JP2008538585A - Asymmetric hydroformylation process - Google Patents

Abstract

  The present invention provides an asymmetric reaction in which an olefin is selected from the group consisting of hydroformylation, hydrocyanation, hydrocarboxylation and hydroesterification, and catalyzes the enantiomerically enriched chiral bis (phosphorane) ligand. It includes a synthetically useful process that undergoes in the presence of a transition metal complex.

Description

  The present invention relates to the reaction of prochiral or chiral olefins with carbon monoxide and hydrogen in the presence of an optically active metal-diphosphine complex catalyst to produce optically active aldehydes or products derived from optically active aldehydes. To an asymmetric hydroformylation process.

  Asymmetric synthesis is important, for example, in the pharmaceutical industry. This is often because only one optically active isomer (enantiomer) is therapeutically active. An example of such a pharmaceutical product is naproxen, a non-steroidal anti-inflammatory drug. The (S) -enantiomer is a potent anti-arthritic agent, while the (R) -enantiomer is a liver toxin. Thus, in many cases, it is desirable to produce one specific enantiomer more selectively than its enantiomer.

  Special techniques ensure the formation of the desired enantiomers because they tend to produce optically inactive racemic mixtures (ie, equal amounts of the respective mirror image enantiomers whose opposing optical activities cancel each other). It is known that it must be used to 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 is known as optical resolution and can be accomplished by actual physical sorting, direct crystallization of the racemic mixture, or other methods known in the art. Such optical resolution techniques are often labor intensive and expensive, and usually the yield of the desired enantiomer is less than 50% based on the raw material of the racemic mixture. Due to these difficulties, asymmetric synthesis is being gained more and more in which one of the enantiomers can be obtained in significantly larger amounts. Specifically, an industrial process for the production of pharmaceuticals and other fine chemicals in an asymmetric synthesis process facilitated by catalysis (chiral catalysis) of a chiral ligand of only one enantiomer with a transition metal complex. More and more applicability has been found.

  Asymmetric hydroformylation of olefins is particularly valuable for synthesizing optically active products because the reaction is a one-carbon homologation that achieves a chiral center and a very versatile aldehyde functionality. For efficient asymmetric hydroformylation, desirably both regioselectivity (branched / linear ratio) and enantioselectivity can be controlled. Optically active aldehydes produced in asymmetric hydroformylation can be further converted to other functional groups either by subsequent reaction steps or by in situ reaction with other reagents. Thus, asymmetric hydroformylation of olefins and related homologation processes can lead to very important transformations in the synthesis of complex molecules, specifically pharmaceutically active compounds.

Various asymmetric hydroformylation catalysts have been described in the art. See van Leeuwen, PWNM and Claver, C., "Rhodium Catalyzed Hydroformylation" (Kluwer Academic Publishers, Dordrecht, 2000). For example, Stille, JK et al., Organometallics, 1991, 10, 1183-1189 are chiral ligands 1- (tert-butoxycarbonyl)-(2S, 4S) -2-[(diphenylphosphino) methyl]. -4- (dibenzophosphoryl) pyrrolidine, 1- (tert-butoxycarbonyl)-(2S, 4S) -2-[(dibenzophosphoryl) methyl] -4- (diphenylphosphino) pyrrolidine and 1- (tert-butoxycarbonyl) Related to the synthesis of three complexes of platinum (II) containing)-(2S, 4S) -4- (dibenzophosphoryl) -2-[(dibenzophosphoryl) methyl] pyrrolidine. Asymmetric hydroformylation of styrene was investigated using 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 reaction was carried out in the presence of triethyl orthoformate, all four catalysts had virtually complete enantioselectivity (greater than 96% ee) and a similar branched / linear ratio. Brought about. However, platinum hydroformylation catalysts have limited utility because of their low catalytic activity and the requirement for high CO / H ₂ (ie, syn gas) pressure.

  Takaya, H. et al. (J. Am. Chem. Soc., 1993, 115, 7033) and Nozaki, K. et al. (J. Am. Chem. Soc., 1997, 119, 4413) are rhodium catalyzed hydroformylation. Reported the use of mixed phosphine-phosphite ligands (BINAPHOS) used in Enantioselectivity as high as 96% was observed for styrene hydroformylation, but its regioselectivity (branched / linear) was relatively low. Lambers-Verstappen, M.M.H. and de Vries, J.G. (Adv. Synth. Catal., 2003, 345, 478-482) report the application of BINAPHOS for Rh-catalyzed hydroformylation of allyl cyanide. This process had only moderate selectivity, resulting in a chiral aldehyde product having an ee of 66% and a branched / linear ratio of 72:28. Wills, M. and co-workers (Angew. Chem. Int. Ed., 2000, 39, 4106) have described chiral diazaphosphoridine ligands (Rh-catalyzed asymmetric hydroformylation of vinyl acetate ( The use of ESPHOS was reported. Enantioselectivity up to 92% ee was obtained for vinyl acetate. However, this ligand was not effective in hydroformylation of styrene and gave a racemic mixture.

