Keywords

1 Introduction

The hydroformylation of alkenes, which was originally discovered by Otto Roelen in 1938 [1,2,3], is nowadays one of the most important industrial applications of homogeneous catalysis (Scheme 1) [4,5,6,7,8,9,10,11,12,13,14]. Today, over 9 million tons of so-called oxo-products are produced per year, a number which is still rising. The majority of these oxo-products are obtained from the hydroformylation of propene 1, which is a fraction of the steam-cracking process. The resulting products iso-butyraldehyde 2 and n-butanal 3 are important intermediates for the production of esters, acrylates, and 2-ethylhexanol [4, 5].

Scheme 1
scheme 1scheme 1

Hydroformylation of propene

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From a synthetic point of view, the reaction is a one-carbon chain elongation caused by the addition of carbon monoxide and hydrogen across the π system of a C=C double bond [15, 16]. As a pure addition reaction, the hydroformylation reaction meets all requirements of an atom-economic process [17]. Furthermore, the synthetically valuable aldehyde function is introduced, which allows subsequent skeleton expansion that may even be achieved in one-pot sequential transformations [18, 19].

In 1968, Wilkinson discovered that phosphine-modified rhodium complexes display a significantly higher activity and selectivity compared to the first generation of cobalt catalysts [20,21,22]. Since that time, ligand modification of the rhodium catalyst has been the method of choice in order to influence the catalyst activity and selectivity [23].

In the asymmetric hydroformylation of alkenes, the first examples of high level of enantioselectivity (ee’s up to 90%) were achieved by Stille and Consiglio using chiral Pt-diphosphine systems [24, 25]. However, these catalysts suffered several disadvantages such as low reaction rates, tendency to hydrogenate the substrates, and low regioselectivity to the branched products. Later, these issues were mainly overcome by the use of Rh-based catalysts [26, 27].

In the low-pressure hydroformylation of internal alkenes, the chemoselectivity (and simultaneously regioselectivity) is one of the remaining problems to be solved in industry. This issue originates from the exponential drop of alkene reactivity when increasing the number of alkene substituents. The known hydroformylation catalysts for internal alkene hydroformylation operating under low-pressure conditions rely on the use of strong π-acceptor ligands, such as bulky phosphites and phosphobenzene systems [28,29,30]. However, the high activity of the corresponding rhodium catalysts is usually associated with a high tendency towards alkene isomerization, which renders a position-selective hydroformylation of an internal alkene extremely challenging, although over the last years, some examples started to appear in the literature.

The regioselectivity of the hydroformylation of alkenes is function of many factors and quantum chemical calculations have been frequently used to gain useful insights into its origin [31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]. These include inherent substrate preferences, directing effects exerted by functional groups as part of the substrate, as well as catalyst effects. In order to appreciate substrate inherent regioselectivity trends, alkenes have to be classified according to the number and nature of their substituents (Scheme 2) [15, 16].

Scheme 2
scheme 2scheme 2

Regioselective trends on hydroformylation of different alkenes

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The regioselectivity issue usually only arises for terminal and 1,2-disubstituted alkenes 7. For alkyl-substituted terminal alkenes 4 there is a slight preference for the linear product 6. For terminal alkenes 4 containing an electron-withdrawing substituent, the formation of the branched product 5 is favored and is sometimes exclusive. This tendency is more or less unaffected by the catalyst structure. Both 1,1-disubstituted 10 and trisubstituted 13 alkenes generally provide only one regioisomer (11 and 14, respectively) based on Keuleman’s rule, which states that the formyl group is usually added in order to avoid the formation of a quaternary carbon center [51].

Asymmetric hydroformylation is a very promising catalytic reaction that produces chiral aldehydes from inexpensive feedstock (alkenes, syngas) in a single step under essentially neutral reaction conditions. Even though asymmetric hydroformylation offers great potential for the fine chemical industry, this reaction has not yet been utilized on an industrial scale due to several technical challenges [4, 5]. Among the most significant issues are (a) the low reaction rates at low temperature where good selectivities are usually observed, (b) the difficulty to control simultaneously the regio- and the enantioselectivity, and (c) the limited substrate scope for any single ligand.

2 Rh-Catalyzed Hydroformylation Mechanism

In Scheme 3, the well-known mechanism of the Rh-catalyzed hydroformylation mechanism proposed by Heck is described for bidentate ligands [52]. It corresponds to Wilkinson’s so-called dissociative mechanism [20,21,22]. The associative mechanism involving 20-electron intermediates for ligand/substrate exchange will not be considered. In this process, a great understanding of the mechanism has been possible due to the observation and structural characterization of the resting state of the catalyst by in situ spectroscopic techniques (HP-IR, HP-NMR) [23, 53]. For bidentate ligands (L–L), the common starting complex is the [RhH(L–L)(CO)2] species 16, containing the ligand coordinated in equatorial positions (denoted eq–eq throughout the scheme) or in an apical-equatorial positions (complexes denoted eq–ax).

Scheme 3
scheme 3scheme 3

Mechanism of the Rh-catalyzed asymmetric hydroformylation in the presence of bidentate ligand (L–L)

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Dissociation of equatorial CO from 16 leads to the square-planar intermediate 17, which associates with alkene to give complexes 18, where the ligand can again be coordinated in two isomeric forms eq–ax and eq–eq, having a hydride in an apical position and alkene coordinated in the equatorial plane. On the basis of experimental results and theoretical calculations, it has been proposed that the regioselectivity is determined by the coordination of the alkene to the square-planar intermediate 17 to give the pentacoordinate intermediates 18 [35]. This step is also crucial in determining the enantioselectivity since the enantioface discrimination occurs between 17 and 19, and particularly from 17 to 18. The CO dissociation from 16 was shown to be much faster than the overall hydroformylation process, indicating that the rate of the reaction is dominated by the reaction of 17 with either CO or the alkene to form 16 or 18 [39]. It has not been established experimentally whether alkene complexation is reversible or not; although in the Scheme 3, all steps are described as reversible except the final hydrogenolysis. Experiments using deuterated substrates suggest that alkene coordination and insertion into the Rh–H bond can be reversible, certainly when the pressures are low. Complexes 18 undergo migratory insertion to give the square-planar alkyl complex 19. This species can undergo β-hydride elimination, thus leading to isomerization or can react with CO to form the trigonal bipyramidal (TBP) complexes 20. Thus, under low pressure of CO more isomerization may be expected. At low temperatures (<70°C) and a sufficiently high pressure of CO (>10 bar) the insertion reaction is usually irreversible and thus the regioselectivity and the enantioselectivity in the hydroformylation of alkenes is determined at this point. Complexes 20 undergo the second migratory insertion (see Scheme 3) to form the acyl complex 21, which can react with CO to give the saturated acyl intermediates 22 or with H2 to give the aldehyde product and the unsaturated intermediate 17. The reaction with H2 involves presumably oxidative addition and reductive elimination, but for rhodium no trivalent intermediates have been observed [54]. At low hydrogen pressures and high rhodium concentrations, the formation of dirhodium dormant species such as 23 becomes significant [55].

Recently, the full catalytic cycle for mono- and bis-ligated monophosphine Rh complexes has been investigated using DFT calculations [56].

