Keywords (Un)functionalized olefins · Asymmetric hydrogenation · Catalysis ·
Imines · Iridium · Ketones
1 Introduction
Metal-catalyzed asymmetric hydrogenation (AH) offers some of the most sustainable and straightforward reactions for producing pharmaceuticals, flavors, fragrances, agrochemicals, and fine chemicals due to its perfect atom economy and
operational simplicity [1–5]. It is estimated that around 10% of all chemical steps in
the synthesis of these compounds are hydrogenations. Despite the extensive research
dedicated to the asymmetric hydrogenation and the important progress reached,
some issues still need to be solved. Most catalysts only work with a limited number
of substrates, and each type of substrates needs a specific catalyst for optimal
enantioselectivity. For example, the asymmetric hydrogenation of functionalized
alkenes is mostly carried out by Ru- and Rh-diphosphine catalysts (see, e.g., [6–9]),
while the asymmetric hydrogenation of unfunctionalized olefins or with poorly
coordinative groups is mainly carried out with Ir-P,N catalysts (for reviews, see
[10–15]). A broad substrate scope is desirable to reduce the time dedicated to ligand/
catalyst design and preparation. A desired additional condition is that the catalyst
family should be synthesized from available starting materials and be easy to handle.
The number and types of functionalized substrates have been remarkably
expanded, and their use is commonplace, as illustrated in the commercial production
of the Parkinson’s L-DOPA drug [16, 17], the broad-spectrum antibiotics
levofloxacin [18] and sitagliptin [19], and the pesticide (S)-metolachlor [20]. The
success of catalysts relies on the ability of the substrate to form a metal chelate
involving the double bond and a donor atom. Although the reduction of
functionalized olefins has been thoroughly studied for decades, there are some
substrate types that are still a challenge. Among them it can be found the cyclic
β-enamides, which have recently attracted attention because their hydrogenation
products are found in many pharmaceutically and biologically active products. Two
representative examples are rotigotine, used to treat Parkinson’s disease, and
alnespirone, a selective 5-HT1A receptor with antidepressant and anxiolytic properties [21–24]. In the last decade, it has been found that Ir-containing catalysts [25–
27] can be used in their reduction with results that surpass the most studied Rh- and
Ru-catalysts [28–38]. Other challenging substrates where Ir-catalysts have shown to
be superior or complementary to the Rh-/Ru-catalysts are unsaturated carboxylic
acids and nitroolefins, among others (see Sects. 3–5).
The absence of a coordinative group in the olefins makes their hydrogenation a
great challenge. So, compared to the AH of functionalized olefins, the reduction of
unfunctionalized alkenes or with poor coordinative groups is much less mature [10–
15]. The best catalysts have two characteristics in common: (1) they mainly contain
P,N-ligands [39–41] and (2) their optimal structure is highly dependent on the
154
J. Margalef et al.
Imines · Iridium · Ketones
1 Introduction
Metal-catalyzed asymmetric hydrogenation (AH) offers some of the most sustainable and straightforward reactions for producing pharmaceuticals, flavors, fragrances, agrochemicals, and fine chemicals due to its perfect atom economy and
operational simplicity [1–5]. It is estimated that around 10% of all chemical steps in
the synthesis of these compounds are hydrogenations. Despite the extensive research
dedicated to the asymmetric hydrogenation and the important progress reached,
some issues still need to be solved. Most catalysts only work with a limited number
of substrates, and each type of substrates needs a specific catalyst for optimal
enantioselectivity. For example, the asymmetric hydrogenation of functionalized
alkenes is mostly carried out by Ru- and Rh-diphosphine catalysts (see, e.g., [6–9]),
while the asymmetric hydrogenation of unfunctionalized olefins or with poorly
coordinative groups is mainly carried out with Ir-P,N catalysts (for reviews, see
[10–15]). A broad substrate scope is desirable to reduce the time dedicated to ligand/
catalyst design and preparation. A desired additional condition is that the catalyst
family should be synthesized from available starting materials and be easy to handle.
The number and types of functionalized substrates have been remarkably
expanded, and their use is commonplace, as illustrated in the commercial production
of the Parkinson’s L-DOPA drug [16, 17], the broad-spectrum antibiotics
levofloxacin [18] and sitagliptin [19], and the pesticide (S)-metolachlor [20]. The
success of catalysts relies on the ability of the substrate to form a metal chelate
involving the double bond and a donor atom. Although the reduction of
functionalized olefins has been thoroughly studied for decades, there are some
substrate types that are still a challenge. Among them it can be found the cyclic
β-enamides, which have recently attracted attention because their hydrogenation
products are found in many pharmaceutically and biologically active products. Two
representative examples are rotigotine, used to treat Parkinson’s disease, and
alnespirone, a selective 5-HT1A receptor with antidepressant and anxiolytic properties [21–24]. In the last decade, it has been found that Ir-containing catalysts [25–
27] can be used in their reduction with results that surpass the most studied Rh- and
Ru-catalysts [28–38]. Other challenging substrates where Ir-catalysts have shown to
be superior or complementary to the Rh-/Ru-catalysts are unsaturated carboxylic
acids and nitroolefins, among others (see Sects. 3–5).
The absence of a coordinative group in the olefins makes their hydrogenation a
great challenge. So, compared to the AH of functionalized olefins, the reduction of
unfunctionalized alkenes or with poor coordinative groups is much less mature [10–
15]. The best catalysts have two characteristics in common: (1) they mainly contain
P,N-ligands [39–41] and (2) their optimal structure is highly dependent on the
154
J. Margalef et al.