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Studies toward the total synthesis of amphidinol 3

Chang, Shuh-Kuen
http://rave.ohiolink.edu/etdc/view?acc_num=osu1150261354

Abstract Details

2006, Doctor of Philosophy, Ohio State University, Chemistry.
Amphidinol 3, one of dinoflagellate derived polyketides, has attracted much attention as a potential therapeutic compound due to its potent membrane-permeabilizing activities in terms of antifungal and hemolytic activities related to its special structural features. Amphidinol 3 revealed stronger hemolysis against human erythrocytes than those of other well-known antibiotics such as amphotericin B and filipin III. Biological assays indicated that amphidinol 3 exhibited different mechanisms in forming pores or lesions in biomembranes depending on dosage concentrations. Structurally, amphidinol 3 has unique properties in terms of its size and conformational complexity. It consists of a central part involving two tetrahydropyran rings comprising a large hydrophilic part, the polyolefin moiety, and the polyhydroxylated chain with a total of 25 stereogenic centers on a contiguous 67 carbon backbone. It represents a challenging synthetic target. The synthesis of the C43-C67 subsector was realized by application of the Julia-Kocienski olefination to the joining of the C53-C67 polyunsaturated chain to the C43-C52 tetrahydropyran ring. The Julia-Lythgoe protocol was exploited in the formation of the former. The latter was derived from D-ribose as the starting material via ensuing 6-ring cyclization in conjunction with opening of the oxirane ring. The highly convergent and stereocontrolled approach to construction of the protected C1-C30 polyoxygenated fragment relied on multiple application of the Kocienski modification of the Julia olefination, accompanying by use of a Wittig reaction in the coupling of phosphonium salt 4.2 to keto aldehyde 4.3. Another key to our success includes the economic manner in which the antipodal malic acids can be transformed into enantiopure building blocks directly suited to the present objectives. Moreover, two different tetrahydropyran intermediates, aldehyde 5.2 and epoxide 5.3 were efficiently derived from the common building block 3.85 in an attempt to approach the C31-C52 central core of amphidinol 3. An alternative route to synthesize this intermediate is also proposed.
Leo Paquette (Advisor)
412 p.
Chemistry, Organic

Recommended Citations

Citations

  • Chang, S.-K. (2006). Studies toward the total synthesis of amphidinol 3 [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1150261354

    APA Style (7th edition)

  • Chang, Shuh-Kuen. Studies toward the total synthesis of amphidinol 3. 2006. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1150261354.

    MLA Style (8th edition)

  • Chang, Shuh-Kuen. "Studies toward the total synthesis of amphidinol 3." Doctoral dissertation, Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1150261354

    Chicago Manual of Style (17th edition)

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© 2006, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.