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SHILPA SINGH
Feb 13th 2009
Department of Medicinal Chemistry
School of Pharmacy, VCU
METAL CATALYZED ASYMMETRIC REDUCTION
Chiral building blocks are fundamental for the synthesis of biologically active compounds such as
pharmaceuticals, agrochemicals, flavors and fragrances. Asymmetric saturation of alkenes, ketones,
and imines by hydrogen or organic hydrogen donors provides an ideal access to chiral alkanes,
alcohols, and amines respectively. A small amount of chiral catalyst repeatedly delivers hydrogen
atoms to one of the enantiofaces of substrates, producing large amounts of optically active
compounds. This chirality multiplication is achieved largely in a homogeneous phase with chiral
molecular catalysts consisting of a metallic element and an optically active organic compound(s) [1].
A great number of transition metal complexes have been prepared and used as homogeneous
catalysts. These include titanium, zirconium and lanthanide based catalysts. Also present are iridium,
rhodium and ruthenium complexes [6-9].
Despite decades of research on homogeneous catalysts for asymmetric hydrogenation, most of the
alkenes studied have some functionality that can coordinate strongly to a metal atom [2].
Comparatively few “unfunctionalized alkenes” have been examined through this methodology.
Consequently no practical methods have been developed for asymmetric hydrogenation of a large
group of alkenes types. There are only a few examples of highly enantioselective hydrogenations of
unfunctionalized alkenes [2,3].
A new class of catalysts has been investigated that overcome these limitations [13]. These comprise
of relatively air and moisture tolerant cationic iridium complexes, with chiral non-racemic ligands and
weakly coordinating counter ions [1-4]. For a wide range of unfunctionalized olefins, excellent
enantioselectivities have been achieved. Because these catalysts do not require the presence of any
particular functional group in the substrate, they considerably broaden the scope of asymmetric
hydrogenation [3,4].
These iridium complexes are usually of Ir(COD)L1L2. (counter ion)type where COD is
cyclooctadiene and L is the chiral ligand [16]. Most commonly used chiral ligands include N,P-ligands
[14]. Early work in this field focused mainly on phosphine-oxazoline ligand systems [10]. Further
variations in ligand designing led to exchange of the phosphine group for phosphinite group. In
addition, recently a new class of ligands was synthesized in which phosphorous was replaced by an
N-heterocyclic carbene unit [15,18]. These were referred to as the N,C-ligands. Apart from these
there were also iridium-phosphine thiazole complexes, which are highly enantioselective for a wide
range of substrates[12].
Fig. 1: A Typical Ir Catalyst
The mechanism of iridium catalyzed hydrogenation of unfunctionalized alkenes has been studied by
density functional theory calculations and kinetic experiments [19]. Several recent experimental and
computational studies have arrived at different conclusions on catalytic cycle. A possible catalytic
Ir+3/ Ir+5 cycle involving a coupled migratory insertion of the alkene into an Ir-H bond, is suggested to
be the mechanism of the reaction. This mechanism is shown to be compatible with the observed
enantioselectivity of the reaction [11.17].
In summary, cationic iridium complexes with chiral ligands are efficient catalysts for asymmetric
hydrogenation. They are readily prepared and are easy to handle. So far, they have been mainly
applied to aryl-substituted unfunctionalized olefins. However, high enantioselectivities have also been
obtained with α,β-unsaturated carboxylic esters [20]. Overall this area is at an intriguing stage of
development.
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