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Title: Carbamoylcobalt (III) compounds in organic synthesis
Author: Reynolds, Stephen J.
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 1991
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This thesis describes the development and use of organocobalt (III) compounds in the formation of carbon-carbon and carbon-heteroatom bonds and, in particular, details the application of this chemistry for the synthesis of functionalised amides and ~, 1" and 8-lactams. Organocobalt chemistry was born from the isolation and characterisation of the vitamin B12 coenzyme (2) in the 1950s and early 1960s. The introduction to this thesis covers the search for vitamin B12 and briefly describes its biological role. Next, the considerable development of the simple vitamin B12 analogues, i.e. organocobalt (II) salophens (10), is outlined. Finally, the exploitation of organocobalt (III) complexes in synthetic organic chemistry is detailed. The preparation of nitrogen heterocycles is initially addressed, with a study of the viability of carbamoylcobalt (III) salophen compounds, i.e. (68), as sources of carbamoyl radicals, i.e. (73), in Chapter 1 of the thesis. Thus, radical quenching, employing several heteroatom trapping agents, successfully afforded the amide derivatives (74) and (75). In addition, carbamoyl radicals were induced to undergo intermolecular oxidative additions to deactivated alkenes, under both thermal and photolytic conditions, to secure the cinnamamides (77) and (78). A unique approach to /3-, y- and o-lactams using cobalt-mediated radical chemistry is described in Chapter 2. Thus, the carbamoylcobalt (m) salophen (111) underwent sequential homolysis, 4-exo-trigonal radical cyclisation, and radical-cobalt (II) recombination, to create the unusual azetidin-2-one (114), which was subsequently transformed into the alcohol (125). Computer generated molecular modelling calculations supporting the novel radical cyclisation are presented. Next, analogous cyclisations are described with the homologous carbamoylcobalt (III) salophens (138) and (150). Subsequent in situ dehydrocobaltation secured the y-lactams (140) and (141), and the 8-lactams (151) and (152). Results concerning the introduction of oxygenation in tandem with cyclisation are also presented in Chapter 2. Chapter 3 of the thesis describes a novel synthetic approach to the broad-spectrum antibiotic (+)-thienamycin (56), harnessing a cobaltmediated 4-exo radical cyclisation as the key step. Model studies showed that the cyclisation would tolerate a range of substitution around the precursor, i.e. (165) and (179), and that the stereochemical outcome delivers the required 3,4-trans geometry for thienamycin, i.e. (187)~(182). Our initial synthetic target towards (56) was the acid (196), but the route was abandoned when the carbamoyl chloride (193) failed to yield the organocobalt (III) compound (194) on treatment with sodium cobalt (I) salophen (12). However, our second approach was successful and culminated in the preparation of the /J-lactam (200), which constituted a fonnal synthesis of (+)-thienamycin. Our synthetic route to (200) involved: (i) the preparation of the amine (197) via Wittig methodology, i.e. (203)~(205); (ii) conversion of (197) to the radical precursor (198); (iii) a 4-exo radical cyclisation to afford the 3,4-transazetidin- 2-one (199) and finally, (iv) a two step sequence to yield the /3- lactam (200).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry Chemistry, Organic Biochemistry