An improved synthesis of the AB spiroketal of spongistatin is reported by making use of an asymmetric Mukaiyama-type aldol to install the C5 hydroxyl group selectively. A hetero- Diels-Alder cycloaddition-elimination sequence provides the pyrone core, upon which spiroketalization and further elaboration occurs to provide the completed AB spiroketal The synthesis of the protected aglycon of yokonolide A is also presented. This synthesis makes use of several asymmetric aldol and alkylation reaction to produce the main fragments. The endgame strategy adopts the use of an esterification-ring closing metathesis sequence to complete the protected core. Efforts toward the total synthesis of yokonolide A are also reported. Studies indicate that the success of the glycosylation reaction is dependent upon the structure of the glycosyl acceptor. Successful glycosyl donors have also been synthesized for use with these acceptors. Several routes have been explored which have led to protecting group challenges along the way. Efforts have also been made toward completion of the unprotected aglycon. This was undertaken to investigate a deprotection strategy for the natural product when a successful route is developed.