Catalytic Asymmetric exo′‐Selective [3+2] Cycloaddition of Iminoesters with Nitroalkenes

Abstract

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...

Catalytic Asymmetric exo′‐Selective [3+2] Cycloaddition for Constructing Stereochemically Diversified Spiro[pyrrolidin‐3,3′‐oxindole]s

“…The absolute configuration at the 2' and 5' positions was the same as the product obtained in the previously reported exo' selective [3+2] cycloaddition of nitroalkenes and iminoesters. [13] Moreover, when the countersubstrate of nitroalkene in the previous study [13] was replaced with the alkenyl amide part of methyleneindolinone, the absolute configurations at 3R, 4'S are also well explained in the mechanism depicted in Scheme 2. Thus, the mechanism for the enantio-face selection of methyleneindolinone and iminoester is considerable by analogy with that for the [3+2] cycloaddition of nitroalkenes and iminoesters.…”

The Future of Catalysis by Chiral Lewis Acids

“…Reaction occurs with preformed ylides (e. g., Scheme 17) [74] or those formed in situ by coordination with the imine nitrogen and base removal of an alpha-hydrogen (e. g., Scheme 18) [75]. Variations of base-stabilizing substituents, dipolarophile, and ligated catalyst give enormous breadth to this transformation [76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91], and enantioselectivities greater than 90% ee are generally achieved. Activation of the dipole occurs at nitrogen which is advantageously located between the two carbon atoms that enclose the five-membered ring formed by cycloaddition.…”

Asymmetric 1,3-Dipolar Cycloadditons of Stabilized Azomethine Ylides with Nitroalkenes

“…Only glycine derived imino esters 6 (R 3 = Ar, R 4 = H, R 5 = Me) and nitroalkenes 10 (R 1 = Ar or alkyl) were essayed using 10 mol% of catalyst loading in the presence of potassium carbonate at -10 ºC in acetonitrile as solvent. Non conventional exo'-5cycloadducts were obtained (corresponds with structure endo-5 epimer at 5 position, R 3 is in trans-relative position with respect to the nitro group, Scheme 16) as major stereoisomers in good yields (64-99%), with variable diastereoselectivity (two or three stereoisomers could be identified) and high enantioselections (91-99% ee) [75].…”