Enantioselective sp³ C–H alkylation of γ-butyrolactam by a chiral Ir(i) catalyst for the synthesis of 4-substituted γ-amino acids

Abstract

Ir-catalyzed sp(3) C-H alkylation of γ-butyrolactam with alkenes was used for the highly enantioselective synthesis of 5-substituted γ-lactams, which were readily converted into chiral 4-substituted γ-amino acids. A broad scope of alkenes was amenable as coupling partners, and the alkylated product using acrylate could be transformed into the key intermediate of pyrrolam A synthesis.

Enantio‐ and Diastereoswitchable C−H Arylation of Methylene Groups in Cycloalkanes

“…Asymmetric induction based on the use of chiral ligands is still in its infancy in directed C(sp 3 )−H functionalization. Encouraging results have been achieved for sterically accessible methyl groups and for methylene groups with electronic bias, including strained cycloalkyl systems, benzylic positions, and α‐heteroatom‐substituted methylene C−H bonds . However, the control of both enantio‐ and diastereoselectivity in directed C−H functionalizations of simple, unbiased methylene groups is still an unsolved challenge.…”

Rhodium(III)‐Catalyzed Enantiotopic C−H Activation Enables Access to P‐Chiral Cyclic Phosphinamides

“…[11] Recently,c hiral cyclopentadienyl ligands allowed the development of several asymmetric variants. To the best of our knowledge,i nc ontrast to asymmetric CÀHf unctionalizations catalyzed by Pd II , [8h, 13] Pd 0 , [8e-g, 14] or Ir I , [15] no example in which the CÀHa ctivation step is enantiodetermining has been reported for Rh III catalysis.Ifthe two difficulties of this step-enantioselection and reversibility-could be addressed, such sequence would offer great advantages.The intermediate would allow product diversification using different downstream trapping agents. To the best of our knowledge,i nc ontrast to asymmetric CÀHf unctionalizations catalyzed by Pd II , [8h, 13] Pd 0 , [8e-g, 14] or Ir I , [15] no example in which the CÀHa ctivation step is enantiodetermining has been reported for Rh III catalysis.Ifthe two difficulties of this step-enantioselection and reversibility-could be addressed, such sequence would offer great advantages.The intermediate would allow product diversification using different downstream trapping agents.…”

“…[ Other solvents such as toluene,a cetonitrile,o rd ioxane caused astrong reduction in conversion, yield, and selectivity (entries [14][15][16].…”

“…[12] However,i na ny reported case,the enantiodetermining step proceeds after the C sp 2 ÀHactivation step,consisting of selective additions across p-unsaturation, [12c-f,i-q] insertions of diazo esters, [12g] or the generation of axial chirality by locking the conformation [12h, r] (Scheme 1). To the best of our knowledge,i nc ontrast to asymmetric CÀHf unctionalizations catalyzed by Pd II , [8h, 13] Pd 0 , [8e-g, 14] or Ir I , [15] no example in which the CÀHa ctivation step is enantiodetermining has been reported for Rh III catalysis.Ifthe two difficulties of this step-enantioselection and reversibility-could be addressed, such sequence would offer great advantages.The intermediate would allow product diversification using different downstream trapping agents. Ideally,t he selectivity would be independent of the used trapping agent, enabling access to abroad variety of attractive products.…”

Pyrrolizidine alkaloids: occurrence, biology, and chemical synthesis

“…Scheme 50 illustrates an application of this to the formal synthesis of (-)-(R)-pyrrolam A. 132 The initial alkylation (step a) was slow, taking one week in boiling dioxane to reach completion, but the product 290 was produced in high yield with a 90% ee. This level of enantiomeric purity was retained during the following four steps that comprised removal of the 2-pyridyl group, ester reduction and tosylation, then basemediated cyclisation.…”