As mentioned above, the catalytic hydroformylation of alkenes is one of the largest applications of homogeneous transition metal catalysis today. Due to the robustness of the process and the wide availability of alkene substrates, enantioselective hydroformylation provides high possibilities to obtain a great variety of enantiomerically pure aldehydes. The first Rh-based systems that were reported in the asymmetric hydroformylation contained diphosphine ligands provided low to moderate enantioselectivities [26, 27]. With this type of ligand, the highest ee value was reported using styrene as substrate and bdpp (bis-diphenylphosphino pentane) as ligand (ee’s up to 64%) [57]. Later, higher enantioselectivities were achieved using more sophisticated diphosphite and phosphine–phosphite ligands [6,7,8,9,10,11,12,13,14,15,16, 23]. The most successful ligands developed for this reaction were recently reviewed [58].

In the following sections, the most relevant results reported in the asymmetric Rh-catalyzed hydroformylation of alkenes are described. The reactions are classified by degree of substitution of the substrates in order to highlight the issue of the substrate/ligand compatibility in this process. For each family of substrates, the most successful ligands are described.

3 Rh-Catalyzed Asymmetric Hydroformylation of Monosubstituted Alkenes

The hydroformylation of monosubstituted alkenes (Scheme 4) was extensively studied due to the interest in the synthesis of linear aldehydes (non-chiral) or the enantioselective synthesis of 2-substituted branched aldehydes using chiral hydroformylation catalysts [4,5,6,7,8,9,10,11,12,13,14,15,16].

Scheme 4
scheme 4scheme 4

Asymmetric hydroformylation of monosubstituted alkenes

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For example, the hydroformylation of vinylarenes (R=aryl) is used as a model for the synthesis of 2-aryl propionaldehydes, which are intermediates in the synthesis of 2-aryl propionic acids, the profen class of non-stereoidal drugs. Nowadays, the application of the Rh-catalyzed asymmetric hydroformylation to obtain enantiomerically pure chiral aldehydes is growing. The Rh-catalyzed asymmetric hydroformylation of several other monosubstituted alkenes was successfully carried out, such as allyl cyanide and vinyl acetate [6,7,8,9,10,11,12,13,14,15,16]. In general, 1,3-diphosphite and phosphine–phosphite ligands provided the best results in these processes [23]. However, the use of bisphosphacyclic ligands has recently emerged as an efficient alternative [6,7,8,9,10,11,12,13,14,15,16].

3.1 1,3-Diphosphite Ligands

The use of disphosphite ligands was intensively studied in this process as they provide high levels of selectivity with these substrates [59]. The initial success in the rhodium-catalyzed asymmetric hydroformylation of vinylarenes came from Union Carbide with the discovery of the diphosphite ligand (2R, 4R)-pentane-2,4-diol 24 (Scheme 5) [60, 61].

Scheme 5
scheme 5scheme 5

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes 4a–c using ligands 24–28

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Good chemo-, regio-, and enantioselectivities (ee up to 90%) were obtained with (2R, 4R)-pentane-2,4-diol diphosphite derivatives (24a,d) but only when the reaction was performed around room temperature. Other research groups synthesized the series of diphosphite ligands 25–28 in order to study the effect of structural modifications on the Rh-catalyzed asymmetric hydroformylation of vinylarenes (Scheme 5) [62,63,64,65,66].

The influence of the bite angle of these ligands was studied with diphosphite ligands (2R, 4R)-pentane-2,4-diol 24, (2R, 3R)-butane-2,4-diol 25, and (2R, 5R)-hexane-2,4-diol 26 [63]. In general, the ligand 24, which contains a three carbon atoms bridge, provided higher enantioselectivities than ligands 25 and 26, which have a two and four carbon atoms bridge, respectively.

The effect of different phosphite moieties was studied with ligands 24a–g [62,63,64]. In general, sterically hindered phosphite moieties are necessary to achieve high enantioselectivities. The results indicated that varying the ortho and para substituents on the biphenyl and binaphthyl moieties has also a great effect on the asymmetric induction. The highest enantioselectivity (ee up to 90% at 20 bar of syngas and 25°C) in the Rh-catalyzed asymmetric hydroformylation of styrene was obtained by using ligands 24a and 24d.

The influence of the backbone was studied comparing the results obtained with the ligands 24 and 27 [62,63,64]. Surprisingly, the ligand 27, which contains a more sterically hindered phenyl group, provided lower enantioselectivity than ligand 24.

A cooperative effect between the different chiral centers of the phosphite ligands 24f–i and 28f–i was demonstrated. Initially, van Leeuwen and co-workers studied the cooperative effect between the chiral ligand bridge and the axially chiral binaphthyl phosphite moieties by comparing ligands 24f,g and 28f,g. The hydroformylation results indicated a suitable combination for ligand 24g (ee’s up to 86%) [62,63,64]. Later, Bakos and co-workers found a similar matched–mismatched effect between the chiral ligand bridge and the chiral phosphite moiety of the ligands 24h,i and 28h,i [65]. Interestingly, the hydroformylation results obtained with ligands 24a and 24d, that are conformationally flexible and contain axially chiral biphenyl moieties, are similar to those obtained with ligand 24g. This indicated that diphosphite ligands containing these biphenyl moieties predominantly exist as a single atropisomer in the hydridorhodium complexes [RhH(CO)2(diphosphite)] when bulky substituents are present in ortho positions [62,63,64]. It is therefore not necessary to use expensive conformationally rigid binaphthyl moieties.

To investigate whether a relationship exists between the solution structures of the [RhH(CO)2(diphosphite)] species and catalytic performance, van Leeuwen and co-workers extensively studied the [RhH(CO)2(diphosphite)] (diphosphite = 24, 28) species formed under hydroformylation conditions by high pressure NMR techniques (HP-NMR) [16, 23]. From these trigonal bipyramidal (TBP) complexes, two isomeric structures are possible: one containing the diphosphite coordinated in a bis-equatorial (eq–eq) fashion and one containing the diphosphite in an equatorial-axial (eq–ax) fashion (Scheme 3). The results indicated that the stability and catalytic performance of the [RhH(CO)2(diphosphite)] (diphosphite = 24, 28) species strongly depend on the configuration of the pentane-2,4-diol ligand backbone and on the chiral biaryl phosphite moieties. Thus, ligands 24a, 24d, and 24g, which form well-defined stable bis-equatorial (eq–eq) complexes, lead to good enantiomeric excesses. In contrast, the ligands 24i and 28g, which form mixtures of complexes, lead to low enantioselectivities [62,63,64, 67]. The ligand 24a was also evaluated in the Rh-catalyzed asymmetric hydroformylation of allyl cyanide 4b and vinyl acetate 4c but low to moderate enantioselectivities (13 and 58%, respectively) were obtained with these substrates [6].

1,3-Diphosphite ligands derived from 1,2-O-isopropyliden-α-d-xylofuranose (29, 32) and 6-deoxy-1,2-O-isopropyliden-α-d-glucofuranose (30, 31, 33, 34) were successfully applied in the Rh-catalyzed asymmetric hydroformylation of vinylarenes (Scheme 6) [68,69,70,71].

