5 Ir-Catalyzed Asymmetric Hydrogenation of Ketones
Over the last decades, the Ir-catalyzed asymmetric hydrogenation of ketones has
experienced a huge advance. Thus, a range of Ir-catalysts have demonstrated to be
highly efficient, achieving excellent enantioselectivities and activities for a range of
ketones. Such progress has made Ir-catalysts good alternatives to the most commonly used Ru-catalysts. Most of the key ligands are phosphine-based, although
there are some important examples that do not contain a P-donor group.
5.1 P-Donor-Based Ligands
One of the key P-containing ligands was disclosed by Poli’s group [282]. They
developed a ferrocenyl-based phosphine-thioether ligand L48 that provided high
enantioselectivities (ees up to 99%) for a range of alkyl aryl ketones (Fig. 44), albeit
activities (TOFs up to 250 h
À1 ) do not compare well with the current state of the art.
In 2010, Xie and Zhou et al. developed chiral spiro aminophosphine ligands L49
(Fig. 44) [283, 284]. The use of Ir/L49 catalyst provided high ees (up to 97%) and
activities (TOFs up to 3.7 Â 10
4 h
À1 ) in the hydrogenation of aryl alkyl ketones and
exo-cyclic α,β-unsaturated ketones. Nevertheless, the catalyst deactivates under
hydrogenation conditions. Mechanistic investigations indicated that the deactivation
was due to the formation of [IrH 2 (L49) 2 ]
+ complex [284].
To prevent the formation of such inactive species, the same group introduced in
L49 a pyridine group as a third coordinating position, leading to the tridentate P,N,N
spiro pyridine-aminophosphine ligands SpiroPAP (Fig. 43) [285–287]. Ir/SpiroPAP
(Ar ¼ 3,5t
Bu 2 -C 6 H 3 and R ¼ 3-Me) system proved to be highly efficient in the AH
of aryl alkyl ketones and aryl β- and δ-ketoesters (ees up to 99.8% and TONs up to
4.550.000; Fig. 45) [285–287]. The excellent performance of SpiroPAP ligands has
been further extended to acyclic α,β-unsaturated acyclic ketones [288]; α-, γ-, and
δ-keto acids [289, 290]; α-amino ketones [291]; and α,β-unsaturated-α-ethoxycarbonyl-β-substituted cyclic ketones [292] (Fig. 45). This catalytic system has
been also used in the deracemization of α-substituted lactones [293, 294] (Fig. 45)
via dynamic kinetic resolution (DKR) as well as in the kinetic resolution of aliphatic
alcohols [295]. The synthetic versatility of Ir/SpiroPAP catalyst was demonstrated
with the synthesis of drugs and natural products such as (À)-mesembrine,
rivastigmine, and (À)-Hamerigan B [288, 296–300].
Xie’s and Zhou’s group developed a P,N,S variant (SpiroSAP; Fig. 44) with a
1,3-dithiane group instead of the pyridine group [301]. Ir/SpiroSAP catalyst proved
to be highly efficient in the asymmetric hydrogenation of β-alkyl-β-ketoesters [301]
as well as in the dynamic kinetic resolution (DKR) of β-ketolactams [302] (Fig. 46).
Ir/SpiroSAP catalyst was also used in the formal total synthesis of (À)-cyanolide A
and (À)-doluculine [303, 304]. Recently, a new SpiroPAP variant has been developed by replacing the pyridine group by an oxazoline moiety (SpiroOAP; Fig. 43)
192
J. Margalef et al.
Over the last decades, the Ir-catalyzed asymmetric hydrogenation of ketones has
experienced a huge advance. Thus, a range of Ir-catalysts have demonstrated to be
highly efficient, achieving excellent enantioselectivities and activities for a range of
ketones. Such progress has made Ir-catalysts good alternatives to the most commonly used Ru-catalysts. Most of the key ligands are phosphine-based, although
there are some important examples that do not contain a P-donor group.
5.1 P-Donor-Based Ligands
One of the key P-containing ligands was disclosed by Poli’s group [282]. They
developed a ferrocenyl-based phosphine-thioether ligand L48 that provided high
enantioselectivities (ees up to 99%) for a range of alkyl aryl ketones (Fig. 44), albeit
activities (TOFs up to 250 h
À1 ) do not compare well with the current state of the art.
In 2010, Xie and Zhou et al. developed chiral spiro aminophosphine ligands L49
(Fig. 44) [283, 284]. The use of Ir/L49 catalyst provided high ees (up to 97%) and
activities (TOFs up to 3.7 Â 10
4 h
À1 ) in the hydrogenation of aryl alkyl ketones and
exo-cyclic α,β-unsaturated ketones. Nevertheless, the catalyst deactivates under
hydrogenation conditions. Mechanistic investigations indicated that the deactivation
was due to the formation of [IrH 2 (L49) 2 ]
+ complex [284].
To prevent the formation of such inactive species, the same group introduced in
L49 a pyridine group as a third coordinating position, leading to the tridentate P,N,N
spiro pyridine-aminophosphine ligands SpiroPAP (Fig. 43) [285–287]. Ir/SpiroPAP
(Ar ¼ 3,5t
Bu 2 -C 6 H 3 and R ¼ 3-Me) system proved to be highly efficient in the AH
of aryl alkyl ketones and aryl β- and δ-ketoesters (ees up to 99.8% and TONs up to
4.550.000; Fig. 45) [285–287]. The excellent performance of SpiroPAP ligands has
been further extended to acyclic α,β-unsaturated acyclic ketones [288]; α-, γ-, and
δ-keto acids [289, 290]; α-amino ketones [291]; and α,β-unsaturated-α-ethoxycarbonyl-β-substituted cyclic ketones [292] (Fig. 45). This catalytic system has
been also used in the deracemization of α-substituted lactones [293, 294] (Fig. 45)
via dynamic kinetic resolution (DKR) as well as in the kinetic resolution of aliphatic
alcohols [295]. The synthetic versatility of Ir/SpiroPAP catalyst was demonstrated
with the synthesis of drugs and natural products such as (À)-mesembrine,
rivastigmine, and (À)-Hamerigan B [288, 296–300].
Xie’s and Zhou’s group developed a P,N,S variant (SpiroSAP; Fig. 44) with a
1,3-dithiane group instead of the pyridine group [301]. Ir/SpiroSAP catalyst proved
to be highly efficient in the asymmetric hydrogenation of β-alkyl-β-ketoesters [301]
as well as in the dynamic kinetic resolution (DKR) of β-ketolactams [302] (Fig. 46).
Ir/SpiroSAP catalyst was also used in the formal total synthesis of (À)-cyanolide A
and (À)-doluculine [303, 304]. Recently, a new SpiroPAP variant has been developed by replacing the pyridine group by an oxazoline moiety (SpiroOAP; Fig. 43)
192
J. Margalef et al.