  US Pat. No. 5,491,266 (Union Carbide) discloses highly effective chiral bisphosphite ligands used in Rh-catalyzed asymmetric hydroformylation. Ligands prepared from optically active diols that bridge two phosphorus atoms have been particularly useful for a variety of olefin substrates. Preferred ligands (eg, the prototype ligand known as Chirapite) were prepared from optically active (2R, 4R) -pentanediol and substituted biphenols. Maximum regioselectivity and enantioselectivity (greater than 85% ee) was observed for the vinylarene substrate. Other substrates were hydroformylated with lower selectivity. A group of newer types of chiral bisphosphites are characterized by ligands with two optically active phosphite moieties linked by an achiral bridge (Cobley, CJ et al., J. Org. Chem., 2004, 69, 4031; Cobley, CJ et al., Org. Lett., 2004, 69, 4031). The best identified ligand (Kelliphite) is enantioselective and regioselective with asymmetric hydroformylation of allyl cyanide (78% ee, b / l = 18, at 35 ° C.) and asymmetric hydroformyl of vinyl acetate (88% ee, b / l = 125 at 35 ° C.).

  Chiral bis-3,4-diazophosphorane-based compounds provide yet another class of ligands that have utility in Rh-catalyzed asymmetric hydroformylation (Clark, TP et al., J. Am. Chem. Soc., 2005, 127, 5040). In these catalysts, effective control of regioselectivity and enantioselectivity is revealed for three different classes of substrates while achieving high catalytic activity.

  Despite the various advances made in asymmetric hydroformylation techniques as described above, existing ligands can be limited in performance range and predictability. Specifically, the high molecular weight of the best multipurpose ligands described in the art (sometimes requiring additional functional groups to facilitate the synthesis of enantiopure ligands Together) can limit industrial applications for economic reasons. Also, in common with chiral ligands designed for other asymmetric reactions, the limited substrate applicability of any single ligand allows asymmetric hydroformylation in the pharmaceutical and fine chemical industries. Brings technical challenges to adoption. Thus, a convenient process that exhibits a broader variety of different chiral ligands for catalytic asymmetric hydroformylation, particularly improved activity and selectivity, and is thus economical across a variety of substrates There is a need for multipurpose ligands that provide Such substrates include, but are not limited to, styrene and other vinyl arenes, vinyl acetate, and vinyl cyanide. Useful for catalytic asymmetric hydroformylation of relatively low molecular weight bisphosphine ligands, where each phosphorus atom forms part of a phosphorus-containing ring (phosphacycle) and the remaining atoms in the phosphorus-containing ring are carbon Little is reported in the field regarding gender. Representative ligands of this class that have found numerous applications in rhodium-catalyzed asymmetric hydrogenation include the DuPhos, BPE and FerroTANE ligands (Burk, MJ, Acc. 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 analogs have been reported in the literature, either having additional substituents on the phosphorus-containing ring or based on another skeleton bridging the P atom (eg, 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).

The present invention provides an enantiomerically enriched olefin having a partial structure according to the following formula (1) as a catalyst for an asymmetric reaction selected from the group consisting of hydroformylation, hydrocyanation, hydrocarboxylation and hydroesterification. Including a synthetically useful process in the presence of a transition metal complex of a chiral bis (phosphorane) ligand:

In formula (1), (a) R is independently in each occurrence from substituted aryl or unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl, and alkyl branched at the carbon atom attached to the phosphorane ring. (B) n is an integer greater than or equal to 1; (c) the dotted line in each occurrence is a single bond, double bond, or part of an aromatic ring system Any additional bond is represented such that it can be linked by a bond that forms

  The main application of the present invention is in hydroformylation reactions. In view of the synthetically useful hydroformylation reactions as described in detail below, the utility of the transition metal complexes in olefin related reactions (including hydrocyanation, hydrocarboxylation and hydroesterification) is Easily understood by vendors.

As used herein, “substructure” means that there are atoms depicted in the structure, but additional atoms or functional groups may also be present as long as the indicated structure does not change. . Thus, for example, all compounds of Formula 2 to Formula 12 have partial structure 1. However, a structure in which one of the five-membered rings is changed to be a six-membered ring or a structure in which P is substituted by C does not have the partial structure 1.
All ratios herein are molar ratios unless otherwise indicated.