Scheme 6
scheme 6scheme 6

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using ligands 29–41

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The use of diphosphite ligands 30a,d and 34a,d in the Rh-catalyzed asymmetric hydroformylation of styrene provided the S- and R-enantiomers of the product with high enantioselectivies (ee up to 93%) and excellent regioselectivity (Scheme 6) [70, 71]. The ligand 30a was also tested in the hydroformylation of vinyl acetate obtaining excellent regioselectivity (99%) with an enantioselectivity of 73% [72].

Recently, related C1-symmetry diphosphite ligands conformationally more flexible (35–38) or incorporating an increase in steric hindrance at the C-6 position (39–41) were synthesized (Scheme 6) [72, 73]. These ligands were probed in the hydroformylation of styrene 4a and vinyl acetate 4c with good regio- and enantioselectivity (up to 81% and 68%, respectively), but these selectivities resulted to be lower than with the ligand 30. Therefore, the bicycle structure and the methyl substituent at C-5 position seem required to achieve high enantioselectivity in the hydroformylation of styrene and vinyl acetate when using 1,3-diphosphites derived from carbohydrates.

In summary, the results obtained in the Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes indicate that: (a) the absolute configuration of the product is governed by the configuration at the stereogenic center C-3; (b) the level of enantioselectivity is influenced by the presence of stereocenters at C-3 and C-5 positions, where the phosphorus atoms are attached; (c) bulky substituents in ortho positions of the biaryl phosphite moieties are necessary to achieve high levels of enantioselectivity; (d) pseudo-enantiomer ligands such as 30 and 34 afford the same level of enantioselectivity for both product enantiomers.

Interestingly, the ligands 30 and 34, for which only [RhH(CO)2(L)] species with eq–eq coordination were observed by HP-NMR techniques, provided higher enantioselectivity (ee up to 93%) than the related ligands 31 and 33 (ee up to 64%), for which an equilibrium between the isomeric eq–eq and eq–ax [RhH(CO)2(L)] species was observed by HP-NMR and HP-IR techniques. Therefore, the presence of a single coordination isomer, in this case with ligand coordinated in an equatorial–equatorial (eq–eq) mode, was observed to produce high levels of enantioselectivity in the Rh-catalyzed asymmetric hydroformylation of styrene, as previously mentioned [70,71,72,73].

In contrast with the diphosphites previously mentioned, the KELLIPHITE ligand (42), which was developed by Dow Chemical Company, incorporates the chirality in the bisphenol unit, while the backbone is achiral (Scheme 7). The catalytic system containing this ligand afforded very good enantioselectivity in the rhodium-catalyzed hydroformylation of vinyl acetate and allyl cyanide, although low selectivities were obtained in the hydroformylation of styrene [74, 75].

Scheme 7
scheme 7scheme 7

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using ligand KELLIPHITE (42)

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Recently, Vidal-Ferran and co-workers reported the use of polyether binders as regulation agents (RAs) to enhance the enantioselectivity of rhodium-catalyzed transformations (Scheme 8) [76, 77]. Using rhodium complexes bearing α,ω-bisphosphite-polyether ligands, the enantiomeric excess was increased by up to 82% in the asymmetric hydroformylation of vinyl benzoate (96% ee), This ligand design enabled the regulation of enantioselectivity by generation of an array of catalysts that simultaneously preserve the advantages of a privileged structure and offer geometrically close catalytic sites.

Scheme 8
scheme 8scheme 8

Supramolecularly regulated bisphosphite ligands with a distal regulation site reported by Vidal and co-workers

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3.2 Phosphine–Phosphite Ligands

The discovery of the (R,S)-BINAPHOS (44) and (S,R)-BINAPHOS (45) ligands in 1993 by Takaya and Nozaki produced a real breakthrough in the Rh-catalyzed asymmetric hydroformylation reaction (Scheme 9) [78].

Scheme 9
scheme 9scheme 9

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using (R,S)- and (S,R)-BINAPHOS (44) and (45)

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These ligands allowed for the first time an increase in the scope of this process since they provided high enantioselectivity in the Rh-catalyzed asymmetric hydroformylation of several classes of monosubstituted alkenes such as vinyl arenes, 1-heteroatom-functionalized alkenes, and disubstituted 1,3-dienes (Scheme 9), and is still currently a reference in this area [79,80,81,82,83,84,85,86,87,88,89,90 ]. Excellent regio- and enantioselectivity were achieved with most of these substrates, although the formation of the branched product (21%) was disfavored when but-1-ene was the substrate. In 2003, De Vries and co-workers reported the first Rh-catalyzed asymmetric hydroformylation of allylcyanide and although moderate regioselectivity was obtained (72%), the highest enantioselectivity (66%) by far was achieved using the ligand 44 [91]. As a general rule, the presence of electron-withdrawing substituents such as phenyl or heteroatoms in the alkene substrate leads to control the regioselectivity in favor of the branched product, independently of the ligand used [6].

It is noteworthy that (R,S)-BINAPHOS (44) or the (S,R)-BINAPHOS (45) ligands yield the two enantiomers of the product with high enantioselectivity; [92, 93] however, the (R,R)- and (S,S)-BINAPHOS, diastereoisomers of ligands 44 and 45, yielded much lower enantioselectivity in this process, thus demonstrating the importance of the combination of opposite configurations at the phosphine and phosphite moieties.

In contrast with the previously mentioned diphosphite ligands which coordinate to the Rh center in an eq–eq fashion, the BINAPHOS ligand was found to coordinate to Rh in an eq–ax mode as a single isomer in the resting state [RhH(CO)2(L-L)] of the process [92, 93]. Recently, DFT calculations on this system demonstrated that the coordination of the ligand with the phosphite moiety in apical position is crucial for the stereoselectivity of this reaction and that the presence of a second chiral center plays a role in determining the R or S configuration of the aldehyde product [94]. They also showed that for styrene, in the stereoselectivity determining transition state, the key substrate–ligand interactions occur between the styrene and the phosphite moiety and that these interactions are repulsive in nature.

The second generation of BINAPHOS-type ligands (Scheme 10) was developed by the introduction of 3-methoxy substituents on the aryl phosphine units 46 [80, 81], and by replacement of the phosphite group by a phosphoramidite function, yielding the YANPHOS ligand (47) (Scheme 10) [95]. The Rh/46 increased the regio- and enantioselectivity in the asymmetric hydroformylation of styrene, vinylfurans and thiophenes (Scheme 10). Recently, the use of (S,R)-Bn-YANPHOS was reported in the asymmetric hydroformylation of vinyl-heteroarenes such as pyrroles and provided excellent regio- and enantioselectivities (up to 96%) [96].

Scheme 10
scheme 10scheme 10

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using the ligands 46 and 47

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YANPHOS (47) (Scheme 10) provided higher enantioselectivity than the BINAPHOS ligand 44 without altering the regioselectivity in the Rh-catalyzed asymmetric hydroformylation of styrene and vinyl acetate (ee up to 99 and 98%, respectively). Additionally, the ligand 47 provided higher enantioselectivity than KELLIPHITE (42) (Scheme 7), although a slight decrease in regioselectivity (80 vs 94%) was observed in the hydroformylation of allyl cyanide (ee up to 96 vs 78%) [97].

