Transannular di- and tetrahydropyran components are present in many biologically active complex polyketides including laulimalide, a promising anticancer agent. A potential mechanism for the formation of the trans dihydropyran in laulimalide has been proposed that involves an elimination/oxa-Michael addition cascade reaction. To determine the scope and stereochemical outcome of this process, several model systems are being chemically synthesized in which two variables are being explored—ring size and type of Michael acceptor. Sizes range from 12 to 20-membered macrocycles and contain either α, β-unsaturated lactones or sorbic functionalities. Conformation of the ring is expected to be a major influence on the stereochemistry in this process. Ab initio calculations using Gaussian03 W on previous laulimalide model systems shows an overall negative ΔG for Michael addition reactions.  Creation of a 20-membered lactone has already been accomplished in 12 steps and synthesis of a 14-membered lactone is four steps from completion.