Person:

Wzorek Jr., Joseph Stanley

I. Efforts Toward the Synthesis of (–)-Tetracycline. A macrocyclic approach toward (–)-tetracycline is described. Traditional approaches towards the synthesis of tetracycline antibiotics employ the linear construction of the core structure starting with either the A- or D-rings. In contrast to this iterative annulation-based strategy, we have sought to employ a chiral macrocycle in our approach. Key to the success of our synthesis endeavor is the execution of two key steps: (1) a transannular Michael addition, which forms the A-ring and sets the C4a-stereogenic center; and (2) an isoxazole substitution reaction, which effects a ring contraction to produce both the B- and C-rings. This work describes our implementation of the strategy and focuses on the stereochemical interplay between the C4-, C4a-, C6-, and C12a-stereocenters within the context of the key steps. II. Analysis of the Peripheral Attack Model. The application of the peripheral attack model to 34 literature examples of intermolecular macrocyclic stereocontrol is described. While the peripheral attack model has been broadly applied in complex molecule synthesis, the validity of the model has not been subjected to analysis since being proposed in the early 1980’s. In order to assess the value of the model to organic chemists, we have developed a systematic method for probing the conformational profile of macrocycles. Using this tool, we then analyzed each of the 34 literature substrates and concluded whether the peripheral attack model predicts the correct stereochemical outcome in both a binary- and magnitude-based capacity. Analysis of both the bulk dataset and subsets of the dataset is included.