The novel C(2)-symmetric bis(imidazolidine)pyridine (PyBidine) ligand was easily synthesized in a single condensation of 2,6-pyridyl aldehyde and optically active (S,S)-diphenylethylenediamine. In the C(2)-symmetric PyBidine-Cu(OTf)(2) complex, imidazolidine rings act as "chiral fences" to shield the first and third quadrants. Use of the PyBidine-Cu(OTf)(2) complex as a catalyst enabled the highly endo-selective reaction of imino esters and nitroalkenes to give the adducts in up to 99% ee.

Highly functionalized complex molecules are key tools for promoting biochemical research and developing pharmaceutical compounds because the positions of the heteroatoms and the direction of lone pairs in the molecules are closely linked to their biological activities. Catalytic asymmetric synthesis is a fundamental technique to supply these complex compounds in a stereoselective manner. As a representative example, the catalytic asymmetric 1,3-dipolar cyclization reaction has been widely studied for the synthesis of multisubstituted pyrrolidines.[1] Azomethine ylides, generated from an iminoester and a nitroalkene, can be used to introduce an additional nitro functionality onto the pyrrolidine ring, thus affording four stereogenic centers and up to eight diastereomers. When a trans nitroalkene is used, the stereoconjunction between the 3-and 4-positions is fixed in a trans conformation, and four diastereomers are possible, classified as endo, exo, endo', and exo' isomers (Scheme 1).In 2005, Carretero and co-workers reported an example of exo-selective pyrrolidine ring construction, [2a, 3] and Hou and co-workers succeeded in switching the endo/exo selectivity by tuning the electron density of the chiral ligand. [4,5] We have also recently succeeded in performing the endo-selective cyclization using a PyBidine/Cu(OTf) 2 catalyst.[6] Success in the endo-selective cyclization led us to undertake the additional challenge of obtaining the other diastereomers. [7] Screening of the metal salts to investigate the exo' (and/or endo') adduct ratio found that nickel salts facilitated the selective production of the exo' product.[8] As the basis for exploring efficient asymmetric catalysts, we prepared a library of solid-phase imidazoline-aminophenol/metal catalysts (Table 1) [9] and developed a new high-throughput screening (HTS) method, in which the reaction mixtures were directly analyzed following the solid-phase catalysis by circular dichroism (CD) spectroscopy. [10] Using this "solid-phase catalysis/CD-HTS" system, appropriate catalysts for the exo'-selective synthesis were explored using the solid-phase imidazoline-aminophenol/Ni(OAc) 2 catalysts (Figure 1). The solid-phase L9/Ni(OAc) 2 and L10/Ni(OAc) 2 catalysts recorded the highest CD intensities among the 20 solidphase catalysts tested. Specifically, the L9/Ni(OAc) 2 catalyst gave the exo' adduct in 32 % yield and 70 % ee, whilst L10/ Ni(OAc) 2 gave the adduct in 23 % yield and 76 % ee. With this fascinating exo'-selective asymmetric catalysts in hand, the reaction conditions were re-examined in the solution phase (for optimization, see the Supporting Information).Under the optimized condition, the L21 (corresponding to L9 without the solid support)/Ni(OAc) 2 catalysis reaction in K 2 CO 3 gave the product in 99 % yield in acetonitrile at À10 8C in a highly exo'-selective manner (exo'/endo/exo/endo' = 82:16:1:1), and the exo' adduct was obtained in up to Scheme 1. Possible diastereomers generated in the pyrrolidine synthesis using an iminoester and a trans nitro...

