The Total Synthesis of Analogues of Withanolide F

The total synthesis of analogues of withanolide F I, a highly oxygenated C-28 steroidal lactone natural product isolated from the leaves of the plant Withania adpressa is discussed herein. Chapter 1 describes the classification of the withanolides, their biological activity and previous studies towards the synthesis of the withanolides. Based on well-established chemistry, commercially available pregnenolone II was transformed into the key aldehyde III in nine steps, two steps fewer than previously published routes, with an optimised 14% yield as summarised in Chapter 2

Chapter 3 outlines the synthetic efforts towards the construction of the δ-lactone side chain in compound IV. The synthesis of 14,17-dideoxy-17-epi-withanolide F V was then completed via a straightforward acetylation-oxidation-elimination sequence from triol IV. Isomerisation of the 2,3-double bond delivered a novel analogue of withanolide F I, 3,4-dihydro-Δ3,4-14,17-dideoxy-17-epi- withanolide F VI, as reported in Chapter 4.

The development of new methodology to form δ-lactone side chain IX, a key structural feature of natural products I, V and VI, from cyclic sulfone VII via the heterocyclic lactone VIII based on the Dreiding-Schmidt reaction was investigated. Chapter 5 discusses the studies towards the synthesis of strategic sulfone VII.