Franklin

SYNTHESIS OF CYCLOPROPYL ANALOGS OF LEUKOTRIENES A4 AND A3 : SYNTHESIS OF CYCLOPROPYL ANALOGS OF ARACHIDONIC ACID : STEREOCONTROLLED TOTAL SYNTHESIS OF ENDIANDRIC ACIDS A-G AND THERMAL STUDIES ON THEIR INTERCONVERSIONS [electronic resource].

Author/Creator:
PETASIS, NICOS ANDREOU.
Format/Description:
Book
423 p.
Contained In:
Dissertation Abstracts International 45-02B.

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Subjects:
Chemistry, Organic.
System Details:
Mode of access: World Wide Web.
Summary:
The field of eicosanoids continues to be a major area of research in chemistry and biology. With the discovery of the leukotrienes (LT's), and the recognition of their significant biological properties, some new possibilities have evolved for the development of new therapeutic methods, particularly for the treatment of inflammation, allergy and asthma. An overview of eicosanoids, with emphasis on recent developments is included in the first chapter of this thesis. This review is followed by the discussion of the design and synthesis of four novel cyclopropyl-containing analogs of the key biosynthetic intermediates leukotrienes A(,4) and A(,3). These analogs (14-cis- and 14-trans-5,6-methanoleukotriene A(,4), 13,13-ethano-5,6-methanoleukotriene A(,4) and 5,6-methanoleukotriene A(,3)) on preliminary testing exhibited some interesting biological properties, including selective and potent inhibition of 5-lipoxygenase. The synthesis of these compounds is characterized by highly stereocontrolled olefin-forming reactions.
The second chapter describes the development of a novel strategy for the modulation of the arachidonic acid (AA) cascade, based on analogs of AA having one or more bisallylic positions blocked with a cyclopropyl group. The synthesis of one of these analogs (13,13-ethanoarachidonic acid), based on two alternative routes is discussed, as well as some preliminary biological data.
The third chapter deals with the synthesis of four novel natural products, namely endiandric acids A-D (structures 1-4, p. 236), as well as the related acids E-G (44, p. 247, 49, p. 249 and 52, p. 249). These compounds were isolated recently from an Australian plant and, despite the many chiral centers present in their highly condensed structures, they occur in nature in racemic forms. This was explained by a novel biosynthetic hypothesis, proposed by their discoverers, which relies heavily on pericyclic reactions. Synthetic studies, described in this chapter, culminated to the stereocontrolled total synthesis of all of these compounds, from a common precursor. The synthetic approach includes a novel application of 8(pi) and 6(pi) electrocyclizations similar to those suggested for their biosynthesis. Thermal studies, carried out with the methyl esters of acids D-G, followed by NMR, revealed some interesting interconversions between isomeric endiandric acids, and provided support for the proposed biogenetic scheme.
Notes:
Source: Dissertation Abstracts International, Volume: 45-02, Section: B, page: 0565.
Thesis (Ph.D.)--University of Pennsylvania, 1983.
Local notes:
School code: 0175.
Contributor:
University of Pennsylvania.
Access Restriction:
Restricted for use by site license.