According to the process of the present invention, (i) an olefin, (ii) as a catalyst, a transition metal complex with a compound having the partial structure (1), and (iii) the desired reaction (eg, hydroformylation, hydrocyanation, hydro Other reactant (s) are provided which are useful in achieving (carboxylation or hydroesterification) and they are reacted to achieve the desired asymmetric reaction. Thus, for example, if asymmetric hydroformylation is desired, the reaction is preferably carried out using syn gas (a mixture of H ₂ and CO). This preferred reaction is discussed in more detail below. For hydrocyanation, the olefin can be reacted with either hydrogen cyanide charged directly to the reaction vessel or hydrogen cyanide generated from a hydrogen cyanide precursor (such as acetone cyanohydrin). For hydrocyanation, nickel is the preferred transition metal. For hydroesterification and hydrocarboxylation applications, the olefin is reacted with carbon monoxide and alcohol (hydroesterification) or water (hydrocarboxylation) in the presence of a catalyst. In these latter cases, palladium or rhodium is the preferred transition metal.

  In one embodiment of the invention, in a process catalyzed by a transition metal complex of a compound according to formula (1), the transition metal is from the group consisting of rhodium, ruthenium, iridium, palladium, cobalt, platinum, nickel, iron and osmium. Selected. Preferably, the transition metal is rhodium. In performing such a process, the complex is pre-formed and isolated prior to use, or pre-formed in a solution that is later combined in the reaction vessel with the substrate to be reacted, or Either occurs in situ during the reaction. In the case of rhodium complexes, it may be preferred that the complex is pre-formed in a solution that is later combined in the reaction vessel with the substrate to be reacted. If desired, various recognized methods can be applied to achieve the immobilization of the ligand (1) and / or the corresponding transition metal complex for the operation of the process according to the invention. It will be readily understood by those skilled in the art.

In another embodiment of the invention, the preferred asymmetric reaction is either hydroformylation or hydrocyanation. More preferably, the reaction is an asymmetric hydroformylation of an olefin and the complex is a rhodium complex. Such asymmetric reactions can cause either enantioselective hydroformylation of prochiral olefins or diastereoselective hydroformylation of enantiomerically enriched chiral olefins. In any case, it is preferred that the required enantioselective excess of product is at least 60%, preferably at least 80% or more. In such hydroformylation reactions, the olefin is typically, but not always, a prochiral α-olefin (ie, a monosubstituted terminal olefin). Hydroformylation of a prochiral α-olefin (RCH═CH ₂ ) results in the formation of two regioisomeric aldehydes: a branched chiral aldehyde (RCH (CHO) CH ₃ ) and a linear achiral aldehyde ( RCH ₂ CH ₂ CHO) can be formed. In the process of the present invention, a branched aldehyde is the main product, so that the branched: linear aldehyde product ratio is at least 3: 1, preferably at least 8: 1 or more. It is desirable that group R in α- olefin, C ₁ ~ ₃₀ hydrocarbons (i.e., aryl includes alkyl (cycloalkyl), aralkyl or alkaryl) may be either or heteroatom-type substituent. When R is a hydrocarbon, the hydrocarbon may be unfunctionalized or may be functionalized with one or more non-interfering groups. Without limitation, such non-interfering groups are from the group consisting of alcohols, protected alcohols, protected amines, ketones, nitriles, carboxylic acids, esters, lactones, amides, lactams, carbamates, carbonates and halides. Can be selected. When R is a heteroatom type substituent, such substituents may be selected from the group consisting of O-acyl, N-acyl and S-acyl, without limitation. In a specific embodiment of the invention, the α-olefin is selected from the group consisting of styrene, vinyl acetate and allyl cyanide.

The hydroformylation process of the present invention also includes the general formula of R ¹ R ² CH═CH ₂ and R ¹ CH═CHR ^{2 wherein} R ¹ and R ² are in the same range as R as defined above. It can also be applied to disubstituted olefins such as those represented by: having and optionally being linked to form part of a ring system.

  In yet another aspect of the present invention, when the process is hydroformylation, the aldehyde product can be subjected to derivatization. For such purposes, depending on the synthesis application, the derivatization reaction may be an oxidation reaction, a reduction reaction, an amination reaction, an olefination reaction, a condensation reaction, an esterification reaction, an alkylation reaction, an arylation reaction or an acyl. Including chemical reaction.

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

(I) More specifically, the ligand comprises a partial structure according to formula (2) or the opposite enantiomer, wherein in formula (2) R is independently substituted aryl or unsubstituted in each occurrence. Selected from the group consisting of aryl, substituted heteroaryl or unsubstituted heteroaryl, and alkyl branched at the carbon atom attached to the phosphorane ring (eg, isopropyl). Typically, all R groups are the same.

(Ii) In formula (2), n = 1 or 2, R is aryl or heteroaryl (collectively Ar), and more preferably the ligand is represented by formula (3) to formula (8). Wherein X in formula (6) is either O or N-alkyl and R in formula (8) is either H or alkyl. Most preferably, in these ligand groups, the ligand is selected from the group consisting of Ph-BPE (9) and the novel bisphosphorane-based ligands (10), (11) and (12). Is done. Regarding the skeletal structure linking the phosphine group in ligand (2) to ligand (12), substitution to an alternative skeletal structure is possible to obtain a ligand with similar properties in asymmetric synthesis applications It can be easily understood by those skilled in the art. In ligand (2) to ligand (12) it is likewise understood that the phosphorane ring can optionally be further substituted in the 3 and / or 4 position.

