Oxaspirobisphosphine Ligands and Their Applications in Asymmetric Hydrogenation of α,β-Unsaturated Carboxylic Acids

Abstract

An oxaspirocyclic bisphosphorus ligand provided by the present invention has the structure of the following general formula (I): wherein, in the general formula (I): R 1 , R 2 , R 3 and R 4 Same, it is an alkyl group, an alkoxy group, an aryl group, an aryloxy group or a hydrogen atom, and the R 1 , R 2 , R 3 and R 4 Including the form of ring formation, non-ring formation, any two formation of rings or the formation of multiple rings between two pairs; R 5 , R 6 is an alkyl group, an aryl group or a hydrogen atom; R 7 , R 8 Alkyl or benzyl or aryl. The present invention also provides an application of O-SDP, an oxaspirocyclic bisphosphine ligand, in the asymmetric hydrogenation of α, β-unsaturated carboxylic acids. Its complexes with ruthenium exhibit excellent activity and enantioselectivity in the asymmetric hydrogenation of various types of α, β-unsaturated carboxylic acids, and can obtain chirality with an enantioselectivity as high as 99%. Carboxylic acid products. This synthesis method can be applied to the construction of the core skeleton of chemical molecules with important biological activities such as Paroxetine, Femoxetine, nipecotic acid and Sacubitril.

Description

technical field

[0001] The invention relates to an oxaspirocyclic bisphosphine ligand O-SDP and its application in the asymmetric hydrogenation of α,β-unsaturated carboxylic acids. Background technique

[0002] Chiral carboxylic acids and their chiral carboxylic acid derivative fragments widely exist in biologically active drug molecules and natural products, and have high potential application value in the field of asymmetric catalysis. Catalytic asymmetric hydrogenation of α,β-unsaturated carboxylic acids is one of the most direct and efficient methods to construct chiral carboxylic acid compounds. Over the past few decades, this field has undergone rapid development with the development of chiral bisphosphine ligands. DIOP synthesized by Kagan group (see Dang, T.P.; Kagan, H.B.J. Chem. Soc. D: Chem. Commun. 1971, 481.), BINAP developed by Noyori group (see Miyashita , A.; Yasuda , A.; Takaya , H.; Toriumi , K.; Ito , T.; Souchi , T.; Noyori R.; J. Am. Chem. ...

Examples

Embodiment 1

[0051] Catalyst Rh(1a)OAc 2 Preparation of:

[0052] in N 2 Under atmosphere, add [RuPhCl 2 ] 2 (25 mg, 0.05 mmol), ligand 1a (61 mg, 0.103 mmol), and then 2 mL of DMF was added. React at 100°C for 3h. After cooling to room temperature, 1.5 mL of anhydrous sodium acetate (0.111 g, 1.3 mmol) in methanol was added. After 20Min, deoxygenated deionized water was added. A gray solid precipitated from the reaction system, filtered, and the solvent and water were removed under reduced pressure to obtain the catalyst Rh(1a)OAc 2 (57 mg, yield = 71%).

Embodiment 2

[0054] Catalyst Rh(1a)(CF 3 CO) 2 Preparation of:

[0055] in N 2 Under atmosphere, add bis-(2-methallyl) cyclooct-1,5-diene ruthenium (32mg, 0.05mmol), ligand 1a (61mg, 0.103mmol) to a 10mL single-necked bottle, and then add 2 mL of acetone. React at 40°C for 0.5h. Then add trifluoroacetic acid (33 mg, 0.3 mmol), stir overnight at 40 ° C, remove the solvent under reduced pressure, then add 1 mL of petroleum ether, and filter to obtain the target product Rh (1a) (CF 3 CO) 2 (81 mg, yield = 88%).

Embodiment 3

[0057] Synthesis of (3R,4R)-1-(tert-butoxycarbonyl)-4-phenyl-3-carboxylic acid 3a:

[0058] in N 2 Under atmosphere, add 2a (0.1mmol), catalyst Ru(1a)OAc to the hydrogenation vial 2 (0.8mg, 0.001mmol) and 1mL of methanol. After 24 h under a hydrogen atmosphere of 60 atm, all the raw materials were converted into products. 29.0mg, product yield=95%,>99%ee, [α] 25 D =+38.0 (c=0.5, CHCl 3 ), yellow oil. 1 H NMR (400MHz, CDCl 3 )δ7.29-7.24(m,2H,Ar),7.23-7.17(m,3H,Ar),4.44(d,J=12.7Hz,1H,CH 2 ), 4.26 (d, J=9.0Hz, 1H, CH 2 ), 3.16(d, J=11.1Hz, 1H, CH), 3.01-2.82(m, 3H, CH 2 ),2.55(dt,J=12.0,8.6Hz,1H,CH),1.68(dd,J=13.0,2.8Hz,1H,CH 2 ),1.39(s,9H,CH 3 ). 13 C NMR (101MHz, CDCl 3 )δ176.9, 154.7, 142.1, 128.3, 127.4, 126.6, 79.8, 46.1, 45.2, 43.8, 43.0, 28.2, 25.6. HRMS (ESI) calcd.for C 17 h 22 NO 4 [M-H] - :304.1554, Found: 304.1556.HPLC conditions: Daicel AD-3, injection volume 2μL (c=1mg / mL), Hexane / IPA=97 / 3, 1.0mL / Min, 208nm, t R (major) = 29.6Min,t R (minor) = 31....

