Synthesis of Functionalized δ‐Hydroxy‐β‐keto Esters and Evaluation of Their Anti‐inflammatory Properties

Abstract

δ‐Hydroxy‐β‐keto esters and δ,β‐dihydroxy esters are characteristic structural motifs of statin‐type natural products and drug candidates. Here, we describe the synthesis of functionalized δ‐hydroxy‐β‐keto esters in good yields and excellent enantioselectivities using Chan's diene and modified Mukaiyama‐aldol reaction conditions. Diastereoselective reduction of δ,β‐dihydroxy esters afforded the respective syn‐ and anti‐diols, and saponification yielded the corresponding acids. All products were evaluated for their anti‐inflammatory properties, which uncovered a surprising structure‐activity relationship.

Synthesis and Spectral Studies of R(2),C(4)-Bis(Tert-Butoxycarbonyl)-C(5)-Hydroxy-T(5)-Methyl-T(3)-Phenyl Cyclohexanone and Their Biological Activity

“…The IR spectra for β-keto esters (1-3) were recorded on FT/IR-4700 type A instrument. All the NMR measurements were made using 5mm tubes and were recorded on a Bruker III HD Nanobay 400 NMR spectrometer operating at 400.23 MHz for 1 H and 100.64 MHz for 13 C. For recording 1 H NMR spectra, solutions were prepared by dissolving 10 mg of the material in 0.5 mL of CDCl 3 . For recording 13 C NMR spectra, solutions were prepared by dissolving 50 mg of the material in 0.5 mL of CDCl 3 .…”

“…All the synthesized β-keto esters of 1-3 compounds have been shown to adopt chair conformations (1C-3C) with an axial orientation of the OH group and equatorial orientations of all other substituents. For the proof of such information, the 1 H NMR, 13 C NMR, IR, MASS, HOMOCOSY, NOESY, HSQC, and HMBC spectra have been recorded for compound 1. Vicinal proton-proton coupling constant can be used for conformational analysis since it depends on the torsional angle between two protons in adjacent carbons [9].…”

“…Vicinal proton-proton coupling constant can be used for conformational analysis since it depends on the torsional angle between two protons in adjacent carbons [9]. For Compounds (1-3), 1 H and 13 C NMR have been recorded for their conformation analysis. The identification of bioactive molecules and synthesis of natural or synthetic drugs is the starting point in drug discovery research, and also, the synthesized chemical entities must have the drug-likeness and obey the Pfizer rule [10,11].…”

“…Heterocyclic compounds are an important class and have been found as a crucial structural core in natural and synthetic drugs [12]. In recent years, β-keto esters have displayed a number of important biological properties such as bactericidal, fungicidal, and anti-inflammatory activities [13][14][15]. Antioxidants have gained a lot of importance because of their potential prophylactic and therapeutic activities against many diseases.…”

Synthesis of Aryl‐ and Alkyl‐Containing 3‐Methylene‐5‐hydroxy Esters via a Barbier Allylation Reaction

“…Driven by the goal to synthesize functionalized lipids of microbial origin for biological testing, we recently investigated the synthesis of chiral aliphatic syn-and anti-β,δ-dihydroxy esters using a combination of Ti-BINOL catalyzed asymmetric Mukaiyama aldol reaction of Chan's diene with various aldehydes and diastereoselective reduction. [4] This time, we investigated a synthetic approach towards the 3-methylene-5hydroxy core motif as building block for the synthesis of complex microbial natural products (Figure 1A). The motif still represents a challenging synthetic target as basic conditions often cause the isomerization of the exo-methylene moiety to the more stable conjugated double bond system.…”