This project targets the development of synthetic strategies, based upon the chemistry of N,O-acetals, that efficiently lead to Fmoc-protected unnatural amino acids. Synthetic methods that provide access to achiral, Fmoc-protected alpha-, beta-, and gamma-amino acids will be explored based upon activation of N,O-acetals using trimethylsilyl halides, a strategy that complements traditional approaches using Lewis acids. Stereoselective strategies for the synthesis of unnatural alpha- and beta-amino acids using thiourea-based organocatalysts will also be investigated. These studies provide undergraduate students with broad experience in organic synthesis and asymmetric reaction development and expose students to issues in chirality and bioorganic chemistry.
With the support of this award from the Chemical Synthesis Program, Professor Timothy J. Peelen, of the Department of Chemistry at Lebanon Valley College, is exploring the synthesis of unnatural amino acids. Amino acids are the primary components of proteins and peptides, which are important molecules in biological research and potential therapeutic agents. Amino acids containing unnatural sidechains or alternative backbone configurations allow chemists to engineer unnatural, protein-like oligomers with properties not found in their natural counterparts. The synthetic approaches in this project target more efficient routes for making the unnatural amino acid building blocks in an environmentally friendly manner. This project provides excellent training for undergraduate students in chemical research.
This project aimed to develop new methods to make unnatural amino acids, particularly Fmoc-protected amino acids. Amino acids are the molecules that are the building blocks of proteins found in nature; unnatural amino acids (those not found in nature) serve many purposes, including serving as building blocks of other molecules, molecular scaffolds in unnatural protein like molecules, or as standalone pharmacologically active molecules. The Fmoc-protecting group is a group used to modify amino acids to allow chemists and biologists to piece unnatural amino acids together using automated technology. The central goal of the project was to find ways of making Fmoc-protected amino acids directly and more efficiently. The Fmoc protecting group can be difficult to use in many chemical reactions (it is sensitive and often falls apart in harsh reaction conditions), and most researchers avoid handling the Fmoc-group, choosing instead to attach it to their amino acid at the end of a reaction sequence. Our prior work suggested that the group is stable during a number of useful reactions and could be incorporated in molecules earlier in the synthesis. Toward this end, we prepared reactive Fmoc-protected molecules and examined reactions that would produce alpha- or beta-amino acids, particularly using catalysts that would control the stereochemistry ("handedness") of the amino acid product. A major focus of the project was the synthesis of Fmoc-protected beta-amino acids. We devised a new strategy for their synthesis using Fmoc-protected amino aldehyde molecules and recently reported organocatalyzed reactions. While these reactions (and the subsequent oxidation of the aldehyde to the carboxylic acid) were successful, the amount of product obtained was often quite low and the stereochemistry ("handedness") of the amino acid product was not as selective as the literature examples. A second major thrust of the project examined the synthesis of Fmoc-protected alpha-amino acids using a relatively new class of catalysts (thioureas) to control the stereochemistry. Through the course of the project, a large number of thiourea molecules were prepared and their catalytic activity was examined . We were not able to identify any amino acid products in these reactions (mostly starting material was recovered). We spent a considerable amount of time and effort making Fmoc-protected starting materials that would be more reactive, or catalysts that would be more reactive (bifunctional catalysts containing basic groups), but at best these efforts resulted in decomposition of our materials. Disappointingly, we conclude that thiourea catalysis is not a viable strategy for making alpha-amino acids. A third project dealt with the synthesis of amino acids starting with sugar-derived starting material. This project was initiated near the end of the grant period, though initial results are encouraging. Fmoc-protected alpha-amino acids containing polar side chains derived from the sugar were synthesized. The product was isolated as a mixture of isomers differing in the stereochemistry ("handedness") of the newly formed stereocenter of the amino acid. The major isomer has not yet been determined, and efforts to find a highly selective version of the reaction sequence have not been successful. The project was carried out using undergraduate students as research assistants. Through the course of the project, 8 different students were supported with summer research stipends. These students received valuable laboratory research experience and training, preparing them for further education in graduate (1 student) and preprofessional schools (6 students) and the chemical industry (1 student). Furthermore, laboratory equipment and supplies were purchased using the grant to ensure safe and effective laboratory research could be conducted. This equipment continues to be used to train students, and will continue to be used for many more years.
