Ligand-Promoted Pd(II)-Catalyzed Functionalization of Unactivated C(sp³)–H Bond: Regio- and Stereoselective Synthesis of Arylated Rimantadine Derivatives

Abstract

Stereoselective functionalization of the adamantyl bridge methylene C­(sp3)–H bonds is a rather appealing, yet challenging strategy due to the bulky and unactivated nature. Here we present a palladium-catalyzed C­(sp3)–H arylation/hetereoarylation of the antivirus drug rimantadine with the picolinamide moiety as the bidentate directing group and a mono-N-protected amino acid (MPAA) as the ligand. Multisubstituted rimantadine substrates and diverse aryl/heteroaryl iodides are well tolerated, and a series of optically pure arylated rimantadine derivatives have been synthesized in high regio- and diastereoselectivity that provides ample compound space for further pharmaceutical research.

Unraveling the Binding, Proton Blockage, and Inhibition of Influenza M2 WT and S31N by Rimantadine Variants

“…It was reported that the reaction of 1-adamantanecarbonitrile with ethyl magnesium bromide and titanium tetraisopropoxide afforded 4 in 52% yield. 15 We tested twice this procedure with 1-adamantanecarbonitrile and methylmagnesium bromide yielding in our hands 3 with only 10% yield, which is lower than the ∼50% yield starting from 6 or 1-adamantanecarboxylic acid (Scheme 2). Table 1 includes thermodynamic parameters of binding against M2TM WT and M2TM S31N.…”

Directed C–H Functionalization of the Adamantane Framework

“…The first diastereoselective functionalization of the 1-(1-aminoethyl)adamantane derivative 97 was presented with picolinamide (PA) as the directing group and a mono-N-protected amino acid (Boc-L-ILeu-OH) as the ligand (Scheme 41). 58 The diarylated compounds 98 were obtained in yields up to 91% with absolute diastereoselectivity. The precomplex C7 formed after the ligand exchange with Pd(OAc) 2 was isolated and characterized by 1 H and 13 C NMR spectroscopy.…”

Palladium-Catalyzed Transformations of Alkyl C–H Bonds

“…The high efficiency and impressive functional group tolerance of Daugulis’ methodology to couple aryl halides with C(sp 3 )–H bonds using bidentate auxiliaries 109–120 have attracted several groups seeking to extend the coupling partner scope of this chemistry. For instance, Corey and coworkers developed a C(sp 3 )–H acetoxylation protocol of α-amino acid derivatives ( 117 ) in the presence of a Pd(OAc) 2 catalyst, manganese(II) acetate, oxone, and acetic anhydride in nitromethane to give 118 with good diastereoselectivity (Scheme 25).…”