ASYMMETRIC HYDROFORMYLATION PROCESS

Field of the invention

This invention relates to asymmetric hydroformylation processes in which a prochiral or chiral olefin is reacted with carbon monoxide and hydrogen in the presence of an optically active metal-diphosphine complex catalyst to produce an optically active aldehyde or a product derived from an optically active aldehyde.

Background to the invention

Asymmetric synthesis is of importance, for example, in the pharmaceutical industry, since frequently only one optically active isomer (enantiomer) is therapeutically active. An example of such a pharmaceutical product is the non-steroidal anti- inflammatory drug Naproxen. The (5)-enantiomer is a potent anti-arthritic agent while the (i?)-enantiomer is a liver toxin. It is therefore often desirable to selectively produce one particular enantiomer over its mirror image.

It is known that special techniques must be employed to ensure production of a desired enantiomer because of the tendency to produce optically inactive racemic mixtures; that is, equal amounts of each mirror image enantiomer whose opposite optical activities cancel out each other. In order to obtain the desired enantiomer (mirror image stereoisomer) from such a racemic mixture, the racemic mixture must be separated into its optically active components. This separation, known as optical resolution, may be carried out by actual physical sorting, direct crystallization of the racemic mixture, or other methods known in the art. Such optical resolution procedures are often laborious and expensive and normally the yield of the desired enantiomer is less than 50% based on the racemic mixture feedstock. Due to these difficulties, increased attention has been placed upon asymmetric synthesis in which one of the enantiomers is obtained in significantly greater amounts. In particular, asymmetric synthesis processes facilitated by catalysis with transition metal complexes of single enantiomer chiral ligands (asymmetric catalysis) is finding ever increasing industrial applicability for the production of pharmaceuticals and other fine chemicals.

Asymmetric hydroformylation of olefins is especially valuable for the synthesis of optically active products, since the reaction is a one-carbon homologation that establishes a chiral center and exceedingly versatile aldehyde functionality. Efficient asymmetric hydroformylation desirably affords the ability to control both regioselectivity (branched/linear ratio) and enantioselectivity. The optically active aldehyde that is produced in asymmetric hydroformylation can be further elaborated into other functional groups, either by subsequent reaction steps or via in situ reaction with other reagents. Accordingly, asymmetric hydroformylation of olefins and related homologation processes may provide a pivotal transformation in the synthesis of complex molecules, particularly pharmaceutically active compounds.

Various asymmetric hydroformylation catalysts have been described in the art, see van Leeuwen, P.W.N.M. and Claver, C, "Rhodium Catalyzed Hydroformylation", Kluwer Academic Publishers, Dordrecht, 2000. For example, Stille, J. K. et al.,

Organometallics 1991, 10, 1183-1189 relates to the synthesis of three complexes of platinum(II) containing the chiral ligands l-(tert-butoxycarbonyl)-(2 ₎ S', AS)-I- [(diphenylphosphino)methyl]-4-(dibenzophospholyl)pyrrolidine , l-(tert- butoxycarbonyl)-(2<S',4 ₁ S)-2-[(dibenzophospholyl)methyl]-4- (diphenylphosphino)pyrrolidine and l-(tert-butoxycarbonyl)-(25',46)-4-

(dibenzophospholyl)-2-[(dibenzophospholyl)methyl]pyrrolidine . Asymmetric hydroformylation of styrene was examined with use of a catalyst system composed of platinum complexes of these three ligands in the presence of stannous chloride. Various branched/linear ratios (0.5-3.2) and enantiomeric excess values (12-77%) were obtained. When the reactions were carried out in the presence of triethyl orthoformate, all four catalysts gave virtually complete enantioselectivity (ee > 96%) and similar branched/linear ratios. However, platinum hydroformylation catalysts are of limited utility due to their low catalytic activity and requirement for high COZH ₂ , i.e. syn gas, pressures.

