Stereospecific Palladium-Catalyzed C–H Arylation of Pyroglutamic Acid Derivatives at the C3 Position Enabled by 8-Aminoquinoline as a Directing Group

Abstract

An efficient and stereospecific Pd-catalyzed protocol for the C-H arylation of pyroglutamic acid derivatives that uses 8-aminoquinoline as a directing group is described. The reaction was shown to proceed efficiently with a variety of aryl and heteroaryl iodides bearing different functional groups, giving C3-arylated cis products in good to high yields. Removal of the 8-aminoquinoline unit from these C-H arylation products enables access to synthetically useful cis and trans pyroglutamic acid-based building blocks.

Synthesis and Molecular Modelling Studies of New 1,3-Diaryl-5-Oxo-Proline Derivatives as Endothelin Receptor Ligands

“…The chemical shifts (δ 3.96-3.85) and, particularly, the low values of the coupling constant (J = 4.4-3.0 Hz) of the doublet attributable to the protons at the 2 position of the ester function suggest a trans configuration for esters 30a-k. These coupling constant values are in accordance with those of the ethyl ester protons of the (±)-trans 6a-11a derivatives (J = 5.6-6.4 Hz) and with the literature data [31,32]. Methyl ester 30k, analogous to what was previously observed for compound 28g, displayed two singlets attributable to the protons of the benzodioxol in the 1 H NMR spectrum.…”

Functionalised Nitrogen Heterocycles and the Search for New Antibacterials and Bioactives

“…7,9 The direct modification of pyroglutamates, using an 8-aminoquinoline amide as a directing group for C-H activation, to access functionalised pyroglutamates has recently been reported. 10 Our initial foray into this area sought to modify a pyroglutamate ester 2 (R 1 = Et) at C-4 by lactam enolate formation followed by alkylation with reactive electrophiles (R 2 = Me, PhCH 2 , CH 2 =CHCH 2 ), but we had difficulty with deprotonations leading to reactions lacking regio-and diastereoselectivity, and also had concerns with the maintenance of enantiocontrol under the conditions of the reaction. 11 We did not follow this up too diligently, but should have, as shown by the elegant work done by others which has been very successful, 12 including the use of protected pyroglutaminol derivatives 4, which at least removed the complication arising from the presence of the acidic centre of pyroglutamic acid.…”

Transition Metal-Catalyzed Directed C(sp3)–H Functionalization of Saturated Heterocycles

“…The AQ auxiliary has since been shown to be highly effective for the C(3)-H arylation of various related N-and Oheterocycles, including piperidines, 61,66,68 azetidines, 70 lactams, 72 and 5-and six-membered cyclic ethers. 61,73,74 In 2016, Bull and co-workers extended their C-H arylation protocol to piperidine rings.…”

“…The Schreiber group reported similar conditions to effect C-H arylation of pyroglutamic acid derivatives. 72 The use of 20 mol% dibenzyl phosphate additive and cyclopentyl methyl ether (CPME) as the solvent promoted the synarylation of substrates 173 (Scheme 29). The reaction was successful in the presence Cbz and PMP N-protecting groups, but failed with either N-Boc or a free N-H lactam.…”