Highly Diastereoselective [3+2] Cycloadditions between Nonracemic p‐Tolylsulfinimines and Iminoesters: An Efficient Entry to Enantiopure Imidazolidines and Vicinal Diaminoalcohols

Abstract

A new procedure for the asymmetric synthesis of imidazolidines and vicinal diamines is reported. The 1,3-dipolar cycloaddition between nonracemic p-tolylsulfinimines and azomethine ylides generated in situ from alpha-iminoesters and LDA produces N-sulfinylimidazolidines with a high degree of stereocontrol. In contrast, the presence of Lewis acids promotes formation of the cycloadducts through a highly diastereoselective process with opposite stereochemistry. Subsequent transformations of the imidazolidines including oxidative, reductive, and hydrolytic processes that provide easy access to vicinal diaminoalcohols have been explored. Among these, reductive cleavage of the aminal with LiAlH4 is an extremely efficient and general reaction for the synthesis of enantiopure N-sulfinyl-N'-benzyldiaminoalcohols

Asymmetric synthesis of γ-chloro-α,β-diamino- and β,γ-aziridino-α-aminoacylpyrrolidines and -piperidines via stereoselective Mannich-type additions of N-(diphenylmethylene)glycinamides across α-chloro-N-sulfinylimines

“…The resulting β-amino deprotected syn -γ-chloro-α,β-diaminocarboxylamide could subsequently ring close further to trans -imidazolidine 12b , which will be less sterically congested than an analogous cis -imidazolidine. In the literature, comparable non-halogenated trans -imidazolidines were already synthesized by 1,3-dipolar cycloaddition of N -benzylidene glycine ester enolates across N -sulfinylaldimines in the presence of a Lewis acid [43]. The trans -stereochemistry of imidazolidine 12b was ensured by the vicinal coupling constant 3 J H4-H5 = 7.43 Hz and the 1 H NMR chemical shift of H4 (3.85 ppm), which were in the same range as for closely related trans -imidazolidines and trans -oxazolidines [43–45].…”

Mastering chiral substituted 2-oxopiperazines

“…Chiral sulfinimines, readily available in both enantiomeric forms, have proven to be valuable intermediates for the synthesis of different nitrogen-containing targets. 77 Viso et al [78][79][80] reported the asymmetric synthesis of enantiopure N-sulfinyl imidazolidines 176 via a diastereoselective 1,3-dipolar cycloaddition between readily available p-toluenesulfinimines 174 and glycine iminoester enolates 175 (Scheme 33).…”

“…Reductive [78][79][80] or hydrolytic cleavage 81 of the aminal moiety transformed N-sulfinyl imidazolidines 176 into differently protected vicinal diamino alcohols 177 and N-sulfinyl diamino esters 179, respectively. These classes of compounds are potential substrates for the synthesis of enantiopure N-sulfinyl piperazinones 178 and 180, respectively, bearing suitable arms for further functionalizations.…”

“…Thus, substrate 186 has been obtained by a five-step sequence featuring cycloaddition between 181 and 182 to produce 183, then taken to 184 by reduction 80 and silylation. 83 This compound was N-acylated to 185 and cyclized in basic media to produce 186.…”

Synthetic Approaches to α,β‐Diamino Acids

“…p-Toluenesulfinimines 11 can participate as chiral inductors in the BF 3 ÁEt 2 O-mediated addition of lithiated a-imino glycinates to afford enantiopure 4,5-trans 4-carbomethoxy N-sulfinylimidazolidines 12 (Scheme 9.2). Interestingly in the absence of BF 3 ÁEt 2 O, enolates derived from phenylalanine, alanine, and leucine treated with lithium diisopropylamide (LDA) provide imidazolidines 12a containing quaternary centers with endo stereocontrol and excellent diastereofacial discrimination of the chiral sulfiminine [10]. Subsequently, enantiopure syn N-sulfinyl-a,b-diamino esters 13 can be selectively produced under acidic conditions modulated by choosing a non-nucleophilic solvent [tetrahydrofuran (THF) : H 2 O versus MeOH] to preserve the sulfinamide moiety and thus achieve different degrees of functionalization at the amino groups [11].…”