Part I. Isodityrosine-derived cyclic peptides: Total syntheses of L,L-isodityrosine, K-13, and OF4949-III and OF4949-IV. Part II. Total syntheses of deoxybouvardin and RA-VII and design, syntheses, and evaluation of structural analogs
Abstract
The glycoprotein characteristic of plant cell walls undergoing extensin growth has been shown to contain the crosslinking amino acid isodityrosine. The structure of isodityrosine is an amino acid dimer in which two tyrosine units are linked through an unsymmetrical diphenyl ether bond. Additional efforts have established the natural occurrence of the antifungal agent piperazinomycin, the aminopeptidase B inhibitors OF4949-I - IV, the angiotensin converting enzyme (ACE) inhibitor K-13, and a class of bicyclic hexapeptide antitumor antibiotics including bouvardin and deoxybouvardin and RA-I - RA-IV bearing structural subunits derived from isodityrosine. The isodityrosine-derived unit present in the agents has proven to be fundamentally important to their properties. The isodityrosine-derived 14-membered segment of bouvardin/deoxybouvardin has been suggested to be responsible for the attainment and/or maintenance of an otherwise inaccessible, active conformation of the parent cyclic hexapeptides. Herein the development of reaction conditions for implementation of an activated Ullmann diaryl ether condensation reaction that may be conducted without amino acid racemization and that has proven suitable for incorporation of the selectively-protected catechol of functionalized scL-Dopa derivatives is described. The application of this procedure in the total syntheses of scL, scL-isodityrosine, K-13, and OF4949-III/OF4949-IV is detailed. A study of the macrolactam cyclization reaction required for formation of the 17-membered tripeptides incorporating a diaryl ether linked meta- and paracyclophane structural subunit is provided. Structural features of K-13 that contribute to its angiotensin converting enzyme inhibitory activity are defined and OF4949 structural features that contribute to aminopeptidase B inhibitory activity are detailed. The demonstration and definition of the scope of an intramolecular Ullmann condensation reaction suitable for the use in macrocyclization reactions leading to 14-membered para- and metacyclophanes possessing a diaryl ether are detailed. A concise synthesis of RA-VII and deoxybouvardin is detailed and is based on the implementation of an intramolecular Ullmann reaction as the key macrocyclization process for the preparation of the 14-membered isodityrosine-derived 14-membered cyclophane unit of the bicyclic hexapeptides. The design, synthesis, and evaluation of structural and conformational analogs of bouvardin/deoxybouvardin are presented.
Degree
Ph.D.
Advisors
Boger, Purdue University.
Subject Area
Organic chemistry|Pharmacology
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