In a preferred embodiment of the present invention, when the reaction is an asymmetric hydroformylation of an α-olefin and the complex is a rhodium complex of a ligand according to formula (2), suitable operating parameters are as follows: And (i) the rhodium: ligand ratio is in the range of 0.5 to 5, preferably in the range of 1 to 1.5, most preferably in the range of 1.1 to 1.3, and (Ii) The ratio of olefin: rhodium is in the range of 100 to 100,000, preferably in the range of 3,000 to 30,000.
(Iii) The ratio of syn gas (H ₂ : CO) is in the range of 0.1 to 10, preferably in the range of 0.5 to 2, and more preferably about 1.
(Iv) The operating pressure is in the range of 1 psia to 1000 psia, preferably in the range of 50 psia to 150 psia.
(V) The operating temperature is in the range of 20 ° C to 140 ° C, preferably in the range of 60 ° C to 100 ° C.

  The invention is further illustrated by the following examples.

  In Example 1, Table 1 shows a pooled mixture of three substrates (equal molar amounts of styrene, allyl cyanide and vinyl acetate) using the preferred ligand (R, R) -Ph-BPE (9). The results of simultaneous screening experiments using parallel reactors for the rhodium catalyzed hydroformylation reaction (method according to Cobley, CJ et al., Org. Lett., 2004, 69, 4031) are shown in FIG. Shown in direct comparison with alternative ligands. These ligands include various bis (2,5-trans-dialkylphosphorane) -based ligands, various bis (2,4-trans-dialkylphosphatane) -based ligands, and publicly known Phosphite-type ligands (Chiraphite, Kelliphite and typical bis-diazaphosphorane ligands). Table 1 was unexpected for diphosphine-based ligands, but (R, R) -Ph-BPE induced the largest enantioselectivity known so far for the hydroformylation of both styrene and allyl cyanide. Show what you can do. Good enantioselectivity and particularly large regioselectivity, which is advantageous for branched aldehyde products, is observed with the combination of (R, R) -Ph-BPE and a third substrate (vinyl acetate). Table 2 in Example 1 confirms these findings at higher substrate: rhodium ratios. Table 1 in Example 1 also highlights the great selectivity of isopropyl-substituted bisphosphorane-based ligands relative to analogs substituted with methyl and n-alkyl groups. Table 3 in Example 1 clearly shows the usefulness of the ligands of formula (4) (wherein Ar = Ph), formula (9), formula (10), formula (11) and formula (12). Is done. A further comparison is made with the new bisphospholane (13 in FIG. 1). Compared to its higher homologue, Ph-BPE (9), (13) is a ligand that is significantly inferior for asymmetric hydroformylation. As described in the co-pending patent application, (13) is a versatile ligand for catalytic asymmetric hydrogenation. Ligand (10) is also compared to its known methyl substituted counterpart (14 in FIG. 1), where the latter is found to be significantly inferior for asymmetric hydroformylation.

Materials Styrene and vinyl acetate were purchased from Aldrich and allyl cyanide was purchased from Fluka. Styrene was purified by passing through activated alumina. Other reagents and solvents were used as received except for degassing by nitrogen purge.

Example 1 Asymmetric Hydroformylation Process Various hydroformylation solutions were prepared by adding each stock solution of coordination and Rh (CO) ₂ (acac) to a toluene solvent followed by an olefin solution. The total amount of liquid in each reactor cell was 4.5 mL. Ligand solutions (0.03M for bidentate ligands) and Rh (CO) ₂ (acac) (0.05M) were prepared in a dry box by dissolving the appropriate amount of compound in toluene at room temperature. An allyl cyanide solution was prepared by mixing 15.2066 g allyl cyanide, 3.2494 g dodecane (as a GC internal standard) and 6.3124 g toluene (1: 0.1: 0.3 molar ratio). A styrene solution was prepared by mixing 14.221 g styrene and 6.978 g dodecane (1: 0.3 molar ratio). A vinyl acetate solution was prepared by mixing 13.426 g vinyl acetate and 7.969 g dodecane (1: 0.3 molar ratio). Styrene: allyl cyanide: vinyl acetate: dodecane solution was charged with 11.712 g styrene, 7.544 g allyl cyanide, 9.681 g vinyl acetate and 5.747 g dodecane (1: 1: 1: 0.3 molar ratio). Prepared by mixing.

The hydroformylation reaction was performed in an Argonaut Endeavor® reactor system placed in an inert atmosphere glove box. This reactor system consists of eight parallel, mechanically agitated pressure reactors in which temperature and pressure are individually controlled. When the catalyst solution was charged, the reactor was pressurized with 150 psi syn gas (H ₂ : CO, 1: 1) and then heated to the desired temperature with stirring at 800 rpm. The experiment was stopped after 3 hours by evacuating the system and purging with nitrogen.

