A free radical approach to ring-D aromatic steroids

The work presented in this thesis describes several new and novel radical macrocyclisation-transannulation cascade reactions directed towards the single step construction of ring-D aromatic steroid ring systems. The introduction introduces the steroid class of natural products, their biosynthesis and previous literature strategies towards their construction. The ring-D aromatic steroids, together with their possible total synthesis via a novel freeradical cascade strategy, are then discussed. The results and discussion chapter summarises the radical cascade strategies towards ring-D aromatic steroid ring systems that have been investigated. It is divided into two sections: Part 1 describes the evolution of our current radical cascade approaches relating to the iododienynone precursors 117a-d (Schemes 26-29). We proposed that the precursors 117a-d would lead to the 6,6,6,6 ring-D aromatic steroid ring system (such as that found in the natural product nicandrenone 67), via a cascade of radical ring-forming reactions. However, the proposed radical cascade from the Z-iododienynones 117a,c halted at the macrocyclisation stage producing the macrocycles 137a,b, whilst a radical cascade from the E-iododienynones 117b,d instead led to the unusual bridged tricyclic structures 148a,b and 155 (depending on whether benzene or heptane was used as the solvent), rather than the anticipated linear tetracycles 116a,b. A rationale for these outcomes is given. Part 2 discusses an approach to 6,6,5,6 ring-D aromatic steroids via a macrocyclisation-transannulation radical cascade from the vinylcyclopropyl seleno ester precursor 193. A synthesis of the radical precursor 193 was first examined using a novel aryl-vinylcyclopropane Stille reaction coupling protocol (the development of which is discussed), as well as several alternative routes. A practical, albeit more lengthy, synthesis of the precursor 193, was then developed. The proposed radical cascade from the vinylcyclopropyl seleno ester 193 led to the desired ring-D aromatic steroid ring system 194a (with the correct trans, anti, trans stereochemistry) together with the methyl epimer 194b. Also isolated from the product mixture was the macrocycle 232, together with the products of reduction and decarbonylation of the acyl radical intermediate 235, i.e. 231 and 230, and the dioxolane 233. The experimental section describes all the procedures used to synthesise the precursor compounds 117a-d and 193 and the products of their radical mediated cascade cyclisations. Full NMR, and other spectroscopic data, alongside mass spectrometry data are also given. The appendices include some relevant X-ray and NMR spectroscopic details

A free radical approach to ring-D aromatic steroids

The work presented in this thesis describes several new and novel radical macrocyclisation-transannulation cascade reactions directed towards the single step construction of ring-D aromatic steroid ring systems. The introduction introduces the steroid class of natural products, their biosynthesis and previous literature strategies towards their construction. The ring-D aromatic steroids, together with their possible total synthesis via a novel freeradical cascade strategy, are then discussed. The results and discussion chapter summarises the radical cascade strategies towards ring-D aromatic steroid ring systems that have been investigated. It is divided into two sections: Part 1 describes the evolution of our current radical cascade approaches relating to the iododienynone precursors 117a-d (Schemes 26-29). We proposed that the precursors 117a-d would lead to the 6,6,6,6 ring-D aromatic steroid ring system (such as that found in the natural product nicandrenone 67), via a cascade of radical ring-forming reactions. However, the proposed radical cascade from the Z-iododienynones 117a,c halted at the macrocyclisation stage producing the macrocycles 137a,b, whilst a radical cascade from the E-iododienynones 117b,d instead led to the unusual bridged tricyclic structures 148a,b and 155 (depending on whether benzene or heptane was used as the solvent), rather than the anticipated linear tetracycles 116a,b. A rationale for these outcomes is given. Part 2 discusses an approach to 6,6,5,6 ring-D aromatic steroids via a macrocyclisation-transannulation radical cascade from the vinylcyclopropyl seleno ester precursor 193. A synthesis of the radical precursor 193 was first examined using a novel aryl-vinylcyclopropane Stille reaction coupling protocol (the development of which is discussed), as well as several alternative routes. A practical, albeit more lengthy, synthesis of the precursor 193, was then developed. The proposed radical cascade from the vinylcyclopropyl seleno ester 193 led to the desired ring-D aromatic steroid ring system 194a (with the correct trans, anti, trans stereochemistry) together with the methyl epimer 194b. Also isolated from the product mixture was the macrocycle 232, together with the products of reduction and decarbonylation of the acyl radical intermediate 235, i.e. 231 and 230, and the dioxolane 233. The experimental section describes all the procedures used to synthesise the precursor compounds 117a-d and 193 and the products of their radical mediated cascade cyclisations. Full NMR, and other spectroscopic data, alongside mass spectrometry data are also given. The appendices include some relevant X-ray and NMR spectroscopic details