Date of Award

Spring 5-15-2022

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Chisholm, John D

Keywords

Medicinal Chemistry, Methodology, Synthesis

Subject Categories

Chemistry | Organic Chemistry | Physical Sciences and Mathematics

Abstract

Trichloroacetimidates have been previously used for glycosidic bond formation in carbohydrate chemistry and in Friedel-Craft reactions. Traditionally, trichloroacetimidates had be synthesized using an alcohol and strongly basic conditions, but in recent years milder preparation methods have been reported. Given the ease of preparation of these versatile reagents, their chemistry has been explored intensely in recent years. While few reported methods suggest they can react under promoter free conditions, activation by Lewis or Brønsted acid leads to a formation of a carbocation from benzylic trichloroacetimidates. Work described herein makes use of these convenient carbocation precursors for new reactions.Isatin is an ambidentate nucleophile and commonly can be N-alkylated using harsh conditions and specialized reaction conditions, while O-alkylation is uncommon and has only been reported utilizing silver salts. These important structures can be alkylated using trichloroacetimidates with a Lewis acid catalyst and the regioselectivity of the alkylation can be varied by changing the solvent. A plethora of secondary trichloroacetimidates participate providing excellent yields of N-alkyl product, while switching the solvent showed a preference for O-alkylation. Substitution of electron donating and withdrawing groups on the isatin ring is also tolerated except at the isatin 7-position, which lowers the yield. Studies have been performed to understand the divergence in the observed selectivity when the solvent was switched and explain the mechanistic pathway this reaction may undergo. Structures containing indolenine core are of great importance to the pharmaceutical and medicinal chemistry research areas. Established methods for the synthesis of 3,3-dialkyl indolenines often require a 3-substituted indole structure. A direct 3,3-dialkylation protocol has been developed by using trichloroacetimidates with Lewis acid catalyst taking advantage of the nucleophilic nature of the C3 position of indole. This method does not depend on the use of transition metal catalyst and two consecutive reactions take place in a single flask providing good yields with a wide substrate scope regarding the imidates and indole substrates. A spirocyclic derivative have also been synthesized to demonstrate the utility of the this developed protocol. Pyrazoles are a group of resourceful heterocyclic compounds with their presence seen in a variety of current medications, potential illness treatments, natural products, and pharmaceutical intermediates. However, N-alkylation of these systems can be done using strongly basic conditions or using transition metal catalyst. Trichloroacetimidates activated by Brønsted acid provide an easy alternative for these N-alkyl pyrazole derivatives. Alkylation using both primary and secondary benzylic imidates provided product in good to excellent yields. While symmetric pyrazoles such as 4-substitute or 3,5-disusbtitued pyrazole showed good reactivity with product formation in moderate yields and good functionality tolerance, unsymmetric pyrazole showed multiple product formation with higher preference to the least sterically hindered one. In addition to the work described above, synthetic studies of small molecule inhibitors for protein phosphatase-5 (PP5) were also undertaken. In recent years, overactivation of PP5 has been linked to the renal cancer and a great need of therapeutic treatment development is necessary. Two previously identified potent inhibitors were synthesized and coupled with biotin and BODIPY dye for pulldown assays and binding data respectively. With the help of docking trials, more structures are actively being developed as potent inhibitors. The results of these studies are also discussed.

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