Two different strategies examine intramolecular cyclizations of chiral, metalated nitriles. Cyclizations onto allylic electrophiles through competitive SN2 or SN2' displacements have different trajectories reflecting the different conformations within the forming ring. Deuterium labeling with allylic electrophiles reveals an inherent preference for SN2 displacements reflecting the optimal orbital overlap for the two different geometries. / Bayer School of Natural and Environmental Sciences; / Chemistry and Biochemistry / MS; / Thesis;

Münster (Westfalen), Univ., Diss., 2003. / Computerdatei im Fernzugriff.

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Nitrile-containing natural products are rare in Nature, and there have been very few studies on the mechanisms by which they are synthesized and utilized. The biosynthesis of 7-deazapurine containing natural products is a unique case whereby both formation of a nitrile and its conversion to an amide are documented. The overall theme of this work is to interrogate the biosynthesis of the nitrile intermediate in the pathway and its subsequent hydration to an amide. The biosynthesis 7-cyano-7-deazaguanine (preQ₀), the key intermediate in the biosynthesis of the hypermodified base queuosine and the toyocamycin natural product, is accomplished by preQ₀ synthetase through a series of unprecedented reactions whereby the carboxylate moiety of the substrate, 7-carboxy-7-deazaguanine (CDG), is successively activated by adenylation, reacted with ammonia, and dehydrated to produce the nitrile. This one-enzyme synthesis of a nitrile is unique as the only other known route to nitriles proceeds through at least two enzymes. Nitrile hydratases are metalloenzymes that selectively hydrate nitriles to the amide and are used industrially to produce acrylamide and nicotinamide. These enzymes use a trivalent iron or cobalt complex comprised of two backbone amidate ligands and three cysteine thiolate ligands of which two are modified to the sulfenato and sulfinato form. This work describes aspects of a particular nitrile hydratase, toyocamycin nitrile hydratase (TNH). Whereas most nitrile hydratases are heterodimeric, TNH is heterotrimeric, and yet what was discovered is that only the subunit containing the active site metal complex is required for activity. This single subunit analog of the protein was used for single turnover assays in ¹⁸O-labeled water to show with high resolution mass spectrometry that the source of the product amide oxygen is actually the enzyme itself and likely the sulfenato ligand oxygen acting as a nucleophile. The mechanism of the active site complex synthesis is described showing that this is self-catalytic in the presence of cobalt(II) and molecular oxygen.

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