Stereoselective Synthesis of Chiral α‐Amino‐β‐Lactams through Palladium(II)‐Catalyzed Sequential Monoarylation/Amidation of C(sp³)H Bonds

Abstract

Give Me an Ar, give Me an N! Arylation of the methyl group in a simple derivative of readily available alanine under palladium catalysis was followed by intramolecular amidation at the same position to give chiral α-amino-β-lactams with a wide range of aryl substituents (see scheme; Phth=phthaloyl). The α-amino-β-lactams were obtained in moderate to high yields with good functional-group tolerance and high diastereoselectivity.

Synthesis of β-alkynyl α-amino acids via palladium-catalyzed alkynylation of unactivated C(sp3)-H bonds

“…Complementary to the conventional synthesis strategies based on the transformation of existing functional groups, we envisioned these molecules could be quickly accessed via selective functionalization of sp 3 hybridized C−H bonds on the side chains of common -AA precursors. Building upon the pioneer work by Daugulis et al [9,10] and Corey et al [11], we and others have developed methods to prepare -aryl, -alkyl, and -vinyl -AAs doi: 10.1007/s11426-015-5392-z via Pd-catalyzed carboxamide-directed C(sp 3 )−H functionalization reactions [12][13][14][15][16][17][18][19][20][21][22][23]. Herein, we report a readily applicable method to prepare -alkynyl -amino acids via Pd-catalyzed diastereoselective C(sp 3 )−H alkynylation of common -amino acids precursors with acetylene bromide (Scheme 1).…”

Ligand‐Enabled β‐C–H Arylation of α‐Amino Acids Without Installing Exogenous Directing Groups

“…Previously, the research in our group has focused on monodentate weak-coordinating groups for C–H activation; these directing groups, compared to bidentate directing groups [6] or strong monodentate-directing groups, offer the advantage of benefiting from ligand-accelerated catalysis. [7] Our work has been continuously influenced by our early studies on oxazoline-directed C(sp 3 )–H activation, [8] in which we used stereochemical information obtained in the C–H insertion step to deduce ideal geometric, steric, and electronic requirements of the reaction pretransition-state.…”

Diastereoselective Substrate-Controlled Transition-Metal-Catalyzed C–H Activation: An Old Solution to a Modern Synthetic Challenge

“…33 They hypothesized that by using the alanine derivate 26 as a starting material, β-arylation of the methyl group and subsequent intramolecular C-N coupling should deliver the common α-amino-β-lactam structural motifs. However, the development of this two-step reaction presents two major difficulties.…”