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. ...

AI Technical Summary

Problems solved by technology

In 2007, Zhou Qilin's group found that the ruthenium complex of SFDP exhibited excellent activity and enantioselectivity in the hydrogenation of tiglic acid and α-methylcinnamic acid (see X.Cheng, Q.Zhang, J.-H .Xie, L.-X.Wang, Q.-L.Zhou, Angew.Chem., Int.Ed.2005,44,1118-1121.), followed by ChenPhos and Trifer based on the ferrocene framework developed by Chen Weiping's group Shows good catalytic effect in the hydrogenation of α-methylcinnamic acid and α-oxo-α,β-unsaturated acids (see a) W.Chen, P.J.McCormack, K.Mohammed, W.Mbafor, S.M.Roberts , J.Whittall, Angew.Chem., Int.Ed.2007, 46, 4141-4144; b) W.Chen, F.Spindler, B.Pugin, U.Nettekoven, Angew.Chem., Int.Ed.2013 , 52, 8652-8656.), Zhang Xumu group also developed Wudaphos based on ferrocene skeleton, which showed excellent activity and enantioselectivity in the hydrogenation of α-acrylic acid derivation (see Chen, C.; Wang, H.; Zhang, Z., Jin, S.; Wen, S., Ji, J., Chung, L.W. Dong, X.-Q.; Zhang, X. Chem. Sci., 2016, 7, 6669-6673 .), but the scope of application of these ligands is very narrow. In order to obtain excellent enantioselectivity, it is often necessary to carry out complex structural modifications on the ligands, and there is still a lack of chiral bisphosphine ligands that are widely applicable to a variety of substrates

The Ir-SIPhOX system developed by Zhou Qilin's research group is a catalytic system with a wide range of substrates (see a) S.Li, S.F.Zhu, J.H.Xie, S.Song, C.M.Zhang, Q.L.Zhou, J.Am.Chem. Soc.2010, 132, 1172-1179; b) S.Li, S.F.Zhu, C.M.Zhang, S.Song, Q.L.Zhou, J.Am.Chem.Soc.2008, 130, 8584-8585; c) S.Song , S.F.Zhu, L.Y.Pu, Q.L.Zhou, Angew.Chem., Int.Ed.2013, 52, 6072-6075; d) S.Song, S.F.Zhu, Y.B.Yu, Q.L.Zhou, Angew.Chem., Int.Ed. .2013,52,1556-1559; e) Q.Wang, Z.Zhang, C.Chen, H.Yang, Z.Han, X.-Q.Dong, X.Zhang, Org.Chem.Front.2017, 4,627-630; f) S.F.Zhu, Q.L.Zhou, Acc.Chem.Res. 2017, 50, 988-1001.) But this system is not reactive towards cyclic tetrasubstituted carboxylic acids (see a) S.Song, S.F.Zhu, Y .Li, Q.L.Zhou, Org.Lett.2013, 15, 3722-3725; b) A.Schumacher, M.G.Schrems, A.Pfaltz, Chem.-AsianJ.2011, 17, 13502-13509.), the same as the system needs The addition of alkali to promote the reaction, to some extent limits the scope of application of the system

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