Takaya, H., et al, J. Am. Chem. Soc, 1993, 115, 7033 andNozaki, K., et al, J. Am. Chem. Soc, 1997, 119, 4413 reported the use of the mixed phosphine-phosphite ligand, BINAPHOS, for use in rhodium catalyzed hydroformylation. Enantioselectivities as high as 96% were observed for styrene hydroformylation,

although the regioselectivity (branched/linear) was relatively low. Lambers- Verstappen, M. M. H. and de Vries. J.G, Adv. Synth. Catal, 2003, 345, 478-482 report application of BINAPHOS for the Rh-catalyzed hydroformylation of allyl cyanide; this process was only moderately selective, giving chiral aldehyde product of 66% ee and a branched/linear ratio of 72:28. Wills, M. and coworkers reported

{Angew. Chem. Int. Ed., 2000, 39, 4106) the use of chiral diazaphospholidine ligand, ESPHOS, for Rh-catalyzed asymmetric hydroformylation of vinyl acetate. Enantioselectivities up to 92 %ee were obtained for vinyl acetate. This ligand, however, was ineffective in the hydroformylation of styrene, giving a racemic mixture.

US patent 5,491,266 to Union Carbide discloses highly effective chiral bisphosphite ligands for use in Rh-catalyzed asymmetric hydroformylation. Ligands prepared from optically active diols which bridge two phosphorus atoms were especially useful for a variety of olefin substrates. Preferred ligands, for example the prototype ligand known as Chiraphite, were prepared from optically active (2i?,4i?)-pentanediol and substituted biphenols. The highest regioselectivities and enantioselectivities (>85 %ee) were observed with vinylarene substrates. Other substrates were hydroformylated with lesser selectivities. A newer type of chiral bisphosphite family is characterized by ligands having two optically active phosphite moieties linked by achiral bridges (Cobley, CJ. et al., J. Org. Chem., 2004, 69, 4031; Cobley, CJ. et al, Org. Lett, 2004, 69, 4031). The best ligand identified, Kelliphite, was shown to be enantio- and regioselective for the asymmetric hydroformylation of allyl cyanide (78 % ee, b/1 =18, at = 35 ⁰ C) and vinyl acetate (88 % ee, b/1 = 125, at = 35 ⁰ C).

Chiral bis-3,4-diazophospholanes provide yet another class of ligands having utility in Rh-catalyzed asymmetric hydroformylation (Clark, T.P et al., J. Am. Chem. Soc, 2005, 127, 5040). These ligands demonstrate effective control of regioselectivity and enantioselectivity for three different classes of substrates while achieving high catalyst activity.

Despite the advances made in asymmetric hydroformylation technology as described above, existing ligands may be limited in scope and predictability of performance, hi particular, the high molecular weight (in some cases combined with the need for

further functional groups to facilitate synthesis of the enantiopure ligand) of the best multipurpose ligands described in the art may limit industrial applications on economic grounds. Also, in common with chiral ligands designed for other asymmetric reactions, limited substrate applicability of any single ligand provides a technical challenge for adoption of asymmetric hydroformylation in the pharmaceutical and fine chemical industries. Accordingly, there is a need for a wider range of chiral ligands for catalytic asymmetric hydroformylation, especially for multi-purpose ligands showing improved activity and selectivity profile, conferring favourable process economics across a range of substrates. Such substrates include, without limitation, styrene and other vinyl arenes, vinyl acetate and allyl cyanide. Little is reported in the art concerning the utility, for catalytic asymmetric hydroformylation, of relatively low molecular weight bisphosphine ligands in which each phosphorus atom forms part of a phosphacycle wherein the remaining atoms are carbon. Representative ligand of this class, which have found multiple applications in rhodium-catalyzed asymmetric hydrogenation, include the DuPhos, BPE and

FerroTANE ligand families (Burk, MJ., Ace. Chem. Res., 2000, 33, 363; Pilkington, CJ. and Zanotti-Gerosa, A., Org. Lett., 2003, 5, 1273; Berens, U. et al., Angew. Chem. Int. Ed, 2000, 39, 1981). Numerous analogues are reported in the literature, either bearing additional substituents on the phosphacycle or based on alternative backbones bridging the P atoms (for examples, see Borner, A. et al., Adv. Synth.

