Sequential alcohol oxidation/putative homo Claisen–Tishchenko-type reaction to give esters: a key process in accessing novel biologically active lactone macrocycles

Abstract

We report an efficient methodology for the direct oxidative esterification of primary alcohols to diether-esters using pyridinium chlorochromate (PCC). Numerous studies were carried out to probe the reaction mechanism and at the same time optimize the reaction conditions. The reaction could be conducted with 1 equivalent of PCC and 1 equivalent of BF3.OEt2. Indications based on literature precident were that the reaction may proceed via a sequential alcohol oxidation to the aldehyde followed by a putative Cr catalyzed or Boron Claisen-Tishchenko-type reaction. Using this efficient methodology, we synthesized a family of novel diether-esters in very good yields; some of these molecules were subsequently tested against both acetylcholinesterase (AChE) and butyrlcholinesterase (BuChE). In addition, we also disclose a new synthetic strategy for the synthesis of lactam macrocycles with potential biological activity. This methodology included the regioselective borylation of the ester substrate and a subsequent Suzuki-Miyaura coupling to obtain the desired lactam macrocycle.

Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases

“…Thus, we decided to evaluate Corey reagent-pyridinium chlorochromate (PCC) as an oxidizing agent (route C) [48,49]. Oxidation of the fluorinated 3-phenylpropylalcohols (compounds 3) gave mixtures of two main products: the desired major product-substituted 3-phenylpropionaldehydes (compounds 4d-4h)-and the symmetric esters (substituted 3-phenylpropyl-3-phenylpropionates -compounds 5d-5h) as side products, most likely via oxidative esterification as reported earlier by Hunsen and Viana [50,51]. Hunsen and coworkers obtained corresponding ester upon oxidizing of phenylethanol to its suitable carbonyl derivative, by using PCC and periodic acid as co-oxidant.…”

Recent Advances and Prospects in the Tishchenko Reaction

“…Using Cr‐catalyzed Claisen‐Tishchenko reaction followed by PCC oxidation, Burke et al . reported efficient methods for the conversion of primary alcohols to diether esters (Scheme ) . The reaction proceeded well with high yields when 1 equiv.…”

Revisiting Hydroxyalkylation of Phenols with Cyclic Carbonates

“…The efficient synthesis of 1 g marked the compatibility of primary amide. We examined the reactions of bromo‐substituted phenols, resulting in the formation of 1 h and 1 i bearing synthetically useful handles for cross‐coupling reactions. We further tested the reaction of electron deficient phenols including 4‐cyanophenol, 4‐nitrophenol, and umbelliferone as challenging substrates since their conjugate bases are of lower nucleophilicity.…”