For experiments where the substrate to catalyst ratio was 5,000: 1 (Table 1), 34 μL of 0.05 M Rh (CO) ₂ (acac) stock solution was mixed with 68 μL of 0.03 M ligand stock solution. Then, 1 mL of the olefin mixture solution and 3.5 mL of toluene were added. The solution was pressurized with syn gas at 150 psi and heated at 80 ° C. for 3 hours. The pressure of the syn gas was maintained at 150 psi (gas on demand) throughout the reaction.
For experiments where the substrate to catalyst ratio was 30,000: 1 (Table 2), 25 μL of 0.05 M Rh (CO) ₂ (acac) stock solution was mixed with 50 μL of 0.03 M ligand stock solution. Then, 4.430 mL of the olefin mixture solution was added. The solution was pressurized with syn gas at 150 psi and heated at 80 ° C. for 3 hours. The pressure of the syn gas was maintained at 150 psi (gas on demand) throughout the reaction.

For experiments where the substrate to catalyst ratio was 3000: 1 (Table 3), 56 μL of 0.05 M Rh (CO) ₂ (acac) stock solution was mixed with 187 μL of 0.03 M ligand stock solution. Then, 1 mL of the olefin mixture solution was added. The solution was pressurized with syn gas at 150 psi and heated at 80 ° C. for 3 hours. The pressure of the syn gas was maintained at 150 psi (gas on demand) throughout the reaction.

  After 3 hours, the reactor was cooled and evacuated. When the reactor was opened, a sample from each reactor was removed, diluted with 1.6 mL toluene, and the solution was analyzed by gas chromatography. For analysis of styrene and vinyl acetate products, a Super Deco Beta Dex225 column was used. Temperature program at 100 ° C. for 5 minutes, then 4 ° C./min to 160 ° C .; retention time: 2.40 minutes for vinyl acetate, acetic acid 1-methyl-2-oxo-ethyl ester (branched regioisomer 6.76 min (R) and 8.56 min (S) for enantiomers of), 11.50 min for acetic acid 3-oxo-propyl ester (linear regioisomer), 2-phenyl-propional 12.11 min (R) and 12.34 min (S) for the enantiomer of the hydride (branched regioisomer) and 16 for the 3-phenylpropional hydride (linear regioisomer) .08 minutes.

  For product analysis of allyl cyanide, an Astec Chiraldex A-TA column was used. Temperature program at 90 ° C. for 7 minutes, then 5 ° C./minute to 180 ° C .; retention time: 5.55 minutes for allyl cyanide, 3-methyl-4-oxo-butyronitrile (branched regioisomer) 14.79 min (S) and 15.28 min (R) for enantiomers and 19.46 min for 5-oxo-pentanenitrile (linear regioisomer).

ジアザホスホラン
（Ｒ，Ｒ）−ｉ−Ｐｒ−Ｐｈ−ホスホラン
The following ligands were used in various hydroformylation reactions: The results are summarized in Tables 1 to 3.

Diazaphosphorane (R, R) -i-Pr-Ph-phosphorane

（Ｓ，Ｓ）−１−ヒドロキシ−１−オキソ−２，５−ｔｒａｎｓ−ジフェニルホスホラン（６００ｍｇ、２．２０ｍｍｏｌ）をトルエン（６ｍｌ）に懸濁した。混合物を、排気および窒素による充填（５回）によって脱気し、その後、油浴において１１０℃（外部温度）で加熱した。フェニルシラン（０．５４ｍｌ、４．４１ｍｍｏｌ）を一度に加え、混合物を２時間加熱した（この期間中、激しい発泡が観測され、透明な溶液が形成する）。溶液を室温に冷却し、溶媒を減圧下でエバポレーションした。粗ホスフィンを高真空下（２．９ｍｂａｒｒ、６０℃）でさらに乾燥した。残渣を室温に冷却し、窒素下でＴＨＦ（３ｍｌ）に溶解した。トリエチルアミン（０．３１ｍｌ、２．２０ｍｍｏｌ）を加え、続いて、２，３−ジクロロマレイン酸無水物（１６７ｍｇ、１．００ｍｍｏｌ）をＴＨＦ（２ｍｌ）に溶解した溶液を加えた。混合物を油浴において６０℃（外部温度）で加熱し、１８時間撹拌した（暗紫色の溶液が形成する）。溶液を室温に冷却し、溶媒を減圧下でエバポレーションした。残渣をシリカでのクロマトグラフィー処理に供し、ＤＣＭ／ヘプタン（２：３）により溶出して、放置したときに固化した深赤色のオイルを得た（１８０ｍｇ、０．３１ｍｍｏｌ、３１％）。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ ７．５１−７．３４（１０Ｈ、ｍ）、６．９０（４Ｈ、ｄ、Ｊ ８Ｈｚ）、６．８０（２Ｈ、ｔ、Ｊ ７Ｈｚ）、６．５６（４Ｈ、ｔ、Ｊ ８Ｈｚ）、４．６０−４．５３（２Ｈ、ｍ）、４．０５−３．９３（２Ｈ、ｍ）、２．７３−２．６１（２Ｈ、ｍ）、２．５８−２．４５（２Ｈ、ｍ）、２．４４−２．３５（２Ｈ、ｍ）および１．９７−１．８５（２Ｈ、ｍ）。
¹³Ｃ ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ １６１．７、１５６．２（ｍ）、１４１．１（ｔ、Ｊ １１Ｈｚ）、１３６．６、１２７．１、１２７．０、１２６．９、１２６．８、１２５．０、１２４．９、１２４．７、４８．２（ｄ、Ｊ ７Ｈｚ）、４１．１（ｄ、Ｊ ５Ｈｚ）、３８．０および３１．６。
³¹Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ ３．５。 Example 2: Synthesis of bisphospholane ligand (10)

