Albert, Brian J.
(2008)
SYNTHETIC, CHEMICAL, AND BIOLOGICAL STUDIES OF FR901464 AND STUDIES OF THE SILVER AND ZIRCONIUM PROMOTED ALKYNYL ADDITION REACTION.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The total synthesis of FR901464 was accomplished in at total of 29 steps, which is the shortest synthesis to date. Degradation studies were performed on the fully functionalized right fragment of FR901464 and this insight was used to rationally design a more stable analog, which led to the rational development of meayamycin, an FR901464 analog with enhanced biological properties. Additional analogs were synthesized examining the A-ring, C4' position, and the C3 position of the B-ring. These analogs demonstrated that the A-ring of FR901464 is optimal, the C4' acetate should remain intact for higher potency, and the spiroepoxide is required for antiproliferative properties. The low potency of the desepoxy analogs indicate that FR901464 covalently modifies is target(s) via its epoxide, which led to the synthesis of cold iodide-containing analog, which could be used for target identification experiments. Due to the concern of non-specific reactions of epoxides with endogenous thiols, a method was developed to study the consumption of epoxides with thiols. Experiments of common epoxide motifs showed that these reactions were negligible under biologically relevant conditions. Moreover, a model system for the amide chain of FR901464 demonstrated that its Z-enamide will not react non-specifically with endogenous thiols.There was a need for a general method for the alkynyl addition to epoxides to give propargylic alcohols as products. Towards this end, the Ag/Zr-promoted alkynyl addition methodology discovered in the Koide laboratories was successfully applied. These studies began with the preparation of 11 silver acetylides and examining their safety as reagents for organic synthesis. Subsequently, these silver acetylides were shown to add to epoxides via 1,2-shifts to give propargylic alcohols in the presence of Cp2ZrCl2 and AgOTf. The scope and limitations of both the epoxide and alkyne were realized and was demonstrated in over 20 successful reactions. Moreover, the 11 new silver acetylides used in the epoxide alkynyl addition methodology should be readily applicable to the aldehyde alkynyl addition methodology. Finally, mechanistic studies were undertaken and were crucial in understanding the roles of all additives necessary for this alkynyl addition reaction to be successful, culminating in the generation of a proposed mechanism.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
18 January 2008 |
| Date Type: |
Completion |
| Defense Date: |
2 November 2007 |
| Approval Date: |
18 January 2008 |
| Submission Date: |
4 December 2007 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
alkynylation; asymmetric; epoxide; FR901464; GI50; half-life; lactolization; meayamycin; Mislow-Evans; N-bromosuccinimide; organometallic; propargylic alcohol; sigmatropic rearrangement; total synthesis; ynoate; zirconocene |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-12042007-102637/, etd-12042007-102637 |
| Date Deposited: |
10 Nov 2011 20:07 |
| Last Modified: |
15 Nov 2016 13:53 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10018 |
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