Carbamoylcobalt (III) compounds in organic synthesis
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-