(S, S) -1-hydroxy-1-oxo-2,5-trans-diphenylphosphorane (600 mg, 2.20 mmol) was suspended in toluene (6 ml). The mixture was degassed by evacuation and filling with nitrogen (5 times) and then heated at 110 ° C. (external temperature) in an oil bath. Phenylsilane (0.54 ml, 4.41 mmol) was added in one portion and the mixture was heated for 2 hours (during this period vigorous bubbling was observed and a clear solution formed). 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 mbarr, 60 ° 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 ° C. (external temperature) and stirred for 18 hours (a dark purple solution formed). The solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica, eluting with DCM / heptane (2: 3) to give a deep red oil that 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, J 8 Hz), 6.80 (2 H, t, J 7 Hz), 6. 56 (4H, t, J 8 Hz), 4.60-4.53 (2H, m), 4.05-3.93 (2H, m), 2.73-2.61 (2H, m), 2 .58-2.45 (2H, m), 2.44-2.35 (2H, m) and 1.97-1.85 (2H, 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, J 5 Hz), 38.0 and 31.6.
³¹ P NMR (162 MHz, CDCl ₃ ) δ ppm 3.5.

（Ｓ，Ｓ）−２，５−ｔｒａｎｓ−ジフェニルホスホラン−ボラン付加物（３８１ｍｇ、１．５０ｍｍｏｌ）を窒素下で乾燥ＴＨＦ（３ｍｌ）に溶解した。溶液を−２０℃に冷却した。ｎ−ＢｕＬｉの溶液（ヘキサン（ｈｅｘａｎｅｓ）における２．５Ｍ、０．６ｍｌ、１．５０ｍｍｏｌ）を滴下して加え、混合物を３０分間撹拌した（黄色の溶液が形成される）。２，３−ジクロロキノキサリン（１３６ｍｇ、０．６８ｍｍｏｌ）を一度に加え、残渣を乾燥ＴＨＦ（１ｍｌ）により洗浄した（２，３−ジクロロキノキサリンはＴＨＦにわずかに可溶性であるにすぎない）。混合物を室温に加温し（赤／橙色の溶液が観測される）。反応混合物を一晩撹拌し、その後、１ＭのＨＣｌ水溶液（５ｍｌ）により反応停止させ（発泡が観測された）、酢酸エチル（１０ｍｌ）で抽出した。有機溶液を水（５ｍｌ）およびブライン（５ｍｌ）により洗浄し、乾燥し（ＭｇＳＯ₄）、ろ過し、減圧下で濃縮した。残渣をシリカでのクロマトグラフィー処理に供し、ＤＣＭ／ヘプタン（２：３）により溶出して、黄色の固体を得た（２００ｍｇ、０．３３ｍｍｏｌ、４８％）。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ ８．１１−８．０６（２Ｈ、ｍ）、７．７７−７．７３（２Ｈ、ｍ）、７．３６−７．２１（１０Ｈ、ｍ）、６．３７（２Ｈ、ｔ、Ｊ ８Ｈｚ）、６．２９（４Ｈ、ｄ、Ｊ ８Ｈｚ）、６．０７（４Ｈ、ｔ、Ｊ ８Ｈｚ）、４．５３−４．４６（２Ｈ、ｍ）、３．８３−３．７３（２Ｈ、ｍ）、２．５８−２．４５（２Ｈ、ｍ）、２．０９−１．９９（４Ｈ、ｍ）および１．８７−１．７５（２Ｈ、ｍ）。
¹³Ｃ ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ １６３．２（ｂｒ ｄ）、１４４．２（ｔ、Ｊ １０Ｈｚ）、１４１．２、１３９．８、１２９．４、１２９．２、１２９．１（ｔ、Ｊ ５Ｈｚ）、１２８．１、１２７．４、１２６．９、１２５．７、１２５．４、４９．６（ｔ、Ｊ １０Ｈｚ）、４３．３、３７．９および３３．７。
³¹Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ ９．１。 Example 3: Synthesis of bisphospholane ligand (11)

