Asymmetric Cycloaddition of N-Metalated Azomethine Ylides with the Optically Active α,β-Unsaturated Esters Derived from α-Amino Acids

Abstract

α,β-Unsaturated esters bearing a chiral oxazolidine or perhydropyrrolo[1,2-c]imidazole auxiliary at the β-position have been prepared and applied to the cycloadditions with N-metalated azomethine ylides derived from α-(benzylideneamino) esters. These reactions are found to proceed with an exclusively high diastereofacial selectivity to give 2,4-pyrrolidinedicarboxylates with four consecutive chiral centers after the removal of chiral auxiliary. Detailed stereochemistry in the transition state is discussed.

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of α‐Iminonitriles

“…[8] This is apparent from the transformations depicted in Scheme 3. As previously reported by Tsuge, [10] the treatment of pyrrolidine endo-5 a with a catalytic amount of DBU in toluene at reflux afforded the 2-pyrroline exo-7 with trans configuration at C4-C5, owing to the epimerisation at C4 under the basic reaction conditions. On the other hand, under milder reaction conditions, the treatment of pyrrolidine endo-5 a with AgBF 4 in CH 2 Cl 2 at room temperature selectively afforded the pyrroline endo-7 [25] without epimerisation at C4 (89% yield).…”

“…To improve the efficiency of the process we next applied this catalyst system to a more reactive dipolarophile, such as dimethyl fumarate (Table 1). Interestingly, unlike the previously reported thermal or LDA-mediated reactions, which give rise to C2/C5 cis/trans mixtures of isomers, [9,10] this catalytic asymmetric reaction provided exclusively the C2/C5 cis-substituted pyrrolidines, mainly as the endo isomer (endo-5 a). After surveying different solvents and bases (entries 1-8), the best results in terms of reactivity and enantioselectivity were obtained in Et 2 O using 20 mol % of NaOAc as base (81 % isolated yield and 81 % ee for endo-5 a; entry 8).…”

“…To access other types of substituted pyrrolidines, a-iminonitrile precursors are very appealing, since in the resulting 2-cyanopyrrolidines [7] the cyano group could further act as leaving group allowing its formal substitution by hydrogen or by a carbon nucleophile, [8] and thus leading to a wider variety of substituted pyrrolidines. Two decades ago Kane-A C H T U N G T R E N N U N G masa, Tsuge et al reported the non-enantioselective thermal [9] and LDA-promoted (LDA = lithium diisopropyl-A C H T U N G T R E N N U N G amide) [10] cycloaddition of alkyl-substituted a-iminonitriles with electron-deficient dipolarophiles, but the catalytic asymmetric version of this process remained to be developed. We describe herein the first catalytic asymmetric procedure for the 1,3-dipolar cycloaddition of a-iminonitriles, as well as some synthetic applications and a DFT theoretical study on the presumed nature of the metalated 1, 3-dipole. To evaluate the viability of a-iminonitriles as dipole precursors in catalytic asymmetric 1,3-dipolar cycloadditions, we first studied the reaction of N-benzylidenaminoacetonitrile (1) with methyl acrylate in the presence of ligand Fesulphos (2, 10 mol %).…”

“…However, unlike the well-established syn arrangement in the five-membered, N,O-bidentate-metalated, azomethine ylides derived from a-iminoesters, the structure of the metal-complex ylides derived from a-iminonitriles is unclear. [10] To shed some light on this point, a theoretical study at the DFT (B3LYP) [16] level by using the Gaussian 03 program [17,18] was carried out. Fesulphos-Ag I complexes with the azomethine ylide derived from N-benzylidenaminoacetonitrile 1 a were used as models.…”

Catalytic Asymmetric Mannich‐Type Reaction of N‐Alkylidene‐α‐Aminoacetonitrile with Ketimines

“…[1] For the rapid assembly of multiple functional groups at the stereogenic center, an a-cyano carbanion bearing a-heteroatom groups is an intriguing class of active nucleophile. [4][5][6][7][8] In contrast to numerous literature precedents on carbon-carbon bond formation using this useful pronucleophile, catalytic and enantioselective reactions have met with only limited success. [4][5][6][7][8] In contrast to numerous literature precedents on carbon-carbon bond formation using this useful pronucleophile, catalytic and enantioselective reactions have met with only limited success.…”