enantioselectivity for this reaction. The growth of asymmetric catalytic reactions is
intertwined with the development of modern electronic structure and parametric
methods [14].
3 Privileged Ligands: Phosphoramidites
Metal-ligand complexes promote many transformations, and in enantiopure, chiral
form, they can be used to effect asymmetric catalysis. While a given transition metal
may catalyse several reaction types with broad substrate scope and efficiency, no
single chiral ligand results in uniformly high levels of enantioselectivity. However,
among the plethora of chiral ligands, a few stand out because of their versatility. A
common feature of these so-called privileged ligands that function across a wide
variety of chemical transformations is the presence of C2 symmetry elements
[15]. These ligands are able to induce good to excellent levels of enantioselectivity
in various reactions, even though the ligated metal and the associated reaction
mechanisms may differ drastically. Members of this privileged ligand class include
BINOL (1,1
0 -bi-2-naphthol) [6] and BINAP (2,2
0 -bis(diphenylphosphino)-1,10 -binaphthyl) [16], used in Diels-Alder reactions, hydrogenation, Heck reactions,
aldol reactions, etc.; Brintzinger’s ligand [17] used in alkene and imine reduction,
Ziegler-Natta polymerization, etc.; TADDOL [18] used in Diels-Alder reactions,
aldehyde alkylation, iodolactonization, etc.; and bisoxazolines [19] used in DielsAlder reactions, Mukaiyama aldol, conjugate addition, cyclopropanation, etc.
(Fig. 3). Salen, tartrate and cinchona alkaloids are also included in this original
group. This array of ligands emphasizes that the source of chirality may come from
stereogenic centres or from axial chirality due to restricted rotation about a biaryl
bond.
DuPhos phospholanes [20], Solvias Josiphos families [21], the Reetz [22] and
Trost ligands [23] and ChiralQuest phosphines [24] (Fig. 3) have all been successfully applied in industrially useful reactions such as hydrogenations, aldol reactions
and asymmetric allylic alkylations. These chiral ligands are notable for their synthetic accessibility and modular structures. Library development of structurally
related ligands is made possible, gaining the attention of computational and synthetic
chemists focussed on ligand design. As we shall also discuss, the modularity of these
ligands is also instrumental when exploring statistical relationships between catalyst/
ligand structure and enantioselectivity. A fixed ‘scaffold’ ensures that structural
variations can be described by their features alone, rather than those of the entire
catalyst structure. Furthermore, the simplifying assumption that mechanistic steps
remain consistent across different catalyst structures can be made more safely when
only minor perturbations are explored in experiment. This is particularly important
for expensive QM studies.
Privileged structures such as BINOL also feature as a core structural element in
many ligands, for example, the Reetz and ChiralQuest ligands. In addition, the
BINOL subunit is a common chiral backbone in phosphoramidite ligands used
Ligand Design for Asymmetric Catalysis: Combining Mechanistic and. . .
159
intertwined with the development of modern electronic structure and parametric
methods [14].
3 Privileged Ligands: Phosphoramidites
Metal-ligand complexes promote many transformations, and in enantiopure, chiral
form, they can be used to effect asymmetric catalysis. While a given transition metal
may catalyse several reaction types with broad substrate scope and efficiency, no
single chiral ligand results in uniformly high levels of enantioselectivity. However,
among the plethora of chiral ligands, a few stand out because of their versatility. A
common feature of these so-called privileged ligands that function across a wide
variety of chemical transformations is the presence of C2 symmetry elements
[15]. These ligands are able to induce good to excellent levels of enantioselectivity
in various reactions, even though the ligated metal and the associated reaction
mechanisms may differ drastically. Members of this privileged ligand class include
BINOL (1,1
0 -bi-2-naphthol) [6] and BINAP (2,2
0 -bis(diphenylphosphino)-1,10 -binaphthyl) [16], used in Diels-Alder reactions, hydrogenation, Heck reactions,
aldol reactions, etc.; Brintzinger’s ligand [17] used in alkene and imine reduction,
Ziegler-Natta polymerization, etc.; TADDOL [18] used in Diels-Alder reactions,
aldehyde alkylation, iodolactonization, etc.; and bisoxazolines [19] used in DielsAlder reactions, Mukaiyama aldol, conjugate addition, cyclopropanation, etc.
(Fig. 3). Salen, tartrate and cinchona alkaloids are also included in this original
group. This array of ligands emphasizes that the source of chirality may come from
stereogenic centres or from axial chirality due to restricted rotation about a biaryl
bond.
DuPhos phospholanes [20], Solvias Josiphos families [21], the Reetz [22] and
Trost ligands [23] and ChiralQuest phosphines [24] (Fig. 3) have all been successfully applied in industrially useful reactions such as hydrogenations, aldol reactions
and asymmetric allylic alkylations. These chiral ligands are notable for their synthetic accessibility and modular structures. Library development of structurally
related ligands is made possible, gaining the attention of computational and synthetic
chemists focussed on ligand design. As we shall also discuss, the modularity of these
ligands is also instrumental when exploring statistical relationships between catalyst/
ligand structure and enantioselectivity. A fixed ‘scaffold’ ensures that structural
variations can be described by their features alone, rather than those of the entire
catalyst structure. Furthermore, the simplifying assumption that mechanistic steps
remain consistent across different catalyst structures can be made more safely when
only minor perturbations are explored in experiment. This is particularly important
for expensive QM studies.
Privileged structures such as BINOL also feature as a core structural element in
many ligands, for example, the Reetz and ChiralQuest ligands. In addition, the
BINOL subunit is a common chiral backbone in phosphoramidite ligands used
Ligand Design for Asymmetric Catalysis: Combining Mechanistic and. . .
159