselective Reaction of 1aa
2 (%)b ee (%)c
entry cat.
M (mol %)
additive (equiv)
T (°C) t (h)
1
2
3
4
5
6
7
8
9
3a Al-Cl (10)
3b Fe-Cl (10)
3c Co (10)
3d Mn-Cl (10)
3e Cr-Cl (10)
3e Cr-Cl (10)
3e Cr-Cl (10)
3e Cr-Cl (10)
3e Cr-Cl (10)
-
-
-
-
-
-
80
80
80
80
rt
rt
rt
rt
rt
24
24
24
24
17
48
96
54
24
16
136
<5
0
nde
-
<5
<5
85d
77d
93
99
97
98
98
nde
nde
99
87
95
96
95
96
96
K2CO3 (1)
K2CO3 (0.2)
Na2CO3 (0.2)
Na2CO3 (0.2)
Na2CO3 (0.2)
10 3e Cr-Cl (5)
11 3e Cr-Cl (2)
rt
rt
a A mixture of enamide 1a (0.3 mmol), catalyst 3 and additive was
stirred at room temperature or refluxed in dry benzene (15 mL). The
reaction was stopped when reactant was consumed. b Isolated yield.
c Determined by chiral HPLC analysis (see Supporting Information). d An
uncharacterizable byproduct was obtained. e Not determined.
Under the optimized conditions, the scope of the reaction was
explored. As indicated by the results in Table 2, almost all amides
tested underwent Cr(III)(salen)Cl catalyzed enaminic reaction to afford
in excellent yield 3,5-diaryl-3-hydroxy-1H-pyrrol-2(3H)-one products
2 of high enantiopurity. Notably, the reaction rate was governed
strongly by the electronic nature of the substituents on enamides. In
the cases of N-benzylated enamides 1a-1g, when Ar1 was a 4-chlo-
rophenyl or 4-bromophenyl group, the reaction proceeded slowly. They
took more than 4 days to go to completion (entries 3 and 5, Table 2).
In contrast, the replacement of Ar2 by a 4-chlorophenyl group led to
the enhancement of the reaction velocity (entry 8, Table 2). The change
of the R substituent on nitrogen from benzyl, para-methoxybenzyl,
allyl to methyl and phenyl resulted in rate acceleration but with a slight
decrease of enantioselectivity (entries 1, 9-12). It is worth noting that
the observed electronic effect was consistent with the nucleophilic
attack of enamide at the carbonyl moiety. The increased electron
density of the enamine double bond and the decreased electron density
of the carbonyl led to an enhanced reaction rate. The Cr(III)(salen)Cl
We initially examined the reaction of enamide 1a. Because of easy
availability and convenience of handling under atmospheric conditions,
Jacobsen’s salen metal complexes11 were chosen as chiral catalysts. The
metal species were found crucial in the reaction. In refluxing benzene, for
example, the complexes of R,R-salen with AlIII-Cl 3a, FeIII-Cl, 3b, CoII
3c, and MnIII-Cl 3d did not show catalytic activity and no reaction was
observed (entries 1-4, Table 1). To our delight, the Cr(III)(salen)Cl
complex 3e, however, was an active catalyst to transform enamide 1a
into (S)-1-benzyl-3-hydroxy-3,5-diphenyl-1H-pyrrol-2(3H)-one 2a in 85%
yield with 99% ee at room temperature within 17 h (entry 5, Table 1).
Other solvents or mixture solvent systems were not superior to benzene,
leading to a long reaction time, low chemical yield, or decreased
enantioselectivity (see Supporting Information). It is interesting to note
† Institute of Chemistry, Chinese Academy of Sciences.
‡ Department of Chemistry, Tsinghua University.
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10390 J. AM. CHEM. SOC. 2009, 131, 10390–10391
10.1021/ja904534t CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
catalyzed reaction was readily scalable. Thus, in a gram-scale reaction,
product 2b was obtained in 99% yield with 99% ee (see Supporting
Information). The S-configuration of the newly formed stereocenter in
products 2, which was determined unambiguously by X-ray crystal-
lography of an O-methylated derivative of 2d (see Supporting Information),
indicated the nucleophilic attack of enamide at the re-face of the carbonyl
in the presence of R,R-Cr(III)(salen)Cl complex 3e.
in which two phenyl group are cis-orientated (see Supporting Information).
