N-aminoaziridine hydrazones, auxiliaries for the synthesis of chiral building blocks and synthetic studies towards tautomycetin, a selective protein phosphatase-1 inhibitor

Chapter one of this dissertation details a review about the general synthetic methods for the synthesis of skipped 1,3-dimethyl patterns, a widespread motif present in a multitude of biologically active natural products. Tautomycetin, a selective protein phosphatase-1 inhibitor is a natural product that encompasses this skipped deoxypolypropionate motif. This chapter also provides an overview of the importance of tautomycetin as a selective protein phosphatase inhibitor, its biosynthesis, and the existing synthetic efforts towards its total synthesis. Augeri and Chamberlin's previous developed hydrazone alkylation methodology for the synthesis of skipped deoxypolypropionate units is also described.;Chapter two of this dissertation focuses on the synthesis of optically active N-aminoaziridine hydrazones based on a modified aziridination method developed by Atkinson. A number of conditions were investigated to effect the optimal formation of aziridines and the removal of the chiral quinazolinone auxiliary. Reaction of the N-aminoaziridine azaenolates with a number of alkyl halide electrophiles resulted in the formation of monoalkylated hydrazones in good yields and diastereoselectivities. Preparation of optically active N-aminoaziridine hydrazones also allowed for the determination of the sense of chiral auxiliary induction and the optimal metalation conditions for the exclusive formation of the 1,3-anti diastereomer. Unfortunately, all attempts to reduce these N-aminoaziridine hydrazones to the corresponding hydrocarbons have proven unsuccessful so far.;Significant progress towards the total synthesis of tautomycetin is also described in this chapter. The complex polyfunctionalized hydrocarbon chain of tautomycetin was successfully constructed via a Mukaiyama aldol condensation between two key synthetic intermediates of comparable stereochemical complexity. The anti 1,2-methyl hydroxyl relationship in tautomycetin was established with the Abiko-Masamune anti aldol reaction. The 1,3-anti skipped deoxypolypropionate of tautomycetin was constructed via two iterative Myers alkylations of enantiomeric pseudoephedrine propionate enolates. Completion of the total synthesis of tautomycetin will require a global silyl deprotection step and unmasking of the dibenzyl ester.;The last section of chapter two focuses on efforts directed at designing and synthesizing selective protein phosphatase inhibitors based on the structure of tautomycetin and related compounds.