Pd-Catalyzed Dimethylation of Tyrosine-Derived Picolinamide for Synthesis of (S)-N-Boc-2,6-dimethyltyrosine and Its Analogues

Abstract

A short and efficient synthesis of (S)-N-Boc-2,6-dimethyltyrosine utilizing palladium-catalyzed directed C-H functionalization is described. This represents the first general method for the ortho-dimethylation of tyrosine derivatives and offers a practical approach for preparing this synthetically important building block. Notably, throughout the reaction sequence no racemization occurs at the susceptible α-chiral centers.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

“…Since the pioneering work of Daugulis, 344 the use of this N , N -bidentate DG has been extensively investigated in various transformations. 556 – 558 The cleavage of this DG was conducted under acidic, 559 , 560 basic 561 – 566 and reductive acidic 562 conditions as well as after a treatment with PCl 5 /2,4-lutidine then MeOH and an aqueous work-up. 567 …”

“…Another protocol from Zhang and Ma described the Pd-catalysed methylation of the amide derived from ( S )-tyrosine analogues ( Scheme 93D ). 559 It is worth to mention that only this DG was efficient for this di-methylation reaction and a scale up on ca. 20 g was successfully achieved with the complete retention of the chiral information.…”

Beyond Friedel and Crafts: Directed Alkylation of C−H Bonds in Arenes

“…Ortho-a nd meta-substituted benzylic picolinamides gave good yields and regioselectivities,w hile double ortho,ortho'-dialkylation was observed in other cases. Thep icolinamide moiety could be cleaved by alkaline hydrolysis.R elated processes for the alkylation of benzylic quinolone-2-carboxamides with a-bromoketones, [205] the dimethylation of tyrosine-derived homobenzylic picolinamides with iodomethane under palladium catalysis, [206] and the (di)methylation of other benzylic picolinamides with trimethylaluminum under iron catalysis [119] were later reported.…”

Jenseits von Friedel und Crafts: dirigierte Alkylierung von C‐H‐Bindungen in Arenen

“…Der Picolinamidrest ließ sich mittels alkalischer Hydrolyse abspalten. Später folgten ähnliche Verfahren fürdie Alkylierung benzylischer Chinolon-2carboxamide mit a-Bromketonen, [205] fürd ie palladiumkatalysierte Dimethylierung Ty rosin-abgeleiteter homobenzylischer Picolinamide mit Iodmethan [206] sowie fürd ie eisenkatalysierte (Di)methylierung anderer benzylischer Picolinamide mit Tr imethylaluminium. [119] In einem ähnlichen Ansatz erweiterte die Gruppe von Ackermann die Verwendung ihrer Tr iazol-abgeleiteten dirigierenden Amide auf die Methylierung und Ethylierung benzylischer Tr iazol-4-carboxamide mit den entsprechenden Grignard-Reagentien in Gegenwart katalytischer Mengen an Eisen(III)-chlorid und dppen sowie 2,3-Dichlorbutan oder 1,2-Dichlor-2-methylpropan als Oxidationsmittel [Schema 43, Alkylierung zu den entsprechenden g-oxoalkylierten Produkten durch eine In-situ-Isomerisierung des Allylalkohols [Schema 47, Gl.…”