Synthetic studies towards tautomycetin and spirastrellolide A and the design and synthesis of tautomycetin/tautomycin analogs

Chapter one of this dissertation details a review about the discovery and development of a pharmacophore model for protein phosphatases 1 and 2A (PP1 and PP2A). This chapter particularly focuses on the determination of the structural elements involved in potent and selective inhibition of a wide variety of protein phosphatase inhibitors. In addition, the potential for the use of potent protein phosphatase inhibitors as novel cancer therapeutics is also discussed. The end of this chapter focuses upon the current synthetic strategies to construct the highly potent and selective natural product toxin inhibitors, spirastrellolide A and tautomycetin, which contain interesting structural features that can provide insight for the SAR of PP1/PP2A.;Chapter two concentrates on our efforts to synthesize the natural product protein phosphatase inhibitors, spirastrellolide A and tautomycetin, as well as a series of tautomycetin/tautomycin analogs. The first section of this chapter describes our synthesis of the C17-C25 fragment of spirastrellolide A. Our approach to construct the C17-C25 fragment uses L-tartaric acid as a building block, which enables the use of a key Mukaiyama alkynyl addition reaction to install the C21 stereocenter. This synthetic route also employs a Brown crotylation to install the stereocenters at C23 and C23. Using this strategy, we were able to produce the desired fragment in 14 linear steps.;Our progress towards the total synthesis of tautomycetin is also described in this chapter. Improvement of the key Mukaiyama aldol reaction has allowed us to produce gram quantities of a late stage intermediate, which is only six steps away from the completion of the natural product. The synthetic sequence leading up our key Mukaiyama aldol reaction features an Abiko anti-aldol used to install the C12 hydroxyl and C13 methyl stereocenters and sequential Myers alkylations to construct 1,3-anti dimethyl moiety of tautomycetin. Our strategy for the completion of tautomycetin entails a vinyl cuperate addition and global deprotection step and is detailed in the final part of this section.;The last section in chapter two describes the synthesis and biological testing of a library of tautomycin/tautomycetin analogs. Nine compounds from the library were found to be nanomolar potent inhibitors for PP1 or PP2A. Two of the inhibitors are extremely selective PP1 inhibitors with potencies that are only three fold weaker than tautomycetin. The analogs combined with tautomycetin/tautomycin analogs generated previously in this lab form a group of compounds where the PP1/PP2A selectivity can be altered simply by changing the apolar tail regions of the molecules.