Asymmetric Approaches to Manzamine A and Substituted Nitriles

This thesis describes research in two areas‒the first relating to early steps in a synthesis of the core ring system of the natural product manzamine A, and the second relating to nitrile anion chemistry. The alkaloid manzamine A I was first isolated from the marine sponge Haliclona sp. It has attracted international attention because of its interesting structure and extraordinary biological activity.
Several approaches were examined towards the asymmetric synthesis of manzamine A. Firstly, a Claisen rearrangement strategy was carried out by reacting alcohol II with diethoxyacrylate III to give diester IV. Reduction of the diester IV using LiAlH4 gave the diol V. To distinguish between the two alcohol groups, enzymatic resolution was utilised, although unfortunately, separation of the mixture of the diastereoisomers was not possible. The enantio selective hydroxymethylation of an aldehyde in the presence of a chiralcatalyst was also investigated, but due to the low yields in this sequence, an alternative approach was explored. An asymmetric Ficini-Claisen rearrangement using chiral ynamides gave mediocre yields and poor selectivities.
Nitriles are important building blocks in several natural products and pharmaceuticals. A deprotonation / electrophile quenching method for an enantioenriched nitrile with stereocentre α to the nitrile group has been developed. Deprotonation was carried out using a magnesium base with the substrate VI, followed by subsequent electrophilic quench to give a range of products VII. Firstly, organomagnesium species were prepared then quenched with acetone and furnished the substituted nitrile VII in reasonable yield ~50% with good levels of enantioselectivity (up to 90:10 er). The optimised conditions were applied to different electrophiles, and good er values and reasonable yields were obtained (45-60%, 90:10-92:8 er). The reaction using the electrophile in situ was demonstrated with a variety of electrophiles to exhibit good yields and selectivity (40-72%, 60:40-91:9 er). In the case of methyl cyanoformate and benzyl cyanoformate as electrophiles, good enantiomer ratios were achieved in moderate yield (40%, 91:9 er, 52%, 91:9 er respectively).