technical field

[0001] The invention relates to an oxaspirocyclic bisphosphine ligand O-SDP and its application in the asymmetric hydrogenation of α,β-unsaturated carboxylic acids. Background technique

[0002] Chiral carboxylic acids and their chiral carboxylic acid derivative fragments widely exist in biologically active drug molecules and natural products, and have high potential application value in the field of asymmetric catalysis. Catalytic asymmetric hydrogenation of α,β-unsaturated carboxylic acids is one of the most direct and efficient methods to construct chiral carboxylic acid compounds. Over the past few decades, this field has undergone rapid development with the development of chiral bisphosphine ligands. DIOP synthesized by Kagan group (see Dang, T.P.; Kagan, H.B.J. Chem. Soc. D: Chem. Commun. 1971, 481.), BINAP developed by Noyori group (see Miyashita , A.; Yasuda , A.; Takaya , H.; Toriumi , K.; Ito , T.; Souchi , T.; Noyori R.; J. Am. Chem. ...

Examples

Embodiment 1

[0051] Catalyst Rh(1a)OAc 2 Preparation of:

[0052] in N 2 Under atmosphere, add [RuPhCl 2 ] 2 (25 mg, 0.05 mmol), ligand 1a (61 mg, 0.103 mmol), and then 2 mL of DMF was added. React at 100°C for 3h. After cooling to room temperature, 1.5 mL of anhydrous sodium acetate (0.111 g, 1.3 mmol) in methanol was added. After 20Min, deoxygenated deionized water was added. A gray solid precipitated from the reaction system, filtered, and the solvent and water were removed under reduced pressure to obtain the catalyst Rh(1a)OAc 2 (57 mg, yield = 71%).

Embodiment 2

[0054] Catalyst Rh(1a)(CF 3 CO) 2 Preparation of:

[0055] in N 2 Under atmosphere, add bis-(2-methallyl) cyclooct-1,5-diene ruthenium (32mg, 0.05mmol), ligand 1a (61mg, 0.103mmol) to a 10mL single-necked bottle, and then add 2 mL of acetone. React at 40°C for 0.5h. Then add trifluoroacetic acid (33 mg, 0.3 mmol), stir overnight at 40 ° C, remove the solvent under reduced pressure, then add 1 mL of petroleum ether, and filter to obtain the target product Rh (1a) (CF 3 CO) 2 (81 mg, yield = 88%).

Embodiment 3

[0057] Synthesis of (3R,4R)-1-(tert-butoxycarbonyl)-4-phenyl-3-carboxylic acid 3a:

[0058] in N 2 Under atmosphere, add 2a (0.1mmol), catalyst Ru(1a)OAc to the hydrogenation vial 2 (0.8mg, 0.001mmol) and 1mL of methanol. After 24 h under a hydrogen atmosphere of 60 atm, all the raw materials were converted into products. 29.0mg, product yield=95%,>99%ee, [α] 25 D =+38.0 (c=0.5, CHCl 3 ), yellow oil. 1 H NMR (400MHz, CDCl 3 )δ7.29-7.24(m,2H,Ar),7.23-7.17(m,3H,Ar),4.44(d,J=12.7Hz,1H,CH 2 ), 4.26 (d, J=9.0Hz, 1H, CH 2 ), 3.16(d, J=11.1Hz, 1H, CH), 3.01-2.82(m, 3H, CH 2 ),2.55(dt,J=12.0,8.6Hz,1H,CH),1.68(dd,J=13.0,2.8Hz,1H,CH 2 ),1.39(s,9H,CH 3 ). 13 C NMR (101MHz, CDCl 3 )δ176.9, 154.7, 142.1, 128.3, 127.4, 126.6, 79.8, 46.1, 45.2, 43.8, 43.0, 28.2, 25.6. HRMS (ESI) calcd.for C 17 h 22 NO 4 [M-H] - :304.1554, Found: 304.1556.HPLC conditions: Daicel AD-3, injection volume 2μL (c=1mg / mL), Hexane / IPA=97 / 3, 1.0mL / Min, 208nm, t R (major) = 29.6Min,t R (minor) = 31....

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