Catal, 2004, 346, 1263; Zhang. X. et al., Org. Lett, 2002, 4, 4471; Borner, A. et al., J. Org. Chem., 1998, 63, 8031; Oisaki, K. et al., Tetrahedron Lett, 2005, 46, 4325).

Summary of the invention

The present invention comprises synthetically useful processes in which an olefin undergoes an asymmetric reaction selected from the group consisting of hydroformylation, hydrocyanation, hydrocarboxylation and hydroesterification, in the presence of, as catalyst, a transition metal complex of an enantiomerically enriched chiral bis(phospholane) ligand comprising the partial structure according to formula

(1):

wherein (a) R, at each occurrence, is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and alkyl branched at the carbon atom bonded to the phospholane ring; (b) n is an integer of 1 or higher; and (c) the dashed lines, at each occurrence, represent an optional additional bond, such that bonded atoms may be connected by a single bond, a double bond or a bond forming part of an aromatic ring system.

The primary application of the present invention is in hydroformylation reactions. In view of the synthetically useful hydroformylation reactions as detailed below, the utility of the aforementioned transition metal complexes in related reactions of olefins, comprising hydrocyanation, hydrocarboxylation and hydroesterification, will be readily appreciated by those skilled in the art.

As used herein "partial structure" means that the atoms drawn in the structure are present but that additional atoms or functional groups may also be present as long as the structure shown is not altered. Thus, for example, compounds of formulas 2-12 all have the partial structure 1. However, a structure where one of the five membered rings was altered such that it was a six membered ring or a P was replaced by a C would not have the partial structure 1.

AU ratios herein are mole ratios unless otherwise specified.

Detailed description of the invention

The according to the process of the invention one provides (i) an olefin, (ii) as catalyst - the transition metal complex with the compound having partial structure (1), and (iii) such other reactant or reactants as would be effective in achieving the desired reaction (e.g. hydroformylation, hydrocyanation, hydrocarboxylation, or hydroesterification) and then reacts those to achieve the desired asymmetric reaction.

Thus, for example, when asymmetric hydroformylation is desired the reaction is preferably performed using syn gas (a mixture OfH ₂ and CO). This preferred reaction is discussed in more detail below. For hydrocyanation, the olefin may be reacted with

hydrogen cyanide, either charged directly to the reaction vessel or generated from a hydrogen cyanide precursor such as acetone cyanohydrin. For hydrocyanation, nickel is the preferred transition metal. For application to hydroesterification and hydrocarboxylation, the olefin is reacted with carbon monoxide and an alcohol (hydroesterification) or water (hydrocarboxylation), in the presence of the catalyst. In these latter instances, palladium or rhodium are preferred transition metals.

In one aspect of the present invention, in the process catalyzed by a transition metal complex of compound according to formula (1), the transition metal is selected from the group consisting of rhodium, ruthenium, iridium, palladium, cobalt, platinum, nickel, iron and osmium. Preferably the transition metal is rhodium. In carrying out such a process, the complex is either pre-formed and isolated prior to use, pre-formed in a solution that is then combined in the reaction vessel with the substrate undergoing reaction, or generated in situ during the reaction, hi the case of rhodium complexes, it may be preferred that the complex is pre-formed in a solution that is then combined in the reaction vessel with the substrate undergoing reaction. It will be readily appreciated by those skilled in the art that if desired, recognized methods can be applied to achieve immobilization of the ligand (1) and/or a corresponding transition metal complex for the operation of a process according to the present invention.