Recently, the efficiency of YANPHOS ligand 47 was again demonstrated in the Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes with N-allylamides, N-allylphthalamides, and N-allylsulfonamides substituents with excellent ee’s (up to 96%), good regioselectivies (up to 84%), and a turnover number (TON) up to 9,700 [98].

DFT calculations on a series of chiral Rh catalysts proposed an explanation for the high enantioinduction observed for Rh–CHIRAPHITE, –BINAPINE, –diazaphospholane, and YANPHOS systems [99]. For BINAPINE and YANPHOS ligands, the main contribution to the selectivity was assigned to the naphthyl groups, while for CHIRAPHITE and diazaphospholane ligands, the tBu and chiral amine groups were highlighted as the key enantioinducting moieties. Importantly, in all cases, the effective placement of these groups to interact with the substrate is achieved through the coordination of phosphane moieties in the apical site of the complex.

Inspired by the excellent results obtained using 44 and 45, several new phosphine–phosphite ligands with different backbones were developed over the last years but the catalytic results using these ligands provided lower enantioselectivity (from 20 to 85%) than those previously achieved with the original BINAPHOS ligand [100,101,102,103,104,105]. Some of these ligands help to elucidate the correlation between the ee and the electronic withdrawing properties of the substituent on the alkene [106].

A new family of phosphine–phosphite and phosphine–phosphoramidite ligands was constituted using a Taddol-based backbone in the phosphite or phosphoramidite moiety, respectively (ligands 48 and 49, Scheme 11) [107, 108]. These ligands were applied in the Rh-catalyzed asymmetric hydroformylation of styrene, allyl cyanide, and vinyl acetate with excellent regioselectivities (up to 98%) and good ee’s (up to 85%). Recently, the group of Vidal-Ferran reported the use of two families of small bite angle phosphine–phosphite ligands 50a and 50b in the hydroformylation of styrene and vinyl acetate, obtaining excellent regioselectivity but with moderate ee’s (up to 74%) [109, 110]. Interestingly, the introduction of P-stereogenic center in ligands 50b slightly increased the ee when styrene was the substrate but resulted in a lower enantioinduction in the case of vinyl acetate. The use of the large bite angle ligands 51 containing a diphenylether backbone only provided moderate ee’s (up to 35%) in the Rh-catalyzed hydroformylation of styrene [111]. The synthesis of phosphine–phosphite ligands built on an α-cyclodextin scaffold was also reported recently and provided moderate regioselectivity (ca. 75%) and ee (50%) in the Rh-catalyzed hydroformylation of styrene [112].

Scheme 11
scheme 11scheme 11

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using Taddol-based ligands (48 and 49) and phosphine–phosphite ligands (50) and (51)

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Reek and co-workers reported the use of supramolecular phosphine–phosphoramidite hybrid ligands in the Rh-catalyzed hydroformylation of styrene derivatives (Scheme 12) [113]. They observed that the electronic and steric properties of the M(II) (M = Zn, Ru) templates had a significant influence on the activity and selectivity of the catalytic reaction. Using styrene as substrate, ee’s up to 59% were obtained using ligand 54.

Scheme 12
scheme 12scheme 12

Asymmetric hydroformylation of styrene using supramolecular phosphine–phosphoramidite ligands

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The production of chiral aldehyde from simple terminal alkyl olefins of formula RCH2CH=CH2 with high regio- and enantioselectivity has been aimed for many years and a large set of ligands was probed in this reaction. However, poor regioselectivity was usually obtained, the linear aldehyde is preferably formed in most cases, although interesting ee’s were achieved, for instance, using the BINAPHOS ligand [87]. However, the phosphine–phosphite ligand BOBPHOS (Scheme 13) was recently reported to be efficient in the production of branched aldehydes from alkyl alkenes with high regioselectivity and ee’s (Scheme 13) [114].

Scheme 13
scheme 13scheme 13

Rh-catalyzed asymmetric hydroformylation of terminal alkyl alkenes using the BOBPHOS ligand 55

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3.3 Bisphosphacyclic Ligands

Several bisphospholane chiral ligands known as efficient ligands for asymmetric hydrogenation were recently evaluated in asymmetric hydroformylation (Scheme 14) [115].

Scheme 14
scheme 14scheme 14

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using the diphosphine ligands 56–61

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Two ligands, namely (S)-BINAPINE (56) and (S,S,R,R)-TANGPHOS(57), were found to give excellent enantioselectivities in the asymmetric hydroformylation of styrene, allyl cyanide, and vinyl acetate (Scheme 14) [98]. It is noteworthy that the enantioselectivities achieved for product 5b with these ligands are the highest ever reported for the allyl cyanide substrate. Recently, the ligand BIBOP 58 was reported to provide excellent results in the asymmetric hydroformylation of vinyl acetate and allylic substrates [116].

The discovery of the biphospholane scaffold as a new privileged structure for asymmetric alkene hydroformylation has triggered new research efforts for novel and improved bisphospholane-type ligands. In this context, the (R,R)-Ph-BPE ligand (59) (Scheme 14), derivative of DuPhos, was identified as an outstanding ligand for asymmetric hydroformylation since excellent regio- and enantioselectivities were achieved for styrene, allyl cyanide, and vinyl acetate as substrates with this ligand [117]. Several spacers between the two phosphorus donor atoms were evaluated and the two carbon bridge of 59 provided the highest selectivity for all three substrates [118]. Recently, both enantiomers of ligand were also utilized in the Rh-catalyzed asymmetric hydroformylation of vinylarenes using formaldehyde as a substitute of syngas providing excellent regioselectivity and enantioselectivity (up to 95%) [119]. This ligand also provided excellent results in the branched selective asymmetric hydroformylation of a wide range of 1-alkenes, including 1-dodecene, with regioselectivity up to 93% and enantioselectivity up to 96% [120].

A series of bis-2,5-diazaphospholane ligands was also probed in this process and the ESPHOS (60) proved to be optimal, with the best results being obtained in the hydroformylation of vinyl acetate (ee up to 89%) (Scheme 14) [121]. The bis-3,4-diazaphospholane ligand 61a also provided excellent regio- and enantioselectivity (ee up to 96%) in this reaction (Scheme 14) [122]. Immobilization of ligand 61a onto resins and silica supports was also recently reported and provided similar performances to those of the homogenous systems with high regio- and enantioselectivity for the Rh-catalyzed hydroformylation of styrene and vinyl acetate [123]. Using these systems, excellent recyclability with only trace levels of Rh leaching was observed in batch and flow reactor conditions. It is noteworthy that silica supported systems provided poorer enantioselectivities that resin-supported catalysts. Recently, a detailed spectroscopic characterization of catalytic Rh intermediates bearing ligand 61a was reported for the hydroformylation of octene, vinyl acetate, allyl cyanide, and 1-phenyl-1,3-butadiene [124].

This catalytic system was recently used for the continuous flow asymmetric hydroformylation of 2-vinyl-6-methoxynaphthalene during 8h of reaction using a reactor consisting of 20 vertical bubble pipe-in-series connected by small tubing jumpers [125, 126].

Two derivatives of the ligand 61a were also used in the synthesis of the Prelog–Djerassi Lactone via an asymmetric hydroformylation/crotylation tandem sequence in which the hydroformylation step provided 93% ee (Scheme 15).

