Dissertation/Thesis Abstract

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A Methodology for Chemoselective Carbonyl Ylide Formation, Total Synthesis of (±)-Aspergilline A, