Biphenol catalyzed enantioselective addition reactions of trifluoroborate salts and the development of novel antileishmanial chemotypes
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Abstract
Enantioselective addition reactions to carbonyls with boronate nucleophiles has been extensively explored. While boronic esters and boronic acids have been employed in these asymmetric transformations, there has been recent interest towards investigating trifluoroborate salts as nucleophilic partners. Herein, we present our findings on enantioselective catalytic versions using trifluoroborate salts. An asymmetric catalytic allylboration of carbonyls was developed. The addition reactions used a pre-made BINOL trifluoroborate salt mix (BTF-mix) composed of allyl trifluoroborate salt, N-benzylcinchoninium chloride, and a chiral 3-3’-BINOL-derived catalyst to generate homoallylic alcohols in good yields and excellent enantioselectivities. The nucleophile scope was successfully expanded to include (E)- and (Z)-crotyl trifluoroborate salt, as well as prenyl trifluoroborate salt in good yields and high selectivities. The formal synthesis of a key chiral amino alcohol intermediate for the synthesis of a pain medication, tapentadol, was accomplished using this methodology. The allyl BTF-mix methodology was successfully applicable to a two step, one-pot Petasis Boron-Mannich reaction. A broad scope of aldehydes and amines with varying electronics and steric effects generated a number of homoallylic amines in good yields and high enantioselectivites. Use of prenyl trifluoroborate salt was achieved by successfully forming the g-addition homoallylic amine product with a high yield and enantioselectivity. The development of pyrazolopyrrolidinones as an effective and novel chemotype against the neglected tropical disease, leishmaniasis, was investigated. The parallel synthesis of over 100 analogs was achieved and assayed in a high-throughput phenotypic screen. Recent optimization focused on building a library of potent compounds with strict adherence to ClogP to address issues related to solubility and high plasma protein binding and expand our knowledge of the structure-activity relationships (SAR) and structure-property relationships (SPR). A pharmacophore model was developed demonstrating a critical degree of steric block and polar/ non-polar groups necessary to improve efficacy. Furthermore, our SAR trends indicate that increased solubility, accompanied by simultaneously decreasing CLogP results in reduction of mouse plasma protein binding. Installation of alkynes with various lengths has provided guidance for affinity probe location for future target identification experiments. Lead compounds with a balance of physicochemical properties (lipophilicity, solubility, plasma protein binding) have been selected for in vivo studies, which are currently pending.
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2024