Development of an Asymmetric Synthesis of a Chiral Quaternary FLAP Inhibitor

Abstract

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.

A novel five‐lipoxygenase activity protein inhibitor labeled with carbon‐14 and deuterium

“…For the synthesis of deuterium labeled ( 1 ), an efficient route was developed (Scheme ). The chiral advanced intermediated ( 15 ) was prepared in two steps from ( 11 ) by either (i) condensation with 1 H ‐pyrazole‐4‐carboxylic acid followed by a Suzuki coupling to ( 14 ), or (ii) by Suzuki coupling between ( 11 ) and ( 14 ) first, followed by condensation with 1 H ‐pyrazole‐4‐carboxylic acid . Both approaches were equally efficient.…”

“…Thus, inhibition of this enzyme may be beneficial in treating allergic conditions, cardiovascular diseases, arthritis, inflammatory bowel disease, psoriasis and other related ailments . Compound ( 1 ), also known as BI665915, has high binding potency to FLAP and excellent pharmacokinetic properties . Herein, we describe the synthesis of this compound labeled with carbon‐14 and with deuterium to aid in drug metabolism, pharmacokinetics and bioanalytical studies.…”

Ligand‐based Modeling for the Prediction of Pharmacophore Features for Multi‐targeted Inhibition of the Arachidonic Acid Cascade

“…The pharmacophore elucidation and searches were performed on Molecular Operating Environment (MOE 2015.1001, Chemical Computing Group, Quebec, Canada) . A database of 18 known FLAP inhibitors was used for elucidating Ph‐FLAP pharmacophore . Two substrate mimic inhibitors of LTA4H, thioamine and amino hydroxamic acid, were used as inputs for elucidation of Ph‐LTA4H pharmacophore .…”

Studies on the Lithiation, Borylation, and 1,2‐Metalate Rearrangement of O‐Cycloalkyl 2,4,6‐Triisopropylbenzoates

“…The reaction is stereospecific, enabling homologated boronic esters to be produced with high enantioselectivity from enantioenriched lithiated carbamates/TIB esters. This lithiation–borylation protocol has been used extensively in the synthesis of natural [1, 7] and unnatural [8] products. Both primary and secondary carbamate/TIB esters can be employed, but in the case of secondary substrates which do not have additional anion‐stabilizing groups (for example, aryl, [9] allyl, [10] or propargyl [11] ) much more forcing conditions are required for deprotonation [12] .…”