(S, S) -2,5-trans-diphenylphosphorane-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 was formed). 2,3-Dichloroquinoxaline (136 mg, 0.68 mmol) was added in one portion and the residue was washed with dry THF (1 ml) (2,3-dichloroquinoxaline is only slightly soluble in THF). The mixture is warmed to room temperature (a red / orange solution is observed). The reaction mixture was stirred overnight, then quenched with 1M aqueous HCl (5 ml) (foaming 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 (2H, m), 7.77-7.73 (2H, m), 7.36-7.21 (10H, m), 6.37 (2H, t, J 8Hz), 6.29 (4H, d, J 8Hz), 6.07 (4H, t, J 8Hz), 4.53-4.46 (2H, m), 3 0.83-3.73 (2H, m), 2.58-2.45 (2H, m), 2.09-1.99 (4H, m) and 1.87-1.75 (2H, 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.

（Ｒ，Ｒ）−２，５−ｔｒａｎｓ−ジフェニルホスホラン−ボラン付加物（５１８ｍｇ、２．０４ｍｍｏｌ）を窒素下で乾燥ＴＨＦ（３ｍｌ）に溶解した。溶液を−２０℃に冷却した。ｎ−ＢｕＬｉの溶液（ヘキサン（ｈｅｘａｎｅｓ）における２．５Ｍ、０．８２ｍｌ、２．０４ｍｍｏｌ）を滴下して加え、混合物を３０分間撹拌した（黄色の溶液が形成される）。２，３−ジクロロピラジン（１３７ｍｇ、０．９２ｍｍｏｌ）をＴＨＦ（２ｍｌ）に溶解した溶液を加え、溶液を室温に加温し（赤／褐色の溶液が、２，３−ジクロロピラジンが添加された直後に観測される）。５時間後、ＴＭＥＤＡ（０．４５ｍｌ、３．０ｍｍｏｌ、１．５当量）を加え、混合物を一晩撹拌した。反応液を１ＭのＨＣｌ水溶液（５ｍｌ）により反応停止させ、酢酸エチル（１０ｍｌ）で抽出した。有機溶液を半飽和ブライン（１０ｍｌ）により洗浄し、乾燥し（ＭｇＳＯ₄）、ろ過し、減圧下で濃縮した。残渣をシリカでのクロマトグラフィー処理に供し、酢酸エチル／ヘプタン（１：８）により溶出して、生成物を黄色の固体として得た（１０５ｍｇ、０．１９ｍｍｏｌ、２１％）。
¹Ｈ ＮＭＲ（４００ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ ８．３６（２Ｈ、ｓ）、７．３５−７．２１（１０Ｈ、ｍ）、６．４８（２Ｈ、ｔ、Ｊ ７Ｈｚ）、６．４０（４Ｈ、ｄ、Ｊ ８Ｈｚ）、６．２４（４Ｈ、ｔ、Ｊ ８Ｈｚ）、４．２７−４．２０（２Ｈ、ｍ）、３．８０−３．６９（２Ｈ、ｍ）、２．５４−２．４３（２Ｈ、ｍ）、２．０７−１．９９（４Ｈ、ｍ）および１．８０−１．６６（２Ｈ、ｍ）。
¹³Ｃ ＮＭＲ（１００ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ １６３．９（ｂｒ ｄ）、１４４．６（ｔ、Ｊ １０Ｈｚ）、１４２．４、１３９．９、１２９．４（ｔ、Ｊ ５Ｈｚ）、１２８．５、１２７．５（ｍ）、１２６．１、１２５．９、５０．０（ｔ、Ｊ １０Ｈｚ）、４３．８、３８．９および３３．５。
³¹Ｐ ＮＭＲ（１６２ＭＨｚ、ＣＤＣｌ₃）δ ｐｐｍ ７．２。 Example 4: Synthesis of bisphospholane ligand (12)

(R, R) -2,5-trans-diphenylphosphorane-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 was 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 solution was added 2,3-dichloropyrazine. Observed immediately after). After 5 hours, TMEDA (0.45 ml, 3.0 mmol, 1.5 eq) was added and the mixture was stirred overnight. The reaction was quenched with 1M 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 (2H, s), 7.35-7.21 (10H, m), 6.48 (2H, t, J 7 Hz), 6.40 (4H , D, J 8 Hz), 6.24 (4H, t, J 8 Hz), 4.27-4.20 (2H, m), 3.80-3.69 (2H, m), 2.54-2 .43 (2H, m), 2.07-1.99 (4H, m) and 1.80-1.66 (2H, 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.

