Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


case1056051840.pdf (3.76 MB)

ETD Abstract Container

Abstract Header

Part 1. Halichondrin B: Synthesis of an H-ring intermediate. Part 2. Levuglandin-protein adducts: Synthesis of an antigen for immunoassay

Kim, Seokchan
http://rave.ohiolink.edu/etdc/view?acc_num=case1056051840

Abstract Details

1992, Doctor of Philosophy, Case Western Reserve University, Chemistry.
Part 1. Halichondrins, a family of macrolide polyethers, were isolated from a sponge, Halichondria okadai Kadota, in 4 × 10-7 to 5 × 10-6% yield. Halichondrin B, the biologically most active member of this new family, is a remarkably effective antitumor agent in vivo. The 32 asymmetric carbons in halichondrin B allow more than four billion stereoisomers. Therefore, a practical total synthesis must be highly stereoselective. A practical synthesis of H-ring intermediate 10 which incorporates carbon 27 to 35 of the halichondrin skeleton from D-glucose requires stereocontrolled homologation at C-6 (glucose numbering), epimerization at C-5, replacement of a hydroxyl at C-3 with a Me group, and C-glycosidation at the anomeric center. Introduction of the Me group at C-3 position was achieved by regioselective opening of the epoxide 13 by axial attack of MeMgCl followed by oxidation of the 2-hydroxyl in 14 and epimerization of the 3-methyl to the desired configuration. Inversion of the configuration at C-5 (glucose numbering) and elongation of the side chain were accomplished by a C-C bond cleavage-reformation sequence exploiting the pyranose to furanose interconversion which accompanies ketalization of glucose with acetone. Oxida tive cleavage of vicinal diol 20 with periodate destroys the center of incorrect chirality at position 5. Entirely stereoselective (>99:1) generation of the requisite configuration at C-5 was achieved by condensation of aldehyde 21 with enol ether 41 in the presence of TiCl4. Hydrolysis and deketalization of 42a is accompanied by furanose to pyranose interconversion and lactonization to provide cis lactone 26. Wittig olefination of 26 at anomeric center and heterocyclization of the resulting α,β-unsaturated ester 45 deliver the H-ring intermediate 10. Part 2. Secoprostanoic acid levulinaldehyde derivatives, which we named levuglandins (LGs), are generated along with PGs by rearrangement of PGH2 under the aqueous environment of its biosynthesis. Our goal is to determine the extent and distribution of LG occurrence in vivo. Previous attempts to detect LGs in biological systems failed due to the complicated covalent adduct formation with proteins. A pyrazole isostere of LGE2-derived pyrrole 141 was designed and synthesized. Structural assignment of pyrazole isomers, generated in the reaction of 1,3-diketone 149 with 6-hydroxylhexylhydrazine 150, was achieved by COSY and NOESY experiments. Coupling of pyrazole isostere 141 with poly-L-lysine was achieved using sodium cyanoborohydride in THF/H2O to provide an antigen for immunoassay. 1H NMR analysis showed the presence of 1 pyrazole for every 2 lysyl residues in the modified protein. Antibodies against pyrazole was raised by immunizing rabbits with isostere-protein conjugate 142. We used the BSA conjugate as a coating reagent for ELISA.
Robert Salomon (Advisor)
172 p.
Chemistry, Organic
Halichondrin Synthesis H-ring intermediate Levuglandin protein adducts Synthesis antigen immunoassay

Recommended Citations

Citations

  • Kim, S. (1992). Part 1. Halichondrin B: Synthesis of an H-ring intermediate. Part 2. Levuglandin-protein adducts: Synthesis of an antigen for immunoassay [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1056051840

    APA Style (7th edition)

  • Kim, Seokchan. Part 1. Halichondrin B: Synthesis of an H-ring intermediate. Part 2. Levuglandin-protein adducts: Synthesis of an antigen for immunoassay. 1992. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1056051840.

    MLA Style (8th edition)

  • Kim, Seokchan. "Part 1. Halichondrin B: Synthesis of an H-ring intermediate. Part 2. Levuglandin-protein adducts: Synthesis of an antigen for immunoassay." Doctoral dissertation, Case Western Reserve University, 1992. http://rave.ohiolink.edu/etdc/view?acc_num=case1056051840

    Chicago Manual of Style (17th edition)

case1056051840
814
© 1992, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
Release 3.2.12