Chiral phosphoric acid catalyzed peroxidation of imines

Article abstract of DOI:10.1002/anie.201002972

Something to COO about: The title reaction provides direct access to α-amino peroxides with high enantioselectivity (see scheme). The phosphoric acid catalyst is thought to activate both the nucleophile and electrophile through hydrogen-bonding interactio

Full text of DOI:10.1002/anie.201002972

Angewandte
Chemie
DOI: 10.1002/anie.201002972
Asymmetric Catalysis
Chiral Phosphoric Acid Catalyzed Peroxidation of Imines**
Wenhua Zheng, Lukasz Wojtas, and Jon C. Antilla*
Peroxide-containing compounds are a class of biologically
important targets, many of which possess antitumor, anti-
bacterial, and antimalarial activities.[1] For example, the
peroxide-containing natural product artemisinin (qinghaosu)
has been shown to be a highly effective antimalarial drug.[2]
The chiral peroxide moiety in this natural product was proven
to be essential for the high antimalarial potency.[2] For this
reason, the development of stereoselective methods and
strategies for the preparation of chiral peroxides has become
considerably important to the practitioners of chemical and
pharmaceutical synthesis. However, catalytic syntheses of
chiral peroxides is still a challenging goal to synthetic
chemists.[3–5] Despite these challenges, the groups of Deng[6]
and List[7] independently reported the use of a chiral base-
catalyzed enantioselective peroxidation of a,b-unsaturated
ketones in 2008.
catalyzed reactions have utilized carbon nucleophiles.
Recently, our group and others reported on the addition of
heteroatoms such as amines and alcohols, to imines catalyzed
by chiral phosphoric acids.[12] Herein, we report the first
example of a chiral phosphoric acid catalyzed addition of
hydroperoxides to imines, thereby allowing the direct access
to chiral a-amino peroxides in high yield and enantiomeric
excess (Scheme 1).
Scheme 1. Catalytic synthesis of optically active a-amino peroxides.
Initial studies were conducted by examining the addition
of tert-butyl hydroperoxide to imine 2a in the presence of a
chiral phosphoric acid. Catalyst screening revealed that
phosphoric acid 1 was the most effective catalyst for the
peroxidation of imine 2a in terms of enantioselectivity.[13]
With toluene as the solvent, the product was obtained in 88%
yield and 75% ee (Table 1, entry 1). The reaction could also
be conducted in CH2Cl2, THF, and EtOAc to give the desired
product in high yields (Table 1, entries 2–4). Isopropyl
acetate, a solvent having a variety uses in manufacturing,
was found to be the best with respect to asymmetric induction
(Table 1, entry 5). To additionally optimize the reaction
Chiral a-amino peroxide moieties, though somewhat rare,
can be found in natural products. For example, verruculogen
(Figure 1) contains an a-amino peroxide, and has been found
Figure 1. Natural products possessing a chiral a-amino peroxide.
Table 1: Optimization of reaction conditions.[a]
to alter GABA receptor binding and inhibit the mammalian
cell cycle.[1a] In addition, dioxetanone is a high-energy natural
product containing a chiral a-amino peroxide found in the
Japanese firefly.[8] To the best of our knowledge, there is no
catalytic asymmetric method that can give direct access to
chiral a-amino peroxides.[9]
Chiral phosphoric acids have proven to be efficient
catalysts for a large number of important enantioselective
transformations.[10–11] So far most of the phosphoric acid
Entry
Imine (R1)
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
2a (Ph)
2a
2a
2a
toluene
CH2Cl2
THF
EtOAc
iPrOAc
iPrOAc
iPrOAc
iPrOAc
iPrOAc
iPrOAc
4a: 88
4a: 88
4a: 86
4a: 93
4a: 84
4b: 83
4c: 92
4d: 83
4e: 82
4 f: 81
75
79
47
84
86
90
84
88
97
96
[*] Dr. W. Zheng, Prof. Dr. J. C. Antilla
Department of Chemistry, University of South Florida
4202 E. Fowler Avenue, CHE 205A, Tampa, FL 33620 (USA)
Fax: (+1)813-974-1733
2a
E-mail: jantilla@usf.edu
2b (4-MeOC6H4)
2c (2-MeC6H4)
2d (3-MeC6H4)
2e (3-MeOC6H4)
2 f (3,5-(MeO)2C6H3)
Dr. L. Wojtas
Department of Chemistry X-Ray Facility
University of South Florida, Tampa, FL 33620 (USA)
[**] We thank the National Institutes of Health (NIH GM-082935) and
the National Science Foundation (NSF-0847108) for financial
support.
[a] Reaction conditions: imine 2a–f (0.1 mmol), hydroperoxide 3a
(0.2 mmol), (R)-1 (5 mol%), solvent (0.6 mL) at room temperature.
[b] Yield of isolated product. [c] Determined by HPLC analysis using a
chiral stationary phase.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002972.
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Communications
