A Practical Strategy for the Structural Diversification of Aliphatic Scaffolds through the Palladium‐Catalyzed Picolinamide‐Directed Remote Functionalization of Unactivated C(sp³)H Bonds

Abstract

Hats off to the director: High levels of regio‐ and stereoselectivity were observed for a broad range of amine substrates with aryl and vinyl iodide coupling partners in the title reaction. The synthetic utility of this strategy was highlighted by the ready preparation from threonine of 1, with a removable picolinamide auxiliary PAr, and its coupling with 2 in a concise formal synthesis of (+)‐obafluorin. TBS=tert‐butyldimethylsilyl.

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).…”

Catalytic C–H Bond Functionalization of Cyclopropane Derivatives

“…Only aryl iodides were tolerated as coupling partners in the reports from Babu and Charette. Mechanistic evidence from the Daugulis lab [36,37] and others [42] supports a Pd(II)/(IV) pathway for bidentate-directed C-H functionalization. Sustac and Charette also investigated the mechanism of their cyclopropane arylation [40].…”

Recent trends in Pd-catalyzed remote functionalization of carbonyl compounds

“…Ag 2 CO 3 , 80°C). 8 Electron-rich, electron-neutral, electron-poor as well as ortho-substituted iodoarenes were coupled with cyclic PA-modified amino esters in moderate to excellent yields (47-85%) (Scheme 1A). In contrast, linear substrates such as the threonine methyl ester shown in Scheme 1(B) were usually obtained in reduced yields.…”