Toward the total synthesis of purpuromycin : a hemiketal conjugate addition strategy and use of a diketone to aid spiroketal formation / Andrew Nesemann Lowell.

Format:

Book

Manuscript

Microformat

Thesis/Dissertation

Author/Creator:

Lowell, Andrew Nesemann.

Contributor:

Kozlowski, Marisa C., 1967- advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Local Subjects:

Penn dissertations--Chemistry.

Chemistry--Penn dissertations.

Physical Description:

xl, 424 pages : illustrations ; 29 cm

Production:

2008.

Summary:

Purpuromycin is a natural product within the rubromycin family of compounds which show unique activity against infectious disease and cancer. An efficient synthesis of purpuromycin has been elusive due to difficulties involved with forming the spiroketal core of the molecule, the portion crucial to its reactivity, on the fully benzannulated system. Instead, competative formation of a benzofuran dominated when the isocoumarin was electron deficient. Two synthetic approaches were undertaken to solve this problem.*

The first approach, a hemiketal conjugate addition strategy, involved removal of the phenol on the electron rich naphthalene portion of the molecule. Oxidation state adjustment of the naphthalene to the naphthaquinone could then allow the intramolecular oxidative conjugate addition of the hemiketal tautomer of the isocoumarin phenol into the naphthaquinone. While benzene and naphthalene based model systems were investigated under a variety of conditions, no spiroketal formation was observed.*

The second approach was based on the hypothesis that if the protons involved in elimination to benzofuran were removed, spiroketalization would result instead. Toward that end, a second ketone functional group was installed in place of the benzylic protons adjacent to the spiroketalizing ketone. This diketone strategy proved effective, furnishing a fully benzannulated spiroketal.*

In addition to complete naphthalene syntheses to probe the above spiroketalization modes, isocoumarin syntheses were also devised producing symmetrically and orthogonally protected forms in high yield. The diketone approach resulted in a fully benzannulated spiroketal, the most advanced substrate produced by our group to date. Oxidation state adjustments are underway to convert this advanced intermediate to authentic purpuromycin.*

*Please refer to dissertation for diagrams.

Notes:

Adviser: Marisa C. Kozlowski.

Thesis (Ph.D. in Chemistry) -- University of Pennsylvania, 2008.

Includes bibliographical references.

Local Notes:

University Microfilms order no.: 3346160