Claims (38)

As a catalyst, a partial structure according to the following formula (1):

Wherein (a) R independently in each occurrence is a group consisting of substituted aryl or unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl, and alkyl branched at the carbon atom bonded to the phosphorane ring. (B) n is an integer greater than or equal to 1; (c) the dotted line in each occurrence forms a bond, a single bond, a double bond, or part of an aromatic ring system Represents any further bonds so that they can be joined by bonds
An asymmetric reaction selected from the group consisting of hydroformylation, hydrocyanation, hydrocarboxylation and hydroesterification, carried out in the presence of a transition metal complex of an enantiomerically enriched chiral bis (phosphorane) ligand containing Process for providing olefins.   The process of claim 1, wherein the transition metal is selected from the group consisting of rhodium, ruthenium, iridium, palladium, cobalt, platinum, nickel, iron, and osmium.   The process of claim 2, wherein the transition metal is rhodium.   The process of claim 1, wherein the asymmetric reaction is either hydroformylation or hydrocyanation.   The process according to claim 4, wherein the reaction is an asymmetric hydroformylation of an olefin by reaction with a syn gas and the complex is a rhodium complex.   6. The process of claim 5 comprising enantioselective hydroformylation of a prochiral olefin.   6. The process of claim 5 comprising diastereoselective hydroformylation of enantiomerically enriched chiral olefins.   The process of claim 6, wherein the olefin is an α-olefin.   9. The process of claim 8, wherein the branched aldehyde produced in the reaction has an enantiomeric excess (ee) of at least 60%.   The process of claim 9, wherein the branched aldehyde has an ee of at least 80%.   9. The process of claim 8, wherein the branched: linear aldehyde product ratio is at least 3: 1.   The process of claim 9 wherein the branched: linear aldehyde product ratio is at least 8: 1. Wherein in α- olefin general formula R'CH = CH ₂ (wherein, R 'is in the α- olefins, unfunctionalized C ₁ ~ ₃₀ hydrocarbon or functionalized C ₁ ~ ₃₀ hydrocarbons (i.e., aryl, 9. The process of claim 8 having any of alkyl (including cycloalkyl), aralkyl or alkaryl), or heteroatom substituents.   14. The process of claim 13, wherein the [alpha] -olefin is selected from the group consisting of styrene, vinyl acetate and allyl cyanide.   6. The process of claim 5, further comprising derivatizing the aldehyde product.   16. The process of claim 15, wherein the derivatization reaction comprises an oxidation reaction, a reduction reaction, an amination reaction, an olefination reaction, a condensation reaction, an esterification reaction, an alkylation reaction, an arylation reaction or an acylation reaction.   The complex is pre-formed prior to use or isolated prior to use or pre-formed in a solution that is later combined in a reaction vessel with a substrate to be reacted The process of claim 1, which sometimes occurs either in situ.   18. The process of claim 17, wherein the complex is preformed in a solution that is later combined in a reaction vessel with a substrate to be reacted.   The process according to claim 1, wherein the 3-position and / or 4-position in each phosphorane ring is either unsubstituted or substituted. The bis (phosphorane) ligand is a partial structure according to the following formula (2):

Or the opposite enantiomer, and R is independently in each occurrence substituted aryl or unsubstituted aryl, substituted heteroaryl or unsubstituted heteroaryl, and alkyl branched at the carbon atom attached to the phosphorane ring The process of claim 18, wherein the process is selected from the group consisting of:   21. A process according to claim 20, wherein n = 1 or 2.   The process of claim 21, wherein n = 1.   23. The dicarbon skeleton connecting the phosphine group is either substituted or unsubstituted and can optionally form part of an isolated or fused ring. Process.   21. The process of claim 20, wherein R is isopropyl.   21. The process of claim 20, wherein R is aryl or heteroaryl (collectively Ar). The ligand is represented by the following formulas (3) to (8):

(However, X in (5) is either O or N-alkyl, and R in (8) is either H or alkyl)
26. The process of claim 25, selected from the group represented by:   26. The process of claim 25, wherein Ar is phenyl or substituted phenyl.   27. The process of claim 26, wherein Ar is phenyl. The ligand is represented by the following formula (9):

29. The process of claim 28, wherein the process is Ph-BPE as represented by The ligand is bisphopholane according to the following formula (10):

30. The process of claim 28, wherein The ligand is bisphopholane according to the following formula (11):

30. The process of claim 28, wherein The ligand is bisphopholane according to the following formula (12):

30. The process of claim 28, wherein   21. The process according to claim 20, wherein the reaction is an asymmetric hydroformylation of [alpha] -olefin by reaction with syn gas and the complex is a rhodium complex.   37. The process of claim 36, wherein the rhodium: ligand ratio is in the range of 0.5-5.   37. The process of claim 36, wherein the olefin: rhodium ratio ranges from 100 to 100,000. The ratio of syn gas (H _2: CO) is in the range of 0.1 to 10, The process of claim 36.   37. The process of claim 36, wherein the operating pressure is in the range of 1 psia to 1000 psia.   The process of claim 36, wherein the operating temperature is in the range of 20C to 140C.