Scheme 15
scheme 15scheme 15

Synthesis of the Prelog–Djerassi Lactone via asymmetric hydroformylation/crotylation tandem sequence in the presence of derivatives of ligand 61a

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The sequential asymmetric hydroformylation/aerobic aldehyde oxidation was recently reported using the same ligand, providing an access to α-chiral carboxylic acids without racemization [127].

3.4 Bis-Phosphonite Ligands

The bis-phosphonite ligand 62 provided moderate selectivities in the hydrofomylation of styrene and allyl cyanide (Scheme 16). However, this ligand provided an excellent 91% ee in the hydroformylation of vinyl acetate [128]. The related diphosphinite ligand derived from ferrocene 63 was also reported by Ding and co-workers and its application in the Rh-catalyzed asymmetric hydroformylation of styrene and vinyl acetate provided good conversion but lower enantioselectivities in the hydroformylation of styrene and vinyl acetate (up to 55% and 83%, respectively) [129] More recently, a family of TADDOL-derived bis-phosphonite ligands was reported, among which the ligands 64 and 65 provided excellent enantioselectivity in the asymmetric hydroformylation of styrene and derivatives [130].

Scheme 16
scheme 16scheme 16

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes with ligands 62–65

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3.5 Bis-Phosphinite Ligands

The diastereogenic bis-phosphinite ligands 66 and 67 were recently reported by Leitner and co-workers (Scheme 17) [131]. The Rh-catalysts bearing these binol-based ligands containing chiral phospholane units provided good regioselectivity for the branched products but only low to moderate selectivities in the hydrofomylation of styrene and vinyl acetate. It is noteworthy that the diastereoisomer 67 provided higher ee than 66 while the opposite trend was observed in the asymmetric hydrogenation of dimethyl itaconate.

Scheme 17
scheme 17scheme 17

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes with ligands 66 and 67

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3.6 Monodentate Phosphorus-Based Ligands

Nowadays, despite the successful use of monodentate ligands in many transition metal-catalyzed processes, there are only a few reports concerning their use in asymmetric hydroformylation and achieving high enantioselectivities in this process using those ligands remains a challenge.

Recently, an Rh complex bearing the monodentate phosphoramidite ligand encapsulated in a self-assembled molecular cage 68 (Scheme 18) provided the highest enantioselectivity (74%) in the asymmetric hydroformylation of styrenes using monoligated catalyst [132]. The presence of the cage was shown to enhance the enantioinduction of the catalyst and can therefore be considered as a second coordination sphere that is reminiscent of enzymatic active sites.

Scheme 18
scheme 18scheme 18

Rh-catalyzed asymmetric hydroformylation of styrene using Rh/monodentate phosphoramidite catalyst encapsulated in a self-assembled molecular cage

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The monophosphite ligand 69 was tested in the Rh-catalyzed asymmetric hydroformylation of styrene and allyl cyanide and provided moderate enantioselectivities (Scheme 19). When vinyl acetate was the substrate, very poor ee’s were obtained (Scheme 19) [74, 75]. However, in 2004, Ojima and co-workers reported the use of the phosphoramidite ligand 70 (Scheme 19), related to monophosphite 69, in the Rh-catalyzed asymmetric hydroformylation of allyl cyanide and achieved excellent regioselectivities together with the highest enantiomeric excess (80%) ever reported for this reaction with a monodentate ligand [133].

Scheme 19
scheme 19scheme 19

Rh-catalyzed asymmetric hydroformylation of monosubstituted alkenes using ligands 69 and 70

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These results, although still far from those obtained with bidentate ligands, clearly indicated that achieving high ee’s using mondentate ligands is possible. Later, Alexakis, Pamies, Dieguez, and co-workers reported the testing of monodentate phosphoramidite and aminophosphine libraries in the asymmetric hydroformylation of styrene derivatives [134]. However, only ee’s up to 50% could be achieved.

In 2005, Breit reports an alternative approach to the classical synthesis of bidentate ligands for hydroformylation by using the self-assembly of bidentate ligands based on an A-T base-pair model [135]. This method presents the advantage of allowing the rapid screening of various pairs of available monodentate ligands to obtain the most suitable combination for each substrate, overcoming the typical synthetic limitations for new bidentate ligands. Later, van Leeuwen and Reek reported the template-induced formation of chelating heterobidentate ligands by the self-assembly of two distinct monodentate ligands on a rigid bis-zinc(II)-salphen template with two identical binding sites (Scheme 20) [136, 137]. The templated heterobidentate ligand 71 induced much higher enantioselectivities (ee up to 74%) than any of the corresponding homobidentate ligands or non-templated mixed ligand combinations (ee up to 13%) in the Rh-catalyzed asymmetric hydroformylation of styrene.

Scheme 20
scheme 20scheme 20

Rh-catalyzed asymmetric hydroformylation of styrene using the templated ligand 71

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4 Other Monosubstituted Alkene Substrates

In this section, recent reports on the Rh-catalyzed asymmetric hydroformylation of “non-common” monosubstituted alkene substrates using chiral phosphorus donor ligands are presented.

The substrate scope for the hydroformylation of dialkylacrylamides 4d 1 –d 4 has so far been limited to methacrylamide, acrylamide, or N-benzylacrylamide, with low enantioinduction (20–50% ee’s) [138, 139].

However, the use of a bis-diazaphospholane ligand (61a) in the Rh-catalyzed asymmetric hydroformylation of N,N-dialkylacrylamides was recently described achieving nearly total regioselectivity and ee’s up to 82% (Scheme 21) [140].

Scheme 21
scheme 21scheme 21

Rh-catalyzed asymmetric hydroformylation of N,N-dialkylacrylamides

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The use of the bis-3,4-diazaphospholane type ligands has also been reported in the rhodium-catalyzed hydroformylation of several 1,3-diene substrates (1,3-dienes, N-vinyl carboxamides, allyl carbamates, and allyl ethers) with excellent regio- and enantioselectivities by Landis et al. [141, 142]. Total conversions with good regioselectivities (>88%) and excellent enantioselectivities (91–97%) were achieved (Scheme 22).

Scheme 22
scheme 22scheme 22

Rh-catalyzed asymmetric hydroformylation of 1,3-dienes with ligands 61a and 72

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The ligand 61a was also successfully employed in the Rh-catalyzed asymmetric hydroformylation of other alkene substrates containing amine (4f) and ether (4g) substituents, with ee’s up to 99% and 97%, respectively [142] (Scheme 23).

Scheme 23
scheme 23scheme 23

Rh-catalyzed asymmetric hydroformylation of monosubstituted enamides and other allylic substrates with the ligand 61a

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Recently, Leitner, Francio, and co-workers reported the highly regio- and enantioselective hydroformylation of vinyl esters using the bidentate phosphine, P-chiral phosphoramidate ligands [143]. The BettiPhos ligand 73 was particularly efficient and provided total regioselectivity and ee’s up to 97% for a number of these substrates (Scheme 24).

