Page 1 - Chiral N,N-Dioxides: New Ligands and Organocatalysts for Catalytic Asymmetric Reactions

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

Reactions

XIAOHUA LIU, LILI LIN, AND XIAOMING FENG*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College
of Chemistry, Sichuan University, Chengdu 610064, China
RECEIVED ON JANUARY 24, 2011

CONSPECTUS

omochiral catalysts that can effect asymmetric transformations are invaluable in
H the production of optically active molecules. Researchers are actively pursuing
the design of new ligands and organocatalysts by exploiting concepts derived
from the application of bifunctional and C 2 -symmetric catalysts. Many homochiral
catalysts containing amines, ethers, alcohols, and phosphines as electron-pair donors
have been successfully developed.
Amine N-oxides are highly polar substances. Despite their pronounced capacity as
electron-pair donors, N-oxides have been underutilized in asymmetric reactions; they
have only made a visible impact on the field in the preceding decade. Systematic
studies have instead largely focused on pyridine- or quinoline-based scaffolds in
organosilicon and coordination chemistry. The application of chiral tertiary amine
N-oxides has not been widely pursued because of the difficulty of controlling the
chirality at the tetrahedral nitrogen of the N-oxide moiety. In this Account, we outline
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the design of a new family of C 2 -symmetric N,N -dioxides from readily available chiral amino acids. We then discuss the application
of these chiral amine N-oxides as useful metal ligands and organocatalysts for asymmetric reactions.
The high nucleophilicity of the oxygen in N-oxides is ideal for organocatalytic reactions that rely on nucleophilic activation of
organosilicon reagents. These catalysts have been successfully applied in the asymmetric addition of trimethylsilylcyanide to
aldehydes, ketones, aldimines, and ketimines, with good yields and excellent enantioselectivities. Asymmetric organocatalytic
chlorination of β-ketoesters with N-chlorosuccinimide has also been achieved through hydrogen bond activation.
The molecular framework of these N,N -dioxides, with their multiple O-donors, also serves as a new tetradentate ligand that
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can coordinate a range of metal ions, including Cu(I), Cu(II), Ni(II), Mg(II), Fe(II), Co(II), In(III), Sc(III), La(III), Y(III), Nd(III), and others.
These versatile metal complexes are efficient catalysts for a variety of asymmetric reactions. Asymmetric cycloadditions have been
achieved with these chiral Lewis acid catalysts. We have also found success with asymmetric nucleophilic additions to CdOorCdN
bonds; substrates include 3-substituted 2-oxindoles, alkenes, enamides, enecarbamates, diazoacetate esters, nitroalkanes, glycine
Schiff bases, and phosphate. Notably, the first catalytic asymmetric Roskamp reaction was realized, which was successful because
of the high efficiency of the catalyst. Asymmetric conjugate additions between R,β-unsaturated compounds and nucleophiles such
as nitroalkane, malonate, thioglycolate, and indoles have been accomplished. The first asymmetric haloamination of chalcones was
discovered, and the reaction proceeded with high regio- and enantioselectivity. In some cases, we were able to reduce the catalyst
loading to just 0.010.05 mol % while maintaining excellent outcomes.
Some particularly interesting phenomena were observed over the course of the research. These include a remarkable
amplification of the asymmetry in a sulfa-Michael reaction, as well as the reversal of enantioselectivity after alteration of the
central metal or the subunits of the ligand in two other reactions. These unusual results have facilitated a deeper understanding of
the catalytic mechanism.

Introduction for asymmetric reactions. The ideal catalyst, in principle,
The ongoing quest for chiral compounds has stimulated should be inexpensive, convenient to manipulate, amen-
intensive research into the development of new catalysts able to structural modification, and stable, and have high
574 ’ ACCOUNTS OF CHEMICAL RESEARCH ’ 574–587 ’ 2011 ’ Vol. 44, No. 8 Published on the Web 06/24/2011 www.pubs.acs.org/accounts
10.1021/ar200015s & 2011 American Chemical Society