Page 2 - Chiral N,N-Dioxides: New Ligands and Organocatalysts for Catalytic Asymmetric Reactions

Chiral N,N -Dioxides Liu et al.
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activity and selectivity. Many homochiral controllers hav-
ing heteroatom-containing groups such as amines, ethers,
alcohols, and phosphines as electron-pair donors have
been developed. Impressive progress has been achieved
using a unique set of privileged chiral catalysts 1 and
the concepts drawn from uses of bifunctional catalysis 2
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and C 2 -symmetry. However, there is no universal chiral
activator that satisfies all of the demands of asymmetric
transformations. The rational design of chiral ligand
metal complexes and organocatalysts presents a formidable
challenge.
Amine N-oxides are highly polar substances that can be FIGURE 1. Design of C 2 -symmetric N,N -dioxide amides.
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easily prepared by N-oxidation of N-heteroaromatic com-
pounds or tertiary amines with H 2 O 2 or peroxoic acid. The
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generated oxygen atom in the N-oxide has a stronger dipole SCHEME 1. General Synthetic Route for N,N -Dioxides
than the oxygen atoms of other common oxo-donors such
as alcohols, ethers, and amides. In N-heteroaromatic
N-oxides, such as pyridine N-oxide, the oxygen 2pπ elec-
trons are conjugated with the N-heteroaromatic ring,
whereas an amine-oxide is approximately tetrahedral.
Therefore, if the parent tertiary amine contains three differ-
ent groups, the corresponding N-oxide will include a stable
chiral center on nitrogen.
Tertiary amine N-oxides can undergo synthetically
useful reactions and serve as selective oxidants or protec-
tive groups. Importantly, the unique properties of the Design and Synthesis of C 2 -Symmetric Chiral
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electron-pairs of N-oxides offer opportunities to form N,N -Dioxides
molecular adducts with protons or alcohols or for com- Our interest in N-oxides was stimulated by investigations of
plexation with various Lewis acids. The coordination the role of these substances as activators in asymmetric
chemistry of N-heteroaromatic N-oxides was thoroughly silylcyanation reactions. A biquinoline N,N -dioxide organo-
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investigated four decades ago. After a period of waning catalyst and a titanium complex of mono N-oxide from
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interest, the use of chiral pyridine or quinoline-type L-prolinol were employed with modest results. The unsa-
N-oxidesasactivatorsofsilicon reagents in asymmetric tisfying outcomes were attributed to the poor activating
allylation and aldol condensation has attracted atten- group and an unfavorable chiral environment. Subsequent
tion. 5,6 However, the design and application of chiral efforts were directed at combining the key characteristics
tertiary amine N-oxide catalysts has been reported rarely, of the catalysts for multidentate bifunctional catalysis. 2
3
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possibly owing to the difficulty in synthesizing optically C 2 -Symmetric N,N -dioxides that can be formed by the
pure compounds. connection of the two N-oxide amide subunits via a linker
Homochiral proline N-oxides were incorporated into pep- were chosen for this purpose (Figure 1).
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tide-like molecules as conformational restraints early in C 2 -Symmetric N,N -dioxides were prepared from com-
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1993. Oxidation of N-alkylated prolinamide proceeded mercially available chiral amino acids and amines. The
diastereoselectively to give a stable chiral N-oxide where linkage unit could be either a conformationally flexible
the amine oxide is syn to the adjacent carboxyamide straight alkyl chain or a rigid aryl chain; the former will
through intramolecular hydrogen bonding. This modular be discussed in this Account. Optically pure N,N -dioxides
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structure enables the formation of an easily fine-tuned were obtained without resolution (Scheme 1). Representa-
catalyst library. In this Account, we highlight our efforts to tive structures are shown in Figure 2.
develop C 2 -symmetric chiral N,N -dioxide amides and to The stereoselective oxidation and formation of six-
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apply them in asymmetric reactions. membered hydrogen bonded rings were confirmed by

Vol. 44, No. 8 ’ 2011 ’ 574–587 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 575