Scheme 24
scheme 24scheme 24

Rh-catalyzed asymmetric hydroformylation of vinyl esters using the BettiPhos ligand 73

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5 Rh-Catalyzed Asymmetric Hydroformylation of Disubstituted Alkenes

The Rh-catalyzed asymmetric hydroformylation of disubstituted alkenes has received much less attention than their monosubstituted counterparts. To the best of our knowledge, only a few examples of asymmetric Rh-catalyzed hydroformylation of 1,2-disubstituted and 1,1-disubstituted alkenes have been reported so far (Scheme 2) [26, 143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180].

5.1 Linear 1,2-Disubstituted Alkenes

The 1,3-diphosphite ligand 29 was used in the Rh-catalyzed asymmetric hydroformylation of trans-anethole 8a and estragole 8b (Scheme 25) but moderate to low enantioselectivities were achieved (ee up to 15%) [145].

Scheme 25
scheme 25scheme 25

Isomerization processes and asymmetric hydroformylation of trans-anethole and estragole

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Nozaki and co-workers reported the asymmetric Rh-catalyzed hydroformylation of trans-anethole 8a into 9a using the BINAPHOS ligand 44 with excellent regioselectivity (98%) and a remarkable 80% ee [146, 147].

In the Rh-catalyzed asymmetric hydroformylation of 1,2-alkyl-disubstituted alkenes (Scheme 26) as substrates, the BINAPHOS ligand 44 provided high ee values [146, 147]. Interestingly, it was reported that the E-isomers 11b and 11d yielded lower enantioselectivity than their Z-counterparts 11a and 11c.

Scheme 26
scheme 26scheme 26

Rh-catalyzed asymmetric hydroformylation of disubstituted alkenes

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More recently, a monodentate phosphoramidite template ligand was used in the asymmetric Rh-catalyzed hydroformylation of trans-2-octene (Scheme 27). This ligand (74) exhibits a supramolecular control over the Rh center, due to the presence of two pyridine functions in the bis(naphthol) skeleton that are bounded to zinc(II) porphyrins. With this ligand, useful conversions (up to 56%) with moderate ee’s (up to 45%) were achieved. When the BINAPHOS ligand 44 was used in the same reaction, similar conversion (55%) was obtained although without significant enantioinduction [148]. More recently, a new supramolecular ligand 75 (Scheme 27) containing two phosphoramidite moieties was reported, providing remarkable enantioselectivities in the asymmetric hydroformylation of internal alkenes [149].

Scheme 27
scheme 27scheme 27

Rh-catalyzed asymmetric hydroformylation of internal alkenes with the ligands 44, 74, and 75

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Very recently, Landis and co-workers showed that the diazaphospholane ligand 61a could provide high enantioselectivity in the hydroformylation of Z-enamides and enol esters, providing excellent enantioselectivities for a broad range of these substrates (Scheme 28) [150].

Scheme 28
scheme 28scheme 28

Rh-catalyzed asymmetric hydroformylation of Z-enamides and enol esters with the (S,S,S)-bis diazaphos ligand 61a reported Landis and co-workers

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Using the same ligand 61a, Burke and Risi reported the total synthesis of (+)-patulolide C, which exhibits both antifungal and antibacterial activities [151, 152], through a methodology based upon Rh-catalyzed asymmetric hydroformylation (Scheme 29) [153]. This synthetic method included an Rh-catalyzed hydroformylation/intramolecular Wittig olefination to set the C4-hydroxyl stereochemistry and E-olefin geometry and form the macrolactone, which afforded a very short, high-yielding synthesis of this compound, which usually required over 14 steps. The hydroformylation substrate is therefore an E-1,2-disubstituted alkene bearing an acetate and an alkyl substituent.

Scheme 29
scheme 29scheme 29

Synthesis of (+)-patulolide C via Rh-catalyzed asymmetric hydroformylation/macrocyclization cascade using ligand 61a

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More recently, the same authors also employed this ligand in the synthesis of other biologically relevant molecule using asymmetric hydroformylation as the key step [55, 154].

5.2 Scaffolding [156] Ligands

The term “catalyst-directing groups” was defined for organocatalysts that are able to form simultaneously covalent bonds with a substrate and dative bonds with a metal catalyst, which allow them to direct metal-catalyzed transformations [157]. In general, these “scaffolding ligands” were named by analogy with scaffolding proteins, which promote biological processes [158].

Using such methodology, the groups of Tan and Breit reported the highly regioselective Rh-catalyzed hydroformylation of homoallylic alcohols [157, 159]. Tan et al. designed the alkoxy benzoazaphophole ligand 76 derived from N-methylaniline that undergo facile exchange with other alcohols or secondary amines (Scheme 30) [141, 142].

Scheme 30
scheme 30scheme 30

Alkoxy benzoazaphosphole catalytic directing group

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The asymmetric hydroformylation of several alkene substrates was performed by Tan and co-workers using scaffolding ligands containing a tetrahydroisoquinoline group on the alkoxy benzoazaphosphole yielding the scaffolding ligand 78 (Scheme 31).

Scheme 31
scheme 31scheme 31

Tetrahydroisoquinoline alkoxy benzoazaphosphole scaffolding ligand

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More recently, the group of Tan reported the use of ligands containing an oxazoline moiety able to bind alcohols (Scheme 32) [160]. They applied these ligands in the diaseteroselective hydroformylation of homoallylic alcohols to afford β-lactams with excellent regio- and diastereoselectivities.

Scheme 32
scheme 32scheme 32

Rh-catalyzed diaseteroselective hydroformylation of homoallylic alcohols using the scaffolding ligand 80

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The Breit research group demonstrated that Ph2POMe was a suitable catalytic directing group for hydroformylation [157]. Notably, the functionalization of 1,2-disubstituted olefins and other substrates containing stereocenters proceeded with excellent regio- and stereoselectivity. Additionally, the chemoselective hydroformylation of homoallylic alcohols over unactivated alkenes was observed.

5.3 Monocyclic 1,2-Disubstituted Alkenes

Among monocyclic 1,2-disubstituted alkene substrates, 5-membered ring heterocycles such as dihydrofurans and dihydropyrroles have been the most studied. With these substrates, the simultaneous control of the chemo-, regio-, and enantioselectivity is a key issue since the presence of a heteroatom in the cycle favors in some cases an isomerization process in the presence of a metal-hydride species. Previous studies using achiral ligands demonstrated that the reaction conditions highly affected the chemo- and regioselectivity of this reaction [161, 162]. Indeed, allyl ethers were shown to rapidly isomerize into its vinyl analogue under hydroformylation conditions (Scheme 33). This isomerization process is of critical importance since it has a direct influence not only on the regioselectivity of the reaction, but also on the enantioselectivity since the opposite enantiomers of tetahydro-3-carbaldehyde are formed from the allylic 17a and vinylic 17b isomers of the substrate [163]. It is therefore required to limit the isomerization in order to obtain high selectivities.

Scheme 33
scheme 33scheme 33

Isomerization processes observed during the Rh-asymmetric hydroformylation of five-membered heterocyclic alkenes

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In the Rh-catalyzed asymmetric hydroformylation of 2,5-dihydrofuran 17a, Nozaki and co-workers reported the first successful results using the BINAPHOS ligand 44 which yielded total regioselectivity to the tetahydro-3-carbaldehyde 18a with 68% ee (R) (Scheme 34) [146, 147, 164]. However, when the 2,3-dihydrofuran 17b was tested with the same catalyst, no regioselectivity was observed and the ee obtained for the aldehyde 18b decreased to 38% with S configuration. This catalytic system was thus suitable to avoid isomerization of 17a into 17b but not selective for the hydroformylation of 17b. In the same study, the amine analogues 17c,d and 17e were also tested as substrates using the same catalytic system (Scheme 34) and similar results were obtained.