hi another aspect of the present invention, the preferred asymmetric reaction is either hydroformylation or hydrocyanation. More preferably, the reaction is asymmetric hydroformylation of an olefin and the complex is a rhodium complex. Such asymmetric reactions may either entail enantioselective hydroformylation of a prochiral olefin or diastereoselective hydroformylation of an enantiomerically enriched chiral olefin. In either case, it is preferred that the enantioselective excess of the required product is at least 60% and is preferably at least 80%, or higher, hi such hydroformylation reactions the olefin is typically, although not always, a prochiral α- olefin, i.e. a monosubstituted terminal olefin. Hydroformylation of a prochiral α- olefin RCH=CH ₂ may result in the formation of two regiosiomeric aldehydes, a branched chiral aldehyde RCH(CHO)CH ₃ and a linear achiral aldehyde RCH ₂ CH ₂ CHO. In the process of the present invention, it is desirable the branched aldehyde is the major product, such that the ratio of branched:linear aldehyde

products is at least 3:1 and is preferably at least 8:1, or higher. The group R in the α- olefϊn may be either be C _1-3 O hydrocarbon, i.e. aryl, alkyl (including cycloalkyl), aralkyl or alkaryl or a heteroatom-based substitutent. When R is hydrocarbon, this may be unfunctionalized or functionalized with one or more non-interfering groups. Without limitation, such non-interfering groups may be selected from the group consisting of alcohol, protected alcohol, protected amine, ketone, nitrile, carboxylic acid, ester, lactone, amide, lactam, carbamate, carbonate and halide. When R is a heteroatom-based substitutent, without limitation this may be selected from the group consisting of O-Acyl, N-Acyl and S-Acyl. In a specific embodiment of the present invention, the α-olefin is selected from the group consisting of styrene, vinyl acetate, and allyl cyanide.

The hydroformylation process of the present invention may also be applied to disubstituted olefins as represented by general formulae R ¹ R ² CH=CEE and R ¹ CH=CHR ² wherein R ¹ and R ² have the same scope as R as defined above and may optionally be linked to form part of the ring system.

In yet another aspect of the present invention, wherein the process is hydroformylation, the aldehyde product may be subjected to derivatizion. For such purpose, depending on the synthetic application, the derivatizing reaction comprises an oxidation, reduction, amination, olefination, condensation, esterification, alkylation, arylation or acylation reaction.

In yet another aspect of the present invention, in the process catalyzed by a transition metal complex of a bis(phospholane) ligand according to formula (1), preferred features of ligand (1) can be characterized as follows:

(i) More specifically, the ligand comprises the partial structure according to formula (2), or the opposite enantiomer thereof, wherein R, at each occurrence, is independently selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and alkyl branched at the carbon atom bonded to the phospholane ring, for example isopropyl. Typically, all R groups are the same.

(ii) Within formula (2), n = 1 or 2 and R is aryl or heteroaryl (collectively, Ar) and more preferably the ligand is selected from the group represented by formulae (3) — (8); X in (6) is either O or N-alkyl; R in (8) is either H or alkyl. Most preferably, within these ligand families, the ligand is selected from the group consisting of Ph- BPE (9) and the novel bisphospholanes (10), (11) and (12). With respect to the backbone structures linking phosphine groups in ligands (2) to (12), it will be readily appreciated by those skilled in the art that substitution of alternative backbone structures may be possible in order to obtain ligands with similar properties in asymmetric synthesis applications. Similarly in ligands (2) — (12), it will be likewise be appreciated that phospholane rings may optionally be further substituted at 3- and/or 4-positions.

In a preferred embodiment of the present invention wherein the reaction is asymmetric hydroformylation of an α-olefϊn and the complex is a rhodium complex of a ligand according to formula (2), suitable operating parameters are as follows: (i) the ratio of rhodium:ligand is in the range 0.5-5, is preferably in the range 1-1.5 is most preferably in the range 1.1-1.3; and (ii) the olefin:rhodium ratio is the range 100- 100,000 and preferably is in the range 3,000-30,000.

(iii) the syngas ratio (H ₂ ICO) is in the range 0.1 - 10, preferably in the range 0.5 - 2 and more preferably is around 1.

(iv) operating pressure is in the range 1-1000 psia and preferably is in the range 50- 150 psia. (v) operating temperature is in the range 20-140 ⁰ C and preferably is in the range 60- 100 ⁰ C.

