This thesis details investigations towards the total synthesis of the naturally occurring alkaloid hodgkinsine, utilising palladium catalysis to achieve desymmetrisation of a meso-chimonanthine derivative.
Initially, a Suzuki cross-coupling approach was envisaged. Meso-chimonanthine is functionalised as its C-7 bisiodide derivative by directed ortho-lithiation. Suitable electrophiles are screened for the successful preparation of additional bisbromide and bistriflate derivatives to broaden the scope of the cross-coupling. The synthesis of a suitable indole-3-boronic ester coupling partner is also achieved.
Investigations into the post-Suzuki coupling elaboration of the indole moiety were conducted with model substrates to assess the viability of a proposed alkylation-cyclisation procedure. C-3 alkylation of various N-protected C-3 phenylindole derivatives was unsuccessful when employing aziridines, sulfamidites and sulfamidates as electrophilic two carbon fragments. Therefore a second generation boronic ester with latent enolate functionality for increased nucleophilicity was prepared in six high yielding steps from oxindole, via trapping 3-bromo-N-BOC-oxindole as the TIPS enol ether and subsequent C-3 palladium catalysed borylation.
The Suzuki coupling of the new boronic ester with meso-chimonanthine derivatives was shown to be unsuccessful in a broad range of anhydrous and aqueous solvent systems. Palladium catalysts, ligands, bases and measures to reduce steric interactions were all screened in an attempt to achieve coupling.
Subsequently the palladium catalysed arylation of N-protected oxindole enolates is developed; aryl bromides, chlorides and triflates are all suitable coupling partners, whilst a broad range of ortho, meta and para functionalised arenes are well tolerated providing C-3 aryl oxindoles in high yield. Extension of this methodology to a C-7 bisbromo meso-chimonanthine substrate was successful, furnishing the desymmetrised product under racemic conditions in 45% yield with the dicoupled product also observed in 20% yield.
|Date of Award||1 Dec 2007|
|Supervisor||Michael Willis (Supervisor)|