Scheme 34
scheme 34scheme 34

Rh-catalyzed asymmetric hydroformylation of five-membered heterocyclic alkenes 17a–e

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Recently, the previously mentioned 1,3-diphosphites 30, 40 (Scheme 6) derived from carbohydrates were successfully applied in the Rh-catalyzed hydroformylation of these substrates [72, 165, 166]. The results indicated that ligands 30, 38–40, which have a glucose configuration, are the most appropriate to obtain high enantioselective induction in the hydroformylation of these substrates. In the case of the 2,5-dihydrofuran 17a, the highest enantioselectivity in the aldehyde 18a was obtained using ligand 38b (88% S). Using this ligand, no isomerization was observed under hydroformylation conditions. Interestingly, the presence of bulky substituents at C-5 such as in ligands 39b–40b was shown to increase the degree of isomerization. When the 2,3-dihydrofuran (17b) was used as substrate, ee’s up to 84% (R) in aldehyde 18b were achieved using ligands 39b–40b, together with a regioselectivity of 80%. The 2,5-dihydropyrrole 17d was also tested with the Rh/30b system, achieving comparable results to those previously reported using ligand 44 (71 and 66%, respectively) (Scheme 9).

Reek and co-workers described the synthesis and application of the ligand 81, containing a skeleton related to the Xantphos diphosphine ligand, in the Rh-catalyzed asymmetric hydroformylation of the dihydrofurans 17a and 17b (Scheme 34). This system provided regioselectivities of 99 and 80%, respectively, and very high enantioselectivities (up to 91%) for these substrates [167, 168]. Recently, Zhang and co-workers reported the Rh-asymmetric hydroformylation of five-membered heterocyclic alkenes using a derivative of the diazaphospholane ligand 82 developed by Landis (Scheme 34) [169]. This system provided excellent regio- and enantioselectivities (up to 92%) for several of these substrates. Vidal-Ferran and co-workers also reported the use of the small bite angle phosphine phosphite ligand 50a (Scheme 11) in the same reaction [109]. When the dihydrofuran 17a was the substrate, they obtained total regioselectivity and ee’s up to 72%, while moderate regioselectivity and ee’s up to 76% were obtained when 17b was tested.

More recently, the same authors reported the use of conformationally transformable α,ω-bisphosphite ligands combined with an alkali metal BArF salt as a regulation agent (RA) [77]. These ligands provide enantioselectivities up to 82% in the asymmetric hydroformylation of 2,5-dihydrofuran 17a and 2,3-dihydrofuran 17b.

The asymmetric Rh-catalyzed hydroformylation of dioxapines 20a,b was reported using the BINAPHOS ligand 44 and 1,3-diphosphite ligands derived from carbohydrates 83 (Scheme 35) [146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166]. Using the ligand 44, total regioselectivity to 21a,b was achieved, together with ee’s up to 76%. Among the carbohydrate derived ligands that were tested, the ligand 83 provided the best results (Scheme 35), affording total regioselectivity to 21a,b and up to 68% ee and thus indicating that no isomerization of 20a,b had occurred. More recently, Vidal-Ferran and co-workers reported the highest ee in the asymmetric hydroformylation of the dioxapines 20a by using an Rh-complex bearing the disphosphite 84 (Scheme 35) [77].

Scheme 35
scheme 35scheme 35

Rh-catalyzed asymmetric hydroformylation of 20a,b

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In 2012, the application of the asymmetric hydroformylation of cyclic disubstituted olefins was employed to provide useful chiral molecules like the Garner’s aldehyde, a popular building block [170, 171]. Both enantiomers of this molecule were prepared through this reaction using catalytic systems bearing the diastereoisomeric bis-diazaphospholane ligands 61a and 61b (Scheme 36) [172]. The S enantiomer can be produced in 97% ee in the presence of (S,S,S)-61a while the R product is formed with a slightly lower ee’s (94%), using the ligand (R,R,S)-61b. The reactions were run on a ca. 5 mmol scale at 55°C under 10 bar of syngas (1:1) using 2 mol% Rh catalyst.

Scheme 36
scheme 36scheme 36

Synthesis of Garner’s aldehyde through Rh-catalyzed asymmetric hydroformylation of the cyclic disubstituted olefin N-Boc-2,2-dimethyl-2,3-dihydrooxazole 23

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5.4 Bicyclic 1,2-Disubstituted Alkenes

The Rh-catalyzed asymmetric hydroformylation of substrates 25a and 25b was reported by Nozaki and co-workers using the ligands 44 and 85 (Scheme 37) [146, 147]. The results are really remarkable, in particular with substrate 25b, for which compound 26b was obtained with practically total regio- and enantioselectivity (Scheme 37). The corresponding products 26a and 26b are of interest since the aldehyde 26a can be converted in a single step into the corresponding amine which exhibits hypotensive activity and the product 26b is a synthetic intermediate to produce a vasoconstrictor tetrahydrozoline [173].

Scheme 37
scheme 37scheme 37

Rh-catalyzed asymmetric hydroformylation of bicyclic alkenes using the ligands (R,S)-BINAPHOS (44) and BIPHEMPHOS (85)

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Another bicyclic alkene substrate of interest for carbonylation reactions is the norbornene 28 and its derivatives. The first reports on the asymmetric Rh-hydroformylation of norbornene afforded low enantiomeric induction with ee’s below 25% [174, 175]. In 2005, Bunel and co-workers reported the first highly enantioselective Rh-catalyzed hydroformylation of norbornene into the exo aldehyde using diphospholane ligands, reaching ee’s up to 92% with the TANGPHOS ligand 50 [176]. Using the same ligand, they also reported the hydroformylation of several derivatives of this substrate with similar enantioselectivities (Scheme 38).

Scheme 38
scheme 38scheme 38

Rh-catalyzed asymmetric hydroformylation of norbornene derivatives using the diphospholane ligand 57

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Recently, the hemispherical diphosphite ligands 86 (Fig. 1) with a conical calixarene skeleton was used in the asymmetric Rh-hydroformylation of norbornene, achieving enantioselectivities up to 61% with the exo aldehyde being the major product [177].

Fig. 1
figure 1figure 1

Hemispherical diphosphite ligands 86 with a conical calixarene skeleton

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More recently, the KELLIPHITE ligand (42) was employed in the Rh-catalyzed asymmetric hydroformylation of bicyclic lactam azababicyclo-[2.2.1]hept-5-en-3-ones with very good results. The reaction was completely exo-selective, yielding total conversions and excellent regioselectivities (up to 90%) [178] (Scheme 39).

Scheme 39
scheme 39scheme 39

Rh-catalyzed asymmetric hydroformylation of bicyclic lactam azababicyclo-[2.2.1]hept-5-en-3-ones using the KELLIPHITE ligand 42

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5.5 1,1′-Disubstituted Alkenes

The asymmetric hydroformylation of 1,1′-disubstituted alkenes differs from the classical asymmetric hydroformylation of monosubstituted terminal alkenes since the desired product is the linear aldehyde (Scheme 2) [179].