The invention is further illustrated by the Examples below.

hi Example 1, Table 1 shows the results of simultaneous screening experiments, using parallel reactors, for rhodium-catalyzed hydroformylation reactions of a pooled mixture of three substrates (equimolar quantities of styrene, allyl cyanide and vinyl acetate; method according to Cobley, CJ. et ah, Org. Lett., 2004, 69, 4031) using a preferred ligand, (i?,i?)-Ph-BPE (9), in direct comparison with several alternative ligands shown in Figure 1. These ligands include various bis(2,5-trø«s- dialkylphospholanes), various bis(2,4-tr<ms-dialkylphosphetanes) and the known phosphite-based ligands Chiraphite, Kelliphite and a representative bis- diazaphospholane ligand. Table 1 shows that, unexpectedly for diphosphines, (R,R)- Ph-BPE is capable of inducing the highest known enantioselectivity for hydroformylation of both styrene and allyl cyanide. Good enantioselectivity and especially high regioselectivity favoring the branched aldehyde product is observed through the combination of (7?,i?)-Ph-BPE and the third substrate, vinyl acetate. Table 2 in Example 1 confirms these findings at a higher substrate:rhodium ratio. Table 1 in Example 1 also highlights high selectivity of isopropyl-substituted bisphospholanes relative to analogues substituted with methyl and n-alkyl groups. Table 3 in Example 1 demonstrates the utility of the ligands of formulae (4) wherein Ar = Ph, (9), (10), (11) and (12). Additional comparison is made with the novel bisphospholane (13 in Figure 1); compared to its higher homologue Ph-BPE (9), (13) is a markedly inferior ligand for asymmetric hydroformylation. As described in a copending application, (13) is a versatile ligand for catalytic asymmetric hydrogenation. Ligand (10) is also compared with its known methyl-substituted counterpart (14 in Figure 1), the latter proving markedly inferior for asymmetric hydroformylation.

Materials

Styrene and vinyl acetate were purchased from Aldrich and allyl cyanide was purchased from Fluka. Styene was purified by passing through activated alumina. Remaining reagents and solvents were used as received with exception of degassing them via nitrogen spurge.

Example 1: Asymmetric hydroformylation processes

Hydroformylation solutions were prepared by addition of ligand and Rh(CO) ₂ (acac) stock solutions to toluene solvent followed by addition of olefin solution. Total amount of liquids in each reactor cell was 4.5 mL. Ligand solutions (0.03 M for bidentate ligands and Rh(CO) ₂ (acac) (0.05 M) were prepared in the dry box by dissolving appropriate amount of compound in toluene at room temperature. The allyl cyanide solution was prepared by mixing 15.3206 g of allyl cyanide, 3.2494 g of dodecane (as a GC internal standard) and 6.3124 g of toluene (1 :0.1 :0.3 molar ratio). The styrene solution was prepared by mixing 14.221 g of styrene and 6.978 g of dodecane (1:0.3 molar ratio). The vinyl acetate solution was prepared by mixing 13.426 g of vinyl acetate and 7.969 g of dodecane (1:0.3 molar ratio). The styrene:allyl cyanide:vinyl acetate:dodecane solution was prepared by mixing 11.712 g of styrene, 7.544 g of allyl cyanide, 9.681 g of vinyl acetate and 5.747 g of dodecane (1:1:1 :0.3 molar ratio).

Hydroformylation reactions were conducted in an Argonaut Endeavor® reactor system housed in an inert atmosphere glove box. The reactor system consists of eight parallel, mechanically stirred pressure reactors with individual temperature and pressure controls. Upon charging the catalyst solutions, the reactors were pressurized with 150 psi of syn gas (H ₂ ICO 1:1) and then heated to the desired temperature while stirring at 800 rpm. The runs were stopped after 3 hrs by venting the system and purging with nitrogen. For runs with substrate to catalyst ratio of 5,000 : 1 (Table 1), the 34 μL of 0.05 M Rh(CO) ₂ (acac) stock solutions was mixed with 68 μL of 0.03 M ligand stock solution followed by addition of 1 mL of olefin mixture solution and 3.5 mL of toluene. Solution was pressurized at 150 psi with syngas and heated at 80 ⁰ C for 3 hr. Syn gas pressure was maintained at 150 psi (gas on demand) throughout the reaction.

