A novel chiral phosphine-oxazoline ligand 3 with an axis-unfixed biphenyl backbone was prepared. This ligand existed as a mixture of two diastereomers in equilibrium in solution. However, when it was coordinated with palladium(II), only one of the two kinds of possible diastereomer complexes with different axial chirality was formed. When this axis-unfixed chiral ligand was used, up to 90% ee was attained for the palladium-catalyzed asymmetric allylic alkylation. Chiral oxazoline ligands derived from readily available amino acids have found widespread use in metal-catalyzed asymmetric reactions, and extensive efforts have been devoted to the preparation of their efficient structural derivatives. 1 As it is well known that axially chiral biaryl catalysts exhibit excellent chirality transfer properties in asymmetric synthesis, a number of oxazoline containing axially chiral biaryl ligands have been developed. 2 These enantiomerically stable biaryls require at least three ortho-substituents to avoid the racemization due to the rotation around the internal bond of the biaryls. Most of these chiral axis-fixed biaryl ligands finally need process of resolution and only one of the two diastereomers shows excellent catalytic activities and enantioselectivities for most cases. Different from these ligands with an axisfixed biaryl backbone, a novel kind of chiral oxazoline ligands with an axis-unfixed biaryl backbone such as ligand 1 was developed by us; it exists as a mixture of two diastereomers in equilibrium in solution. 3 When this ligand was coordinated to Cu(I), only one of the two possible diastereomeric complexes was formed and showed excellent enantioselectivities in metal-catalyzed asymmetric reactions. On the other hand, we had also developed a novel chiral phosphino-oxazoline ligand 2 with an axis-fixed binaphthyl backbone. 4 These chiral P,Nligands were successfully employed in the palladium-catalyzed allylic alkylation and showed excellent enantioselectivities. Taking into account of the advantages of chiral P,N-chelating binaphthyl ligand 2 and axis-unfixed biphenyl ligand 1 (Figure 1) with high usage efficiency and unnecessary resolution process, we designed a novel chiral phosphine-oxazoline ligand 3 with an axis-unfixed biphenyl backbone. We report here the synthesis and complexation of 3, and its application in the palladiumcatalyzed allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate. Figure 1Compound 3 was synthesized as shown in Scheme 1. 2,2¢-Biphenol as starting material was treated with trifluoromethanesulfonic anhydride (Tf 2 O) to give triflate 4. Then the palladium-catalyzed insertion reaction of 4 with diphenylphosphine oxide was carried out to afford compound 5. Furthermore, in the presence of methanol, the palladium-catalyzed insertion reaction of 5 with CO gave monocarboxylic acid ester 6. In the presence of a catalytic amount of sodium hydride, the reaction of 6 with amino alcohol afforded amide compound 7. Then, 7 was treated with methanesulfonyl chloride in the pr...

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Two approaches to large-scale synthesis of the key intermediate 9, a precursor of novel dual inhibitors of SERT/5-HT 1A receptor, are described. These two approaches each feature a mild and efficient method for construction of the chroman-4-one scaffold, which can be used with substrates containing base-sensitive functionalities and enable synthesis on kilogram scale without chromatographic purification. The first-generation synthesis enables quick delivery of a kilogram quantity of the key intermediate 9 with only one slurry purification step. On the other hand, the highly practical second-generation synthesis is suitable for the multikilogram campaign.

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