Applications of Asymmetric Catalysis and Green Chemistry Principles Towards the Synthesis of Chiral Multifunctional Alcohols and Organofluorine Compounds

Abstract

Asymmetric reaction development and synthesis of chiral building blocks are fundamental to the pharmaceutical and agrochemical sciences. Specifically, the field of asymmetric catalysis has amassed a growing body of reactions that permit the stereoselective introduction of complex functionalities into organic compounds. In this dissertation, the optimization of two enantioselective reactions catalyzed by a readily available chiral catalyst was achieved. It was shown that the asymmetric Reformatsky reaction between ethyl iodoacetate and aldehydes in the presence of a bisoxazolidine ligand, dimethylzinc and air produces ethyl 3-hydroxy-3-(4-aryl)propanoates in high yields and in 75 to 80% ee at room temperature within one hour. The scalable asymmetric addition of ynamides to isatins in the presence of the same ligand and copper(I) triflate produces novel, highly functional, 3-hydroxy-2-oxoindolines in high yields and 89 to 98% ee in a base-free environment. This reaction simplifies access to multifunctional 3-hydroxyoxindoles and natural products such as (S)-Chimonamidine.

Green chemistry syntheses that are environmentally benign and address the increasing emphasis on operational safety, waste minimization and efficiency have become generally important in recent years. To this end, a highly diastereoselective organocatalytic method that produces 3-fluoro-3’-hydroxy-3,3’-bisoxindoles in protic solvents at room temperature, without the need of chromatographic product purification was developed. The reaction occurs within 30 minutes in the presence 10 mol% of triethylamine as catalyst and the bisoxindole formation can be scaled without compromising yields and diastereoselectivity.

The successful role of organofluorines and organochlorines in the pharmaceutical and agrochemical industries requires the development of new synthetic methodologies. An efficient organocatalytic method that achieves decarboxylative cyanomethylation using cyanoacetic acid and difluoromethyl and trifluoromethyketones in the presence of catalytic amounts of triethylamine to give β-hydroxynitriles in 90-99% yields without concomitant water elimination was accomplished. The reaction protocol is scalable and was extended to an asymmetric Mannich reaction with a tert-butylsulfinyl difluoromethyl ketimine derivative. A mild catalytic procedure accomplished by detrifluoroacetylative in situ generation of dihalogenated enolates from readily available geminal diols was developed and used to prepare bromochlorofluoromethyl ketones in 82-98% yield. The synthetic utility of these ketones was showcased with high-yielding dibromoalkenylations, Wittig and Horner-Wadsworth-Emmons reactions.

As a result of the continuing difficulty with the regulated use of atropisomeric compounds, a chiral DHPLC study was undertaken. The on-column enantiomerization of 1-(o-tolyl)naphthalene and 2-cyclohexyl-2’-dimethylaminobiphenyl between 10 °C and 35 °C, generating characteristic HPLC elution profiles was investigated. Computer simulation of the experimentally obtained chromatograms allowed determination of the Gibbs free energies of activation, ΔG‡, as 93.2 kJ/mol and 88.4 kJ/mol, respectively.