For runs with substrate to catalyst ratio of 30,000 :1 (Table 2), the 25 μL of 0.05 M Rh(CO) ₂ (acac) stock solutions was mixed with 50 μL of 0.03 M ligand stock solution followed by addition of 4.430 mL of olefin mixture solution. Solution was pressurized at 150 psi with syngas and heated at 80 ⁰ C for 3 hr. Syn gas pressure was maintained at 150 psi (gas on demand) throughout the reaction.

For runs with substrate to catalyst ratio of 3,000 :1 (Table 3), the 56 μL of 0.05 M Rh(CO) ₂ (acac) stock solutions was mixed with 187 μL of 0.03 M ligand stock solution followed by addition of 1 mL of olefin mixture solution. Solution was pressurized at 150 psi with syngas and heated at 80 ⁰ C for 3 hr. Syn gas pressure was maintained at 150 psi (gas on demand) throughout the reaction.

After 3 hrs reactors were cooled and vented. Upon opening the reactor sample from each reactor was taken out and diluted with 1.6 mL of toluene, and this solution was analyzed by gas chromatography. For analysis of styrene and vinyl acetate products Supelco's Beta Dex 225 column was used. Temperature program of 100 ⁰ C for 5 min, then 4 °C/min to 160 ⁰ C; retention times: 2.40 min for vinyl acetate, 6.76 (R) and 8.56 (S) min for the enantiomers of the acetic acid l-methyl-2-oxo-ethyl ester (branched regioisomer), 11.50 min for acetic acid 3-oxo-propyl ester (linear regioisomer), 12.11 (R) and 12.34 (S) min for the enantiomers of 2-phenyl-proρionaldehyde (branched regioisomer) and 16.08 min for 3-phenyl-propionaldehyde (linear regioisomer). For allyl cyanide product analysis Astec Chiraldex A-TA column was used. Temperature program of 90 ³ C for 7 min, then 5 ⁹ C/min to 180 ⁹ C; retention times: 5.55 min for allyl cyanide, 14.79 (S) and 15.28 (R) min for the enantiomers of the 3- methyl-4-oxo-butyronitrile (branched regioisomer), and 19.46 for the 5-oxo- pentanenitrile (linear regioisomer).

The following ligands were used in hydroformylation reactions the results of which summarized in Tables 1-3

(2R,4R)-Chiraρhite

Diazaphospholane (S,S)-Kelliphite

R = Me, (R ₅ R)-Me-DuPhOS R = Me, (R ₅ R)-Me-BPE R = Me, (R,R)-Me-FerroTANE R = Et, (R ₅ R)-Et-DuPhOs R = Et, (S ₅ S)-Et-BPE R = t-Bu, (R,R)-/-Bu-FerroTANE R = i-Pr, (S,S)-i-Pr-DuPhos R = i-Pr, (S,S)-i-Pr-BPE

(R _^ R)-I-Pr-S-Fc (14)

(R,R)-z-Pr-Ph-Phospholane (13)

Table 1. Percent conversion (Conv.), branched:linear ratio (b:l), and enantioselectivity (%e.e.) for hydroformylation of styrene, allyl cyanide, and vinyl acetate with chiral phosphorus ligands.

Styrene Allyl cyanide Vinyl acetate

Ligand Conv b:l %e.e. Conv b:l %e.e. Conv. b :1 %e.e.

(S,S)-i-Pr-BPE 11 9.5 82(S) 48 6.7 83(S) 28 142 70(R)

(S ₁ S)-Et-BPE (comparative) 10 11.3 55(R) 40 6.2 49(R) 23 152 66(S)

(R,R)-Me-BPE (comparative) 8 14 43(5) 36 5.8 37(5) 23 97 59(R)

(S,8)-i-Pr-DuPhos 15 11.3 83(S) 55 7.2 82(S) 29 322 74(R)

Table 2. . Percent conversion (Conv.), branched:linear ratio (b:l), and enantioselectivity (%e.e.) for hydroformylation of styrene, allyl cyanide, and vinyl acetate with chiral phosphorus ligands.

