Synthesis of steroidal analogues of prostacyclin

Strathclyde theses - ask staff. Thesis no.: T7222This body of work is concerned with the development of synthetic routes to steroidal analogues of prostacyclin. Chapter one, the introduction, gives a concise historical account of prostaglandins beginning with their discovery in the 1930's to their biosynthesis from fatty acid precursors and structure elucidation in the 1960's. The major routes of metabolic inactivation of prostaglandins are discussed. Prostacyclin, the most recent addition to the family of prostaglandins, is introduced and the chemical and metabolic instability of this prostanoid highlighted.The particular selection of reported analogues of prostacyclin is presented in an attempt to illustrate how structural modification of prostacyclin has led to congeners with improved hydrolytic and metabolic stability profiles. Where structural change has also resulted in an improvement in potency and/or selectivity of action attention is drawn to this.The increased complexity in structures of the biologically active prostacyclin analogues is a feature of this selection which culminates in tetracyclic non-steroidal analogues. The synthesis of steroidal analogues of prostaglandins containing an intact steroidal nucleus is reviewed. The concept of steroidal prostacyclin analogues, the central trust of this research, is introduced and the analogy explained by reference to three classes, type I-III, of proposed steroidal prostacyclin analogues. Chapter two, the discussion, highlights the problems of the original synthetic approach to α-androstan-16-one (56) and details the alternative synthetic strategies pursued in an attempt to obtain this essential ketone (56) in acceptable yield. Ketalisation of (56) afforded the fungal substrate which is dihydroxylated by Calonectria decora and hydrolysed to give 6α,12β-dihydroxy-5α-androstan-16-one(54). This microbiologically derived product occupies a pivotal position in the synthesis of the steroidal prostacyclin analogues.The use of the keto-steroid (56) as a model for establishing the amenabilty of the C-16 position to the Wittig olefination is discussed and the rationale behind the exploration of various strategies for introducing C-16 alkylidene and substituted alkylidene side chains into (56) is discussed. Once reaction conditions were established, the microbiologically derived dihydroxy ketone (54) was transformed to the type III steroidal prostacyclin analogue, 16(4-carboxybutylidene)-5α-androstan-6α,12β-diol (129). Derivatisation of (129) to the methyl ester (130) is followed by nonselective oxidation to afford the corresponding 6,12-dione ester (132). Selective reduction of (132) gave to the corresponding 12-ol-6-one (133). Although constraints of time did not allow the fulfilment of all research objectives valuable ground work has been laid to support future research. An outline of the synthetic routes to other proposed steroidal prostacyclin analogues is briefly discussed. This chapter also includes a brief report on the results of preliminary biological studies on analogue (129), which has been shown to have similar potency to prostacyclin as an inhibitor of collagen-induced platelet aggregation in human and pig whole blood .A discussion of proposed development work leading to a series of type III steroidal analogues based on lead compound (129) closes this chapter. Chapter three catalogues the experimental procedures and the appendix contains the details of the pharmacological evaluation of analogue (129).This body of work is concerned with the development of synthetic routes to steroidal analogues of prostacyclin. Chapter one, the introduction, gives a concise historical account of prostaglandins beginning with their discovery in the 1930's to their biosynthesis from fatty acid precursors and structure elucidation in the 1960's. The major routes of metabolic inactivation of prostaglandins are discussed. Prostacyclin, the most recent addition to the family of prostaglandins, is introduced and the chemical and metabolic instability of this prostanoid highlighted.The particular selection of reported analogues of prostacyclin is presented in an attempt to illustrate how structural modification of prostacyclin has led to congeners with improved hydrolytic and metabolic stability profiles. Where structural change has also resulted in an improvement in potency and/or selectivity of action attention is drawn to this.The increased complexity in structures of the biologically active prostacyclin analogues is a feature of this selection which culminates in tetracyclic non-steroidal analogues. The synthesis of steroidal analogues of prostaglandins containing an intact steroidal nucleus is reviewed. The concept of steroidal prostacyclin analogues, the central trust of this research, is introduced and the analogy explained by reference to three classes, type I-III, of proposed steroidal prostacyclin analogues. Chapter two, the discussion, highlights the problems of the original synthetic approach to α-androstan-16-one (56) and details the alternative synthetic strategies pursued in an attempt to obtain this essential ketone (56) in acceptable yield. Ketalisation of (56) afforded the fungal substrate which is dihydroxylated by Calonectria decora and hydrolysed to give 6α,12β-dihydroxy-5α-androstan-16-one(54). This microbiologically derived product occupies a pivotal position in the synthesis of the steroidal prostacyclin analogues.The use of the keto-steroid (56) as a model for establishing the amenabilty of the C-16 position to the Wittig olefination is discussed and the rationale behind the exploration of various strategies for introducing C-16 alkylidene and substituted alkylidene side chains into (56) is discussed. Once reaction conditions were established, the microbiologically derived dihydroxy ketone (54) was transformed to the type III steroidal prostacyclin analogue, 16(4-carboxybutylidene)-5α-androstan-6α,12β-diol (129). Derivatisation of (129) to the methyl ester (130) is followed by nonselective oxidation to afford the corresponding 6,12-dione ester (132). Selective reduction of (132) gave to the corresponding 12-ol-6-one (133). Although constraints of time did not allow the fulfilment of all research objectives valuable ground work has been laid to support future research. An outline of the synthetic routes to other proposed steroidal prostacyclin analogues is briefly discussed. This chapter also includes a brief report on the results of preliminary biological studies on analogue (129), which has been shown to have similar potency to prostacyclin as an inhibitor of collagen-induced platelet aggregation in human and pig whole blood .A discussion of proposed development work leading to a series of type III steroidal analogues based on lead compound (129) closes this chapter. Chapter three catalogues the experimental procedures and the appendix contains the details of the pharmacological evaluation of analogue (129)