Biomimetic Total Synthesis of (-)-Arabilin and (±)-Kingianins A, D, F, and H, and An approach to the total synthesis of (±)-Arisugacin A
Biomimetic Total Synthesis of (-)-Arabilin and (±)-Kingianins A, D, F, and H, and An approach to the total synthesis of (±)-Arisugacin A
| dc.identifier.uri | http://hdl.handle.net/11401/77123 | |
| dc.description.sponsorship | This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree. | en_US |
| dc.format | Monograph | |
| dc.format.medium | Electronic Resource | en_US |
| dc.language.iso | en_US | |
| dc.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dc.type | Dissertation | |
| dcterms.abstract | Chapter 1 demonstrates the total synthesis of -)-arabilin. (‒ )-Arabilin is a potent androgen receptor antagonist that was isolated from Streptomyces sp. MK756-CF1. We hypothesized that the enol ether-containing skipped-tetraene structure of arabilin is formed from a conjugated tetraene system by a thermally allowed, nonenzymatic rearrangement- a [1,7]-hydrogen shift. The feasibility of this transformation was first demonstrated in a model system and subsequently incorporated into the first total synthesis of arablin. The synthesis supports the premise that a [1,7]-hydrogen shift is a nonenzymatic step in the biosynthesis of arabilin. Chapter 2-4 demonstrate the total synthesis of some members of kingianins. The kingianins, a family of structurally complex polyketides, were isolated from the species Endiandra kingiana. They are reported to have low- to mid-micromolar binding to the antiapoptotic protein Bcl-xL. All of the kingianins share a pentacyclic core, itself believed to be the Diels-Alder dimer of monomeric bicyclooctadienes. We proposed that, in nature, the Diels-Alder dimerization proceeds by a cation radical-mediated reaction (presumably photo-initiated). In addition, the regioselectivity and stereoselectivity of the Diels-Alder reaction is presumed to result from steric factors in the transition state for cycloaddition. In the synthesis of kingianin A, we used a tether-mediated intramolecular reaction to control the regioselectivity of the Diels-Alder reaction and to avoid difficulty during separation. Then kingianin A was prepared by a double homologation method from the endo RCDA diol. We postulated that the isomeric diols in the kingianin series might have usefully different chromatographic behaviors. Indeed, the intermolecular RCDA dimerization of the endo and exo bicyclooctadienes afforded separable endo diols that corresponded to kingianins D, F, and H. With the same double-homologation methods, the synthesis of kingianins D and F were completed. Manchand's three-carbon homologation was adapted to prepare kingianin H. Chapter 5-7 demonstrate the synthetic approach of (±)-Arisugacin A. (±)-Arisugacin A is a potent inhibitor of acetylcholinesterase (Ache). We designed a synthesis based on a polyene cyclization and a Tamao oxidation. Thus, we have studied the catalytic polyene cyclization of the substrates containing vinyl silanes. In addition, we sought the stereoselective synthesis of (E)-vinyl silanes by a relay-ring closing metathesis reaction. | |
| dcterms.abstract | Chapter 1 demonstrates the total synthesis of -)-arabilin. (‒ )-Arabilin is a potent androgen receptor antagonist that was isolated from Streptomyces sp. MK756-CF1. We hypothesized that the enol ether-containing skipped-tetraene structure of arabilin is formed from a conjugated tetraene system by a thermally allowed, nonenzymatic rearrangement- a [1,7]-hydrogen shift. The feasibility of this transformation was first demonstrated in a model system and subsequently incorporated into the first total synthesis of arablin. The synthesis supports the premise that a [1,7]-hydrogen shift is a nonenzymatic step in the biosynthesis of arabilin. Chapter 2-4 demonstrate the total synthesis of some members of kingianins. The kingianins, a family of structurally complex polyketides, were isolated from the species Endiandra kingiana. They are reported to have low- to mid-micromolar binding to the antiapoptotic protein Bcl-xL. All of the kingianins share a pentacyclic core, itself believed to be the Diels-Alder dimer of monomeric bicyclooctadienes. We proposed that, in nature, the Diels-Alder dimerization proceeds by a cation radical-mediated reaction (presumably photo-initiated). In addition, the regioselectivity and stereoselectivity of the Diels-Alder reaction is presumed to result from steric factors in the transition state for cycloaddition. In the synthesis of kingianin A, we used a tether-mediated intramolecular reaction to control the regioselectivity of the Diels-Alder reaction and to avoid difficulty during separation. Then kingianin A was prepared by a double homologation method from the endo RCDA diol. We postulated that the isomeric diols in the kingianin series might have usefully different chromatographic behaviors. Indeed, the intermolecular RCDA dimerization of the endo and exo bicyclooctadienes afforded separable endo diols that corresponded to kingianins D, F, and H. With the same double-homologation methods, the synthesis of kingianins D and F were completed. Manchand's three-carbon homologation was adapted to prepare kingianin H. Chapter 5-7 demonstrate the synthetic approach of (±)-Arisugacin A. (±)-Arisugacin A is a potent inhibitor of acetylcholinesterase (Ache). We designed a synthesis based on a polyene cyclization and a Tamao oxidation. Thus, we have studied the catalytic polyene cyclization of the substrates containing vinyl silanes. In addition, we sought the stereoselective synthesis of (E)-vinyl silanes by a relay-ring closing metathesis reaction. | |
| dcterms.available | 2017-09-20T16:52:01Z | |
| dcterms.contributor | Carrico, Isaac | en_US |
| dcterms.contributor | Parker, Kathlyn A | en_US |
| dcterms.contributor | Kerber, Robert | en_US |
| dcterms.contributor | Lim, Yeon-Hee. | en_US |
| dcterms.creator | Lim, Hee Nam | |
| dcterms.dateAccepted | 2017-09-20T16:52:01Z | |
| dcterms.dateSubmitted | 2017-09-20T16:52:01Z | |
| dcterms.description | Department of Chemistry. | en_US |
| dcterms.extent | 500 pg. | en_US |
| dcterms.format | Application/PDF | en_US |
| dcterms.format | Monograph | |
| dcterms.identifier | http://hdl.handle.net/11401/77123 | |
| dcterms.issued | 2015-08-01 | |
| dcterms.language | en_US | |
| dcterms.provenance | Made available in DSpace on 2017-09-20T16:52:01Z (GMT). No. of bitstreams: 1 Lim_grad.sunysb_0771E_11507.pdf: 21549152 bytes, checksum: 3ee265b0c131205ecfa8f560e3e527a3 (MD5) Previous issue date: 2013 | en |
| dcterms.publisher | The Graduate School, Stony Brook University: Stony Brook, NY. | |
| dcterms.subject | Chemistry | |
| dcterms.subject | Arabilin, Arisugacin, Kingianin, Natural product, Total Synthesis | |
| dcterms.title | Biomimetic Total Synthesis of (-)-Arabilin and (±)-Kingianins A, D, F, and H, and An approach to the total synthesis of (±)-Arisugacin A | |
| dcterms.title | Biomimetic Total Synthesis of (-)-Arabilin and (±)-Kingianins A, D, F, and H, and An approach to the total synthesis of (±)-Arisugacin A | |
| dcterms.type | Dissertation |