Styrene Allyl cyanide Vinyl acetate

Ligand Conv b:l %e.e. Conv b:l %e.e. Conv. b:l %e.e.

(R,S)-Binaphos 35 4.6 81 (R) 58 2.1 68 (R) 23 7.1 5S (S)

(comparative) (S,S)-Kelliphite 32 9.2 3 (5) 99 10.1 66 (S) 32 100 75 (R)

(comparative) (2R,4R)-Chiraphite 32 10.8 51 (R) 74 5.8 13 (R) 34 204 50 (R)

(comparative)

Diazaphospholane 73 5.7 80 (i?) 100 3.9 80 (R) 92 47 95 (5) (comparative)

(R,R)~Ph-BPE 33 45.0 92 (R) 67 7.6 90 (R) 34 263 82 (5) (compound 9)

Table 3. Percent conversion (Conv.), branched: linear ratio (b:l), and enantioselectivity (%e.e.) for hydroformylation of styrene, allyl cyanide, and vinyl acetate with chiral phosphorus ligands.

Styrene Allyl cyanide Vinyl acetate

Ligand Conv b:l %e.e. Conv b:l %e.e. Conv. b:l %e.e.

(4), n = 2, R = Ph 11 20.9 67 (5) 42 8.7 80 (5) 27 197 31 (R) (9); (S,S)-Ph-BPE 61 45.2 94 (S) 98 6.7 90 (S) 51 515 81 (R)

(10) 43 38.5 90 (S) 16 8.1 81 (S) 48 111 68 (5)

(11) 98 36.4 90 (5) 100 6.0 11 (R) 96 190 70 (S)

(12) 95 39.7 9Q (R) 100 7.1 19 (R) 92 221 69 (5)

(13) ^* (comparative) 12 20 1 (5) 44 4.5 2 (S) 24 603 24 (R) (14) (comparative) 9 14 49 (5) 31 6.1 38 (5) 16 75 30 (R)

*0.5 mL of olefin mixture solution was used and L:Rh was 1.2

Example 2: Synthesis of bisphospholane ligand (10)

(5,S)-Ph-Malphos

(S ₅ S)-I -Hydroxy- l-oxo-2,5-tra«s-diphenylphospholane (600 mg, 2.20 mmol) was suspended in toluene (6 ml). The mixture was degassed by evacuation and filling with nitrogen ( ^χ 5) and then heated in an oil bath at 110 ⁰ C (external temperature). Phenylsilane (0.54 ml, 4.41 mmol) was added in one portion and the mixture was heated for 2h (during this time vigorous effervescence is observed and a clear solution forms). The solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude phosphine was further dried under high vacuum (2.9 mbar, 6O ⁰ C). The residue was cooled to room temperature and dissolved in THF (3 ml) under nitrogen. Triethylamine (0.31 ml, 2.20 mmol) was added, followed by a solution of 2,3-dichloromaleic anhydride (167 mg, 1.00 mmol) in THF (2 ml). The mixture was heated in an oil bath at 60 ⁰ C (external temperature) and stirred for 18h (dark purple solution forms). The solution was cooled to room temperature and solvent was evaporated under reduced pressure. The residue was chromatographed on silica, eluting with DCM/heptane (2:3) to give a deep red oil which solidified on standing (180 mg, 0.31 mmol, 31%)

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.51-7.34 (10 H, m), 6.90 (4 H, d, J8 Hz), 6.80 (2

H, t, J 7 Hz), 6.56 (4 H, t, J 8 Hz), 4.60-4.53 (2 H, m), 4.05-3.93 (2 H, m), 2.73-2.61 (2 H. m), 2.58-2.45 (2 H. m), 2.44-2.35 (2 H, m) and 1.97-1.85 (2 H, m).

¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 161.7, 156.2 (m), 141.1 (t, J 11 Hz), 136.6, 127.1, 127.0, 126.9, 126.8, 125.0, 124.9, 124.7, 48.2 (d, J 7 Hz), 41.1 (d, J5 Hz), 38.0 and 31.6.