Indeed, the Rh-catalyzed asymmetric hydroformylation of 1,1-methylstyrene (38a) using diphosphite ligand 87 (Scheme 40) to form the linear product (40a) was recently patented. The enantioselectivity was, however, moderate (ee up to 46%) [180].

Scheme 40
scheme 40scheme 40

Rh-catalyzed asymmetric hydroformylation of 1,1′-disubstituted alkenes

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Interestingly, when dehydro amino acid derivatives 38b and dimethyl itaconate 38c were used as substrates (Scheme 40) in the presence of [RhH(CO)(PPh3)3] and 1–6 equivalents of the (R,R)-DIOP ligand 88, the formation of the branched products was largely favored with moderate enantioselectivity (ee’s up to 59%). In this process highly functionalized quaternary carbons are easily obtained from common products. This interesting reaction deserves more attention by researchers in the field. It should be noted that when the α,β-unsaturated carboxylic compounds such as 38c are hydroformylated in the presence of the [PtCl(SnCl3)], the only hydroformylation product obtained was the linear aldehyde with ee’s up to 82% [26].

Recently, Buchwald et al. reported the Rh-catalyzed asymmetric hydroformylation of 1,1-disubstituted alkenes (α-alkylacrylates) using the 1,3-diphosphine ligand BenzP (89). With this ligand, good regio- (up to 91%) and enantioselectivities (up to 94%) were achieved (Scheme 41) [181]. The fine-tuning of the partial pressures of CO/H2 minimizes the problem of the side reactions; in fact, the mild reaction conditions make it safe for general laboratory use (10 bar 1:5 CO/H2, 100°C).

Scheme 41
scheme 41scheme 41

Rh-catalyzed asymmetric hydroformylation of α-alkylacrylates

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More recently, the same authors reported the asymmetric hydroformylation of 3,3,3-trifluoroprop-1-en-2-yl acetate 39h using the P-stereogenic ligands QuinoxP (90) and DuanPhos (91) with 92% ee [182]. After oxidation of the resulting aldehyde and hydrolysis, crystallization provided enantiomerically pure 2-trifluoromethylallylic acid.

6 Conclusions

Rhodium is currently the metal of choice to achieve high enantioselectivities in the hydroformylation of a relatively large variety of alkene substrates. The elucidation of the different steps of the catalytic cycle and the characterization of the resting state, together with the discovery of several types of ligands that are able to provide high enantioselectivities, have made the rhodium-catalyzed hydroformylation a synthetically useful tool.

In the catalytic cycle, the complex 16 has been identified as the resting state of the process. An important feature for bidentate ligands is their possible coordination to the rhodium center in eq–eq or eq–ax fashions. Indeed, although the enantioface discrimination occurs at the alkene coordination step from the square-planar species 17, experimental observations showed that high enantioselectivity in asymmetric hydroformylation of alkenes is obtained using ligands that lead to the formation of only one isomer of the resting state 16. This fact could be attributed to the similitude in the structures of the Rh hydride species 16 and 18. The co-existence of the two possible isomers in solution was shown to always provide lower enantioselectivity.

Commonly, the synthesis of a chiral compound by asymmetric hydroformylation involves the introduction of a formyl group in a substituted olefinic carbon. This process has been widely studied mainly for monosubstituted alkenes. However, since the favored process is usually the introduction of this group in the less substituted carbon, this transformation is only useful for substrates containing electron-withdrawing group(s) (R = Ph, heteroatom) which direct the introduction of the formyl group in the most substituted carbon. Consequently, a regioselectivity problem must be first considered. The presence of a functional group at the allylic position, which contributes to stabilize the double bond, always supposes an additional issue, since isomerization takes place easily. This isomerization can be controlled by the appropriate choice of ligand and reaction conditions. For instance, increasing the CO pressure and/or decreasing the reaction temperature reduce the degree of isomerization.

Furthermore, low temperatures (<70°C) are usually required to achieve high enantioselectivities although under these conditions, the reaction rate is usually low. A way to partially circumvent this problem is increasing the H2 pressure thus shifting the equilibrium from the inactive complex 23 towards the active species 16.

1,2-Disubstituted substrates are particularly challenging when similar substituents such as alkyl substituents are present in both positions. However, higher regio- and enantioselectivity can be achieved when one of the substituents direct the regioselectivity, as is the case of 2,3-dihydrofuran, dihydropyrrol, indene, or 1,2-dihydronaphthalene. In the case of symmetrically substituted alkenes such as 2,5-dihydrofuran and norbornene, no regiocontrol is required and high activities and enantioselectivities have been achieved in asymmetric hydroformylation.

1,1-Disubstituted or 1,1,2-trisubstituted are more challenging substrates. The general trend is the introduction of the formyl group onto the less substituted carbon, thus creating the chiral center at the more substituted carbon atom. This trend is respected in the hydroformylation of such substrates using Pt catalysts, achieving high regio- and enantioselectivities. Interestingly, it is also possible to introduce the formyl group at the more substituted carbon using Rh catalysts, thus creating a highly functionalized chiral quaternary center.

For years, ligands containing phosphite moieties such as diphosphites and phosphine–phosphites were considered as the most successful ligands to achieve high enantioselectivies. For instance, diphosphite ligands 24, 30, and 42 are highly effective in the asymmetric Rh-catalyzed hydroformylation of several alkene substrates and the phosphite–phosphine BINAPHOS (44) or its derivatives 46 and 47 have been very successful ligands in terms of selectivity and scope. Recently, however, diphosphines in which the P atoms are incorporated in a ring (56–59) have also shown to induce high levels of enantioselectivity in this process. Furthermore, diazaphospholane ligands 61a, 61b, and 72 are currently the most efficient ligand in the asymmetric hydroformylation of alkenes, with exceptional results in terms of regio- and enantioselectivity. These ligands have also been successfully immobilized onto solid support in order to recycle and reuse the corresponding catalysts and employ them under continuous conditions. Over the last years, these ligands were also applied in the enantioselective hydroformylation of specific substrates for the synthesis of various organic molecules of biological and/ or synthetic interest.

It can consequently be concluded that the key to achieve high enantioselectivities is not the type of phosphorus function involved in the coordination to the metal, but the particular spatial arrangement of the coordinated ligand. Furthermore, recently, supramolecular strategies have also been very successful in asymmetric hydroformylation, clearly indicating that the control of the second coordination sphere could be key to reach selectivity for challenging substrates.

Nowadays, a variety of chiral products incorporating a formyl unit can be enantioselectively prepared by Rh-catalyzed asymmetric hydroformylation and this process can therefore be considered as a powerful and useful tool in organic synthesis.

Recently, an Rh catalyst was reported to convert alkenes to aldehydes without the need of gases through transfer hydroformylation [183, 184]. In this promising process, the catalyst transfers the equivalent of H2 and CO between a sacrificial aldehyde and an alkene under mild conditions without evolving gases. Although this reaction is still at a very early stage, the development of efficient catalysts for the control of the selectivity could provide a general method for the formation of chiral aldehydes without the need of syngas.