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Wzorek Jr., Joseph Stanley

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Wzorek Jr.

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Joseph Stanley

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Wzorek Jr., Joseph Stanley

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2012 - 20152

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Author's Publications: search.filters.isAuthorOfPublication.3e2c7f98-124e-41ef-8d73-01018137a58b

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    Macrocyclic Stereocontrol in Organic Synthesis: I. Efforts toward the Synthesis of (-)-Tetracycline II. Analysis of the Peripheral Attack Model
    (2012-10-23) Wzorek Jr., Joseph Stanley; Evans, David A.; Myers, Andrew; Shair, Matthew
    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.
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    Inhibition of the βbarrel assembly machine by a peptide that binds BamD
    (Proceedings of the National Academy of Sciences, 2015) Hagan, Christine; Wzorek Jr., Joseph Stanley; Kahne, Daniel
    The protein complex that assembles integral membrane β-barrel proteins in the outer membranes of Gram-negative bacteria is an attractive target in the development of new antibiotics. This complex, the β-barrel assembly machine (Bam), contains two essential proteins, BamA and BamD. We have identified a peptide that inhibits the assembly of β-barrel proteins in vitro by characterizing the interaction of BamD with an unfolded substrate protein. This peptide is a fragment of the substrate protein and contains a conserved amino acid sequence. We have demonstrated that mutations of this sequence in the full-length substrate protein impair the protein’s assembly,implying that BamD’s interaction with this sequence is an important part of the assembly mechanism. Finally, we have found that in vivo expression of a peptide containing this sequence causes growth defects and sensitizes E. coli to antibiotics to which they are normally resistant. Therefore, inhibiting the binding of substrates to BamD is a viable strategy for developing new antibiotics directed against Gram-negative bacteria.