³¹ P NMR (162 MHz, CDCl ₃ ) δ ppm 3.5.

Example 3: Synthesis of bisphospholane ligand (11)

(£,S)-2,5-trø«s-diphenylphospholane-borane adduct (381 mg, 1.50 mmol) was dissolved in dry THF (3 ml) under nitrogen. The solution was cooled to -20°C. A solution of n-BuLi (2.5 M in hexanes, 0.6 ml, 1.50 mmol) was added dropwise and the mixture was stirred for 30 minutes (a yellow solution is formed). 2,3- Dichloroquinoxaline (136 mg, 0.68 mmol) was added in one portion and the residues were washed in with dry THF (1 ml) (the quinoxaline is only sparingly soluble in THF). The mixture was allowed to warm to room temperature (red/orange solution is observed). The reaction mixture was stirred overnight and then quenched with IM aqueous HCl (5 ml) (effervescence was observed) and extracted with ethyl acetate (10 ml). The organic solution was washed with water (5 ml) and brine (5 ml), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with DCM/heptane (2:3) to give a yellow solid (200 mg, 0.33 mmol, 48%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.11-8.06 (2 H, m), 7.77-7.73 (2 H, m), 7.36-7.21 (10 H, m), 6.37 (2 H, t, J 8 Hz), 6.29 (4 H, d, J 8 Hz), 6.07 (4 H, t, J 8 Hz), 4.53-4.46 (2 H, m), 3.83-3.73 (2 H, m), 2.58-2.45 (2 H, m), 2.09-1.99 (4 H, m) and 1.87-1.75 (2 H, m).

¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 163.2 (br d), 144.2 (t, J 10 Hz), 141.2, 139.8, 129.4, 129.2, 129.1 (t, J 5 Hz), 128.1, 127.4, 126.9, 125.7, 125.4, 49.6 (t, J 10 Hz), 43.3, 37.9 and 33.7.

³¹ P NMR (162 MHz, CDCl ₃ ) δ ppm 9.1.

Example 4: Synthesis of bisphospholane ligand (12)

(i?,R)-2,5-trøns-diphenylphospholane-borane adduct (518 mg, 2.04 mmol) was dissolved in dry THF (3 ml) under nitrogen. The solution was cooled to -20°C. A solution of n-BuLi (2.5 M in hexanes, 0.82 ml, 2.04 mmol) was added dropwise and the mixture was stirred for 30 minutes (a yellow solution is formed) A solution of 2,3-dichloropyrazine (137 mg, 0.92 mmol) in THF (2 ml) was added and the solution was allowed to warm to room temperature (red/brown colour is observed instantly when the pyrazine is added). After 5h, TMEDA (0.45 ml, 3.0 mmol, 1.5 eq.) was added and the mixture was stirred overnight. The reaction was quenched with IM aqueous HCl (5 ml) and extracted with ethyl acetate (10 ml). The organic solution was washed with half saturated brine (10 ml), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was chromatographed on silica, eluting with ethyl acetate/heptane (1:8) to give the product as a yellow solid (105 mg, 0.19 mmol, 21%).

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 8.36 (2 H, s), 7.35-7.21 (10 H, m), 6.48 (2 H, t, J 7 Hz), 6.40 (4 H, d, J 8 Hz), 6.24 (4 H, t, J 8 Hz), 4.27-4.20 (2 H, m), 3.80-3.69 (2 H, m), 2.54-2.43 (2 H, m), 2.07-1.99 (4 H, m) and 1.80-1.66 (2 H, m).

¹³ C NMR (100 MHz, CDCl ₃ ) δ ppm 163.9 (br d), 144.6 (t, J 10 Hz), 142.4, 139.9, 129.4 (t, J 5 Hz), 128.5, 127.5 (m), 126.1, 125.9, 50.0 (t, J 10 Hz), 43.8, 38.9 and 33.5.

31 P NMR (162 MHz, CDCl ₃ ) δ ppm 7.2.