Amide Bond Formation and Oxazoline Synthesis Using Tris(o-phenylenedioxy)cyclotriphosphazene as a Dehydration Promoter

概要

The present thesis outlines the employment of a TAP-derived organocatalyst, tris(o-phenylenedioxy)cyclotriphosphazene (TAP-1), as the promoter for the in situ generation of the phosphate species, which proved to be practical in dehydrative reactions, such as amide bond formation and 2-oxazoline synthesis. The main objective of this thesis is to discover a protocol for amide bond formation, and subsequently to develop and advance this approach to other research areas in organic synthesis.

This thesis contains three chapters. Chapter 1 presents the utilization of TAP- 1 in amide bond formation between simple carboxylic acids and amines under azeotropic reflux. The atom-efficient amide bond formation has emerged as a top- priority research field in organic synthesis, as amide bonds constitute the backbones of proteins and represent an important structural motif in bioactive molecules. Currently, the increasing demand for novel discoveries in this field has arisen a challenge among chemists to design practical catalytic protocols, which ensure the market stability of synthetic pharmaceuticals for the future. Despite the extensive amount of research performed on developing the stoichiometric coupling of carboxylic acids and amines, effective catalytic amide bond formation remains an elusive concept. In particular, aromatic carboxylic acids such as benzoic acids are less reactive than aliphatic ones in dehydrative amide bond formation; therefore, we envisioned a dehydrative protocol to facilitate the condensation between aromatic carboxylic acids and amines. To monitor the transformation of TAP-1, the mechanistic study was conducted to demonstrate that the in situ generation of catechol cyclic phosphate (CCP) from the stoichiometric decomposition of TAP-1 is in fact possible. Due to the absence of the background reaction, valuable insights were collected during the amidation reaction monitoring.

The framework of Chapter 2 is related to the extension of the work performed in Chapter 1, which discloses the application of the promoter, TAP-1, in peptide bond formation. Hardly is it possible to gainsay the significance and value of peptide units, for they are the backbones of proteins, otherwise known as the molecule of life. Although the biosynthesis of proteins occurs in living organisms, the accurate design of protein analogs containing unnatural residues can fairly expand the current limitations of the genetic codes that scientists encounter following the traditional biological ligation methods. The lack of atom-efficient protocols for peptide bond formation has kindled enthusiasm among chemists to fulfill the quest for discovering and developing novel coupling approaches. A panoramic range of protected α-amino acids was subjected to the TAP-1-mediated amide bond formation to provide the related dipeptides. The investigation on the background reaction revealed that the presence of TAP-1 can moderately increase the dehydrative amidation between a large number of protected α-amino acids. The continuous monitoring of the reaction revealed that TAP-1 decomposition partially happens for cases in which the background reaction is highly present. At this juncture, histidine derivatives were found to stand as the only peptide residues devoid of any background reactions, due to the insufficient solubility under the reaction conditions. Several surveys performed on diverse protected α- amino acids convinced us that the positive contribution of TAP-1 can merely be ascribed to the oxophilicity of the phosphorus atoms. According to the 31P NMR and HRMS analyses, it is evident that even the phosphate CCP is hydrolyzed to H3PO4 and catechol within the reaction time frame. Given the above-mentioned shortcomings of the TAP-1-mediated peptide bond formation, we strived to find a more suitable reaction environment to assess the dehydrative ability of our proposed CCP/PP dehydrative system.

Chapter 3 contains the employment of TAP-1 in the dehydrative cyclization of N-(2-hydroxyethyl)amides into 2-oxazolines. 2-Oxazolines have an extensive range of applications as important naturally occurring pharmacophores and bioactive molecules. Oxazoline motifs also appear as building blocks for functional copolymers. Numerous optically active 2-oxazoline ligands for asymmetric catalysis in various protocols such as aldol and Henry reactions have been developed. Despite the high potential of the heterocyclic units in natural products and pharmaceuticals, practical and cost-efficient syntheses of oxazolines that meet ever more economic and environmental demands have yet to be developed. Contemporary organic chemistry strives to establish approaches with a high atom economy, which has recently become a crucial concept in green chemistry. To this end, the catalytic synthesis of oxazolines via the dehydrative cyclization of N-(2-hydroxyethyl)amides represents an attractive method that produces only water as a by-product. Using 1 mol % of the promoter (TAP-1) leads to the generation of the related 2-oxazolines in high yields with retention of the configuration at C(4) position. The reaction screening was conducted by the simultaneous 1H, 31P NMR, and HRMS analyses, which provided encouraging results supporting our initial hypothesis to use CCP/PP interconversion as the effective dehydrative catalytic cycle. Further investigations on the robustness of CCP in the reaction mixture after the completion of the reaction are clearly supported by 31P NMR, and HRMS measurements. During the survey on the ring closure of the substrate, N-(2-hydroxyethyl)amides, we realized that the ring closure differs depending on the stoichiometric TAP-1-mediated reaction or the CCP-catalyzed dehydrative reaction. To take one step forward and provide concrete evidence to this hypothesis, HPLC measurement and an 18O-labeling experiment were performed, both of which corroborated our theoretical conclusion. In order to examine the practical aspect of the TAP-1-mediated cyclization protocol, a large-scale experiment was carried out and the 2-oxazoline was isolated in high yield.

In summary, we found that tris(o-phenylenedioxy)cyclotriphosphazene (TAP- 1) works as an effective dehydrative promoter for intermolecular amide bond formation between carboxylic acids and amines, and as a precatalyst to generate a practical catalyst for the synthesis of 2-oxazolines by the intramolecular dehydration of N-(2-hydroxyethyl)amides.