conditions, variation of protecting group on the nitrogen atom
have a detrimental effect on the enantioselectivity or reaction
efficiency. Notably, prolonged reaction times did not lead to a
decrease in optical purity. This suggests that retro-addition
leading to subsequent product racemization through an
iminium ion was not observed.
of the imine was investigated. As shown in Table 1, the
enantiomeric excess increased with introduction of a methoxy
group in the para position of phenyl ring (Table 1, entry 6).
Placement of the same substituent in the meta position gave
an even higher ee value (Table 1, entries 7–8). Installation of
electron-rich groups in the meta position of the phenyl ring
enhanced the ee value to 97% (Table 1, entry 9) and 96%
(Table 1, entry 10). Two equivalents of tert-butyl hydroper-
oxide were used to ensure reaction completion and did not
With the optimized conditions in hand, we started to
investigate the substrate scope for the asymmetric peroxida-
tion of imines. The representative results are summarized in
Scheme 2. To our delight, catalyst 1 gave excellent results for
the reaction of a wide range of different imines with
hydroperoxides. With 3,5-dimethoxybenzoyl as a protecting
group, electron-withdrawing substituents (F, Cl, and Br) in the
para position (4g, 4h, and 4i) were all shown to be excellent
substrates for the peroxidation reaction. Likewise, electron-
donating substituents in the para and ortho positions (4j and
4k) also provided excellent asymmetric induction. With 3-
methoxylbenzoyl as the protecting group, substrates having
electron-withdrawing and electron-donating groups led to
highly enantioselective products (4m and 4n). When cumene
hydroperoxide was used as a nucleophile, products 4p, 4q,
and 4r were obtained with high enantioselectivity.
The absolute configuration of the peroxide product was
determined to be (R)-4i by single-crystal X-ray diffraction
analysis of compound 4i (Figure 2).[14] Configurations of other
products were assigned by analogy.
Figure 2. ORTEP representation of the X-ray structure of Compound
(R)-4i. The thermal ellipsoids are shown at 50% probability.
We believe the bifunctional nature of the chiral phospho-
ric acid is responsible for concurrent activation of both the
nucleophile and the electrophile through hydrogen-bonding
interactions (Figure 3). These hydrogen-bonding interactions
presumably serve to create a chiral environment, which allows
for high selectivity during the addition of the peroxide to the
activated imine.
Scheme 2. Substrate scope for the chiral phosphoric acid catalyzed
enantioselective peroxidation of imines. Reaction conditions: imine
2g–o (0.1 mmol), hydroperoxide 3a–b (0.2 mmol), (R)-1 (5 mol%),
iPrOAc (0.6 mL) at room temperature. The reported yields are for the
isolated product, and the reported ee values were determined by HPLC
analysis using a chiral stationary phase.
Figure 3. Proposed transition state for the chiral phosphoric acid
catalyzed peroxidation of imines.
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In summary, we have successfully discovered a novel
catalytic enantioselective peroxidation of imines using a
chiral phosphoric acid. This approach provides direct access
to optically active a-amino peroxides with high enantioselec-
tivities. Additional investigation into the expansion of the
reaction scope and synthetic utility, with the aim of develop-
ing more enantioselective transformations (novel chiral
oxidizing reagents), reaction methodologies, and applications
to total synthesis, are currently underway in our laboratory
and will be reported in due course.
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[13] Please see the Supporting Information for a table of chiral
phosphoric acids that were screened.
Experimental Section
General procedure: The imine 2 (0.1 mmol) and catalyst (R)-1
(5 mol%) were placed in a flame-dried reaction tube. Dry isopropyl
acetate (0.6 mL) was added to the mixture. The reaction mixture was
stirred for 5 min, and then hydroperoxide 3 (0.2 mmol) was added and
the mixture was stirred for an additional 24 h at RT. The reaction
mixture was directly subjected to silica gel column chromatography
(hexanes/ethyl acetate 10:1) to give the pure product 4.
Received: May 17, 2010
Published online: July 26, 2010
Keywords: asymmetric catalysis · imines · organocatalysis ·
.
peroxides · phosphoric acids
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[14] CCDC 775266 ((R)-4i) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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