Synthesis of conformationally restricted glutamate and glutamine derivatives from carbonylation of orthopalladated phenylglycine derivatives

Abstract

SummaryA new method for the regioselective synthesis of 2-alkoxycarbonyl- and 2-(aminocarbonyl)phenylglycinate methyl esters has been developed. The reaction of the orthopalladated complex [Pd(μ-Cl)(C6H4(CH(CO2Me)NMe2)-2)]2 (1) with nucleophiles HNu under a CO atmosphere results in the selective incorporation of the C(O)Nu moiety to the phenyl ring and formation of the carbonyl species ortho-C6H4(C(O)Nu)(CH(CO2Me)NMe2) (2a–j) (Nu = OR, NHR, NR2). Compounds 2a–j are conformationally restricted analogues of glutamic acid and glutamine and are interesting due to their biological and pharmacological properties. The reaction of [Pd(μ-Cl)(C6H4(CH(CO2Me)NHTf)-2)]2 (3) with nucleophiles in a CO atmosphere results, however, in the formation of the cyclic isoindolinone or the open 2-carboxyphenylglycine methyl esters, with the reaction outcome being driven by the choice of the solvent.

Cyclopalladation and Reactivity of Amino Esters through CH Bond Activation: Experimental, Kinetic, and Density Functional Theory Mechanistic Studies

“…The studied reactions and the obtained products are summarized in Scheme . The trends observed can be easily compared to those reported previously for the isosteric amino esters 8a. c, d…”

“…The reactivity pattern is identical to that observed with the isosteric amino ester,8c, d but when the reaction was carried out in methanol, instead of CH 2 Cl 2 , the same isoindolinone 10 m was obtained. This is a remarkable result because it implies that the cyclization step is faster than the formation of the ester, in contrast to results obtained with the amino ester derivative 8a…”

“…The influence exerted by substituents at the N‐amine atom is also highly dependent on their nature. We have recently reported that the orthopalladation of 1 b ,8a containing an electron‐withdrawing triflate group, requires at least 48 h to achieve a modest 56 % yield, whereas metalation of dimethyl‐substituted compound 1 c affords yields of more than 65 % in only 24 h reaction time. Furthermore, in none of these reactions was the presence of bis‐amino complexes 2 detected.…”

“…Compound 1 a⋅ HCl is commercially available and was used without further purification. The amino esters 1 b 14 and 1 c ,8a, 15 and the hydrochlorides 1 d⋅ HCl,8c 1 e⋅ HCl,8c 1 f⋅ HCl,8c and 1 g⋅ HCl8c have been prepared as previously described. Hydrochlorides of the quaternary amino esters 1 i⋅ HCl, 1 j⋅ HCl, 1 k⋅ HCl, 1 l⋅ HCl,16 as well as aminophosphonates 1 m⋅ HCl17 and 1 n⋅ HCl,18 were prepared through modifications or adaptations of previously reported methods; their syntheses are detailed in the Supporting Information.…”

“…Hydrochlorides of the quaternary amino esters 1 i⋅ HCl, 1 j⋅ HCl, 1 k⋅ HCl, 1 l⋅ HCl,16 as well as aminophosphonates 1 m⋅ HCl17 and 1 n⋅ HCl,18 were prepared through modifications or adaptations of previously reported methods; their syntheses are detailed in the Supporting Information. The orthopalladated derivatives 3 a – g were already known ( 3 a ,19 3 b ,8a 3 c ,8a, 15 3 d ,8c 3 e ,8c 3 f ,8c and 3 g 8c); they were synthesized by following reported procedures and identified by comparison of their spectroscopic data with those published. Compounds closely related to 3 l and 3 k have been reported recently,13a, b but they differ in the nature of the halide bridge (μ‐Cl in 3 l and 3 k whereas μ‐Br in the reports13a, b) and in the method of synthesis (solvents, temperature, time).…”