geometry and substitution pattern of the olefin [10–15]. The consequence is that for
each particular olefin type, a different ligand family needs to be developed. It is also
important to notice that catalysts have been developed in different grades for each
olefin substitution pattern. The most successful cases have been reported for trisubstituted olefins and, to a less extent, for disubstituted. The asymmetric hydrogenation
of tetrasubstituted unfunctionalized substrates is still underdeveloped.
In this book chapter, we describe the development in Ir-catalyzed asymmetric
hydrogenation with particular emphasis on the achievements made during the last
10 years. We also present their applications to the synthesis of complex molecules.
Most of the work has been devoted to the hydrogenation of nonfunctionalized olefins
or with poorly coordinative groups (Sect. 2), with significant advances in both
substrate scope and mechanistic studies. However, also notable advances have
been made in improving the catalytic performance in the reduction of relevant and
more challenging functionalized substrates, such as unsaturated carboxylic acids,
nitroolefins, cyclic β-enamides, imines, etc. (see Sects. 3–5).
2 Ir-Catalyzed Asymmetric Hydrogenation
of Unfunctionalized Olefins or with Poorly Coordinative
Groups
Among the most challenging substrates to date are the unfunctionalized olefins or
olefins with poorly coordinative groups [10–15]. A breakthrough in the hydrogenation of this type of substrates came in 1997 when Pfaltz et al. used phosphineoxazoline PHOX ligands L1 (Fig. 1) to design [Ir(L1)(cod)]PF 6 (cod ¼ 1,5cyclooctadiene), a chiral analogue of Crabtree’s catalyst ([Ir(py)(PCy 3 )(cod)]PF 6 )
that enantioselectively hydrogenated imines [42]. Although this catalyst also hydrogenated unfunctionalized olefins highly enantioselectively, it was unstable to the
reaction conditions. Pfaltz and co-workers overcame this problem by changing the
catalyst anion to [(3,5-(F 3 C) 2 -C 6 H 3 ) 4 B]
À ([BAr F ]
À ). The result was [Ir(L1)(cod)]
BAr F (Fig. 1), an active, enantioselective, and stable catalyst library for olefin
hydrogenation. Despite this success, its scope was limited to mainly E-trisubstituted
olefins [43]. It was also seen that the optimal catalyst was highly dependent on the
geometry and substitution pattern of the olefin. This triggered the search for new
catalysts that would reach a wider substrate scope.
In this respect, Pfaltz group continued to develop new versions of the PHOX
complexes, modifying the ligand backbone, with the discovery of very efficient
ligand libraries [44–52]. Successive work incorporated pyridine and quinoline rings
instead of the oxazoline, which allowed the successful reduction of challenging
purely alkyl-substituted substrates in high ee [53–55]. A notable application was the
total synthesis of γ-tocopherol as a single diastereoisomer in 98% ee, controlling two
stereocenters in one reductive step (see below) [54]. The various developed ligands
also enabled the reduction of various type of substrates, such as allylic alcohols,
Iridium-Catalyzed Asymmetric Hydrogenation
155
each particular olefin type, a different ligand family needs to be developed. It is also
important to notice that catalysts have been developed in different grades for each
olefin substitution pattern. The most successful cases have been reported for trisubstituted olefins and, to a less extent, for disubstituted. The asymmetric hydrogenation
of tetrasubstituted unfunctionalized substrates is still underdeveloped.
In this book chapter, we describe the development in Ir-catalyzed asymmetric
hydrogenation with particular emphasis on the achievements made during the last
10 years. We also present their applications to the synthesis of complex molecules.
Most of the work has been devoted to the hydrogenation of nonfunctionalized olefins
or with poorly coordinative groups (Sect. 2), with significant advances in both
substrate scope and mechanistic studies. However, also notable advances have
been made in improving the catalytic performance in the reduction of relevant and
more challenging functionalized substrates, such as unsaturated carboxylic acids,
nitroolefins, cyclic β-enamides, imines, etc. (see Sects. 3–5).
2 Ir-Catalyzed Asymmetric Hydrogenation
of Unfunctionalized Olefins or with Poorly Coordinative
Groups
Among the most challenging substrates to date are the unfunctionalized olefins or
olefins with poorly coordinative groups [10–15]. A breakthrough in the hydrogenation of this type of substrates came in 1997 when Pfaltz et al. used phosphineoxazoline PHOX ligands L1 (Fig. 1) to design [Ir(L1)(cod)]PF 6 (cod ¼ 1,5cyclooctadiene), a chiral analogue of Crabtree’s catalyst ([Ir(py)(PCy 3 )(cod)]PF 6 )
that enantioselectively hydrogenated imines [42]. Although this catalyst also hydrogenated unfunctionalized olefins highly enantioselectively, it was unstable to the
reaction conditions. Pfaltz and co-workers overcame this problem by changing the
catalyst anion to [(3,5-(F 3 C) 2 -C 6 H 3 ) 4 B]
À ([BAr F ]
À ). The result was [Ir(L1)(cod)]
BAr F (Fig. 1), an active, enantioselective, and stable catalyst library for olefin
hydrogenation. Despite this success, its scope was limited to mainly E-trisubstituted
olefins [43]. It was also seen that the optimal catalyst was highly dependent on the
geometry and substitution pattern of the olefin. This triggered the search for new
catalysts that would reach a wider substrate scope.
In this respect, Pfaltz group continued to develop new versions of the PHOX
complexes, modifying the ligand backbone, with the discovery of very efficient
ligand libraries [44–52]. Successive work incorporated pyridine and quinoline rings
instead of the oxazoline, which allowed the successful reduction of challenging
purely alkyl-substituted substrates in high ee [53–55]. A notable application was the
total synthesis of γ-tocopherol as a single diastereoisomer in 98% ee, controlling two
stereocenters in one reductive step (see below) [54]. The various developed ligands
also enabled the reduction of various type of substrates, such as allylic alcohols,
Iridium-Catalyzed Asymmetric Hydrogenation
155