Highly functionalized complex molecules are key tools for promoting biochemical research and developing pharmaceutical compounds because the positions of the heteroatoms and the direction of lone pairs in the molecules are closely linked to their biological activities. Catalytic asymmetric synthesis is a fundamental technique to supply these complex compounds in a stereoselective manner. As a representative example, the catalytic asymmetric 1,3-dipolar cyclization reaction has been widely studied for the synthesis of multisubstituted pyrrolidines.[1] Azomethine ylides, generated from an iminoester and a nitroalkene, can be used to introduce an additional nitro functionality onto the pyrrolidine ring, thus affording four stereogenic centers and up to eight diastereomers. When a trans nitroalkene is used, the stereoconjunction between the 3-and 4-positions is fixed in a trans conformation, and four diastereomers are possible, classified as endo, exo, endo', and exo' isomers (Scheme 1).In 2005, Carretero and co-workers reported an example of exo-selective pyrrolidine ring construction, [2a, 3] and Hou and co-workers succeeded in switching the endo/exo selectivity by tuning the electron density of the chiral ligand. [4,5] We have also recently succeeded in performing the endo-selective cyclization using a PyBidine/Cu(OTf) 2 catalyst.[6] Success in the endo-selective cyclization led us to undertake the additional challenge of obtaining the other diastereomers. [7] Screening of the metal salts to investigate the exo' (and/or endo') adduct ratio found that nickel salts facilitated the selective production of the exo' product.[8] As the basis for exploring efficient asymmetric catalysts, we prepared a library of solid-phase imidazoline-aminophenol/metal catalysts (Table 1) [9] and developed a new high-throughput screening (HTS) method, in which the reaction mixtures were directly analyzed following the solid-phase catalysis by circular dichroism (CD) spectroscopy. [10] Using this "solid-phase catalysis/CD-HTS" system, appropriate catalysts for the exo'-selective synthesis were explored using the solid-phase imidazoline-aminophenol/Ni(OAc) 2 catalysts (Figure 1). The solid-phase L9/Ni(OAc) 2 and L10/Ni(OAc) 2 catalysts recorded the highest CD intensities among the 20 solidphase catalysts tested. Specifically, the L9/Ni(OAc) 2 catalyst gave the exo' adduct in 32 % yield and 70 % ee, whilst L10/ Ni(OAc) 2 gave the adduct in 23 % yield and 76 % ee. With this fascinating exo'-selective asymmetric catalysts in hand, the reaction conditions were re-examined in the solution phase (for optimization, see the Supporting Information).Under the optimized condition, the L21 (corresponding to L9 without the solid support)/Ni(OAc) 2 catalysis reaction in K 2 CO 3 gave the product in 99 % yield in acetonitrile at À10 8C in a highly exo'-selective manner (exo'/endo/exo/endo' = 82:16:1:1), and the exo' adduct was obtained in up to Scheme 1. Possible diastereomers generated in the pyrrolidine synthesis using an iminoester and a trans nitro...

Chiral ligand: The [PyBidine–Cu(OTf)2] (Tf=trifluoromethanesulfonate) complex catalyzed the asymmetric Mannich reaction of sulfonyl imines and iminoesters to give the products in a high syn‐selective manner. For both 4‐toluene (Ts)‐ and 4‐nitrophenylsulfonyl (Ns)‐imines, the syn‐adducts were obtained in up to 99 % ee (see scheme).

A new bis(imidazolidine)pyridine ligand is easily synthesized in a single condensation of 2,6‐pyridyl bisaldehyde and optically active diphenylethylenediamine.

Carboxylic acid esters Q 0530Kinetic Resolution of 1,2-Diols Using Nitrogen-Tethered Bisimidazoline-Copper(I) Catalyzed Benzoylation. -The resolution of racemic diols (I) proceeds with moderate enantioselectivity. Although the benzoylated alcohol (IV) is the minor product, it records higher enantioselectivities than major product (III). However, conducting the experiments with the sterically hindered benzoyl chloride (V) improves the stereoselectivity essentially. -(ARAI*, T.; MIZUKAMI, T.; MISHIRO, A.; YANAGISAWA, A.; Heterocycles 76 (2008) 2, 995-1000; Dep. Chem., Fac. Sci., Chiba Univ., Inage, Chiba 263, Japan; Eng.) -H. Hoennerscheid 18-091

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The reaction is effective for the N‐tosyl and N‐4‐nosylimines but can not be applied to the 2‐nosylimines.