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Title page for ETD etd-03282011-182026


Type of Document Dissertation
Author Chandra, Aroop
Author's Email Address aroop.chandra3525@gmail.com
URN etd-03282011-182026
Title The application of new methods to the synthesis of constrained proline derivatives, (+)-serratezomine A, and hapalindoles A, G, I, and K
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Dr. Jeffrey N. Johnston Committee Chair
Gary A. Sulikowski Committee Member
Lawrence J. Marnett Committee Member
Ned A. Porter Committee Member
Keywords
  • (+)-serratezomine A
  • alkaloids
  • peptide conformation
  • hapalindole
  • ambiguine
Date of Defense 2011-01-25
Availability unrestricted
Abstract
The development of new chemical methods to tackle synthetic challenges is presented in this dissertation. Application of these methods has led to the completion of the following projects:

The first total synthesis of the Lycopodium alkaloid (+)-serratezomine A, a strong acetyl-choline esterase inhibitor. Key aspects of the synthesis include (a) the first deployment of free-radical-mediated vinyl amination (an intramolecular alkyne aminostannation) in a complex target synthesis, (b) the use of a â-stannyl enamine as the lynchpin for convergent assembly of the natural product backbone, (c) the use of an oxidative allylation promoted by cerium(IV) (CAN) to establish the all-carbon quaternary chiral center with the proper configuration, and (d) an intramolecular substitution reaction to form the sensitive bridging lactone. Overall, 15 steps (longest linear sequence) are required to prepare the natural product from commercially available starting materials, and assembly of the contiguous array of six stereocenters is accomplished with high stereocontrol.

The first total synthesis of marine indole alkaloids hapalindoles K and A, and a formal synthesis of hapalindole G. In so doing, use of (a) a two-fold electrophilic aromatic substitution (EAS) reaction between indole and á-methyl tiglic acid chloride, (b) a demanding intermolecular [4+2] cycloaddition, and (c) a late stage Ritter reaction provided the needed convergency and functional group installation to deliver each target in 15 steps or less.

An examination of the effects of proline analogs, indoline and azaindoline amino acids, on prolyl N-terminal cis-trans amide isomer population. A series of di, tri, and tetrapeptides containing indoline amino acids with or without a nitrogen mutation at C7 were synthesized, utilizing a free-radical-mediated aryl amination (an intramolecular aryl aminostannation), and evaluated. Because of A1,3-strain between the fused aromatic group (indoline) and prolyl N-terminal residue in unmutated indoline amino acids, the cis-amide bond geometry about the L-Ind fragment was able to be favored. However, all the peptides incorporating the N7Ind mutations resulted in exclusive formation of the trans-rotamer about the Phe-N7Ind amide bond. This conformation preference for N7Ind containing peptides was due to an unfavorable lone-pair/lone-pair repulsion between the preceding carbonyl oxygen and azaindoline nitrogen in the s-cis conformation. The subtle, yet predictable control that these proline frameworks provides at this stage may lead to a more effective chemical tool and ultimately, more effective therapeutics.

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