The diastereoselectivity is probably due to the directing effect of the
3-hydroxy group of 2h. O-Acetylation of 9 with Ac2O followed by
deprotection of para-methoxybenzyl (PMB) with ceric ammonium nitrate
(CAN) afforded product 11. Deacetylation of 11 with K2CO3 in methanol
and reduction of the resulting lactam 12 with LiAlH4 gave the desired
(3S,5S)-3,5-diphenyl-3-pyrrolidinol 13 (Scheme 2).
Table 2. Catalytic Enantioselective Reaction of Enamides 1a
Scheme 2. Synthesis of (3S,5S)-3,5-Diphenyl-3-pyrrolidinol 13
entry
1
R
Ar1
Ar2
t (h)
2 (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a Bn
1b Bn
1c Bn
1c Bn
1d Bn
1e Bn
1f Bn
1g Bn
1h PMB Ph
1i Allyl Ph
1j Me
1k Ph
Ph
Ph
16
4
114
2a (98)
2b (99)
2c (99)
96
98
96
97
99
97
97
97
98
94
89
88
4-Me-C6H4 Ph
4-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
17d 2c (93)
96
68
72
16
11
15
4
2d (97)
2e (98)
2f (99)
2g (98)
2h (99)
2i (99)
2j (99)
2k (97)
In summary, we have provided a general and powerful approach
to highly enantiopure functionalized γ-lactams that bear a hydroxylated
quaternary carbon center from R,R-Cr(III)(salen)Cl complex-catalyzed
intramolecular addition of tertiary enamide to a carbonyl moiety.
Exploration of intramolecular and intermolecular enaminic reactions
of tertiary enamides with other electrophiles is underway.
4-Me-C6H4
4-F-C6H4
4-Cl-C6H4
Ph
Ph
Ph
9
10
11
12
Ph
Ph
Ph
4
Acknowledgment. We thank the NNSFC (20820102034), MOST
(2006CB806106 and 2009CB724704), and CAS for financial support.
a Substrate 1 (0.5 mmol) was reacted in benzene (25 mL). b Isolated
yield. c Determined by chiral HPLC analysis (see Supporting Information).
d 10 mol % of 3e were used.
Supporting Information Available: Experimental procedures, com-
pound characterization, 1H and 13C NMR spectra, X-ray structure of
O-methylated derivative of 2d and 6 (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
The Cr(III)(salen)Cl-catalyzed enantioselective reaction was also
applicable to other substrates (Scheme 1). Enamide 5, which contains
a t-Bu group, underwent an equally efficient reaction to afford highly
enantiopure product 6 (94% ee) in 99% yield. The reaction of tetralone-
derived enamide 7 was slow due to probably the steric effect of 1,2-
dihydronaphthalene moiety. Use of 20 mmol % of catalyst loading
led to a complete transformation of 7 within 144 h into a fused
heterocyclic product 8 with an ee of 94%.
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Scheme 1. Catalytic Enantioselective Addition Reaction of 5 and 7
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The resulting (S)-3-hydroxy-3,5-diaryl-1H-pyrrol-2(3H)-one compounds
2 are valuable compounds. The highly functionalized quaternary carbon
center in 1H-pyrrol-2(3H)-one is hardly accessible by other methods. In
a closely related system, for example, catalytic asymmetric addition of
arylboronic acids to N-benzylisatin gave 1-benzyl-3-aryl-3-hydroxyindolin-
2-ones in only moderate yield and enantioselectivity (ee <73%).12 To
demonstrate the synthetic utility of products 2, we undertook the practical
synthesis of (3S,5S)-3,5-diphenyl-3-pyrrolidinol, its racemic form found
to possess various useful pharmacological properties.13 As illustrated in
Scheme 2, catalytic hydrogenation of 2h gave a single diastereoisomer 9
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(13) Mead Johnson & Compony, U.S. Patent 1016830, 1966.
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