The development of practical asymmetric allylborations and the synthesis of achiral heterocycles as chemotherapeutics

The asymmetric allylation of carbonyl compounds has been extensively studied.However, many reported methodologies require the use of cold temperatures, toxic reagents, and/or the use of a glove-box. The asymmetric allylboration of ketones was previously developed using chiral biphenol catalysts to access homoallylic alcohols in excellent yields and enantioselectivities, and has since been adapted for industrial use. This reaction was further optimized to consider safety, environmental factors, and reproducibility to allow for easier transition into industrial applications. An asymmetric synthesis of homoallylic cyanohydrins via nucleophilic boronate addition to acyl cyanides was developed. Chiral biphenol catalysts were used to access cyanohydrins in yields up to 98% and enantioselectivities up to 98:2 er. Reproducibility was prioritized as all reactions were performed in triplicate and the results were reported with the standard error of the mean. Asymmetric crotylborations of benzoyl cyanide were also developed to afford the corresponding α-methyl cyanohydrins in excellent yields and good selectivities. The Petasis borono-Mannich reaction is a multicomponent reaction between an aldehyde, amine, and boronic acid or ester to access 1,2-amino alcohols. The traceless Petasis reaction utilizes arylsulfonyl hydrazides to allow for the decomposition of the Petasis product to a diazene intermediate that fragments to extrude nitrogen. The asymmetric traceless Petasis reaction of non-allylic aldehydes was investigated to access remote tertiary and quaternary stereocenters. Reactions with glyoxylates, tosylhydrazide, and crotyl or cinnamyl boronates afforded the Petasis products in good yields with excellent enantio- and diasteroselectivity. Reactions with geranyl boronic acid and esters were also studied to afford products with a quaternary stereocenter in moderate yields, but low selectivities. Further optimization to promote diazene formation is required, and mechanistic studies are proposed to examine the non-allylic diazene fragmentation pathway. A class of small molecules termed “Factor Quinolinone Inhibitors” were previously discovered to target LSF, an oncogenic transcription factor overexpressed in several cancers. Recent optimization focused on addressing the chiral center of the previous lead compounds through the introduction of a carbon-carbon double bond, or by replacing the chiral center carbon with a nitrogen to form the quinoxalinone. These unsaturated analogues demonstrate a seven-fold increase in potency with low nanomolar activity in liver cancer cells in vitro. The new lead compound, FQI2-34, is currently undergoing in vivo studies and has displayed excellent pharmacokinetics thus far.2023-02-16T00:00:00