Synthetic studies towards the pyrrolo [2,1-c][1,4] benzodiazepine natural products

The work detailed in this thesis describes the development of a suitable synthetic strategy for the synthesis of pyrrolo[2,1-c][1,4]benzodiazepine (PBD) natural products such as anthramycin (1), porothramycin (2) and sibiromycin (3) - antitumour antibiotics which are capable of covalently binding to DNA and exhibit potent in vitro and in vivo cytotoxicity. The synthetic sequence involved introduction of the key stereocentre by asymmetric alkylation and construction of the C-ring dihydropyrrole moiety by ring-closing enyne metathesis (RCEYM). Studies into the metathesis rearrangement involved investigations into the employment of relay-ring closing metathesis (RRCM) on substrate A (R = CO2Allyl) to aid delivery of the chosen catalyst. However, these attempts proved unsuccessful and the metathesis substrate was redesigned to include an allylic alcohol moiety (A; R = CH2OH) which led to the successful metathesis rearrangement and delivered the dihydropyrrole moiety with an allylic alcohol side chain (B; R = CH2OH). Following the metathesis rearrangement, subsequent oxidation of the allylic alcohol moiety (B; R = CH2OH) proved difficult and thus, was extensively investigated to provide a suitable protocol for the synthesis of the required dimethyl amide (B; R = CONMe2) associated with porothramycin (2). A brief investigation into appropriate nitrogen protecting groups led to the use of the 2-trimethylsilylethanesulfonyl (SES) protecting group. Unfortunately, there were problems related to the removal of the SES group from the dihydropyrrole B (PG2 = SES; R = CONMe2) and this led to the development of substrate C which successfully participated in an intramolecular substitution upon SES deprotection to give amide D. Studies into the conversion of this compound to the desired natural product by way of an oxidation and Staudinger reaction were also undertaken, however, results obtained could not conclusively determine that porothramycin (2) had been synthesised. The sum of the efforts presented in this thesis, whilst not delivering a total synthesis of the target compound (2), does provide a suitable and feasible protocol with which to synthesise the target natural product (2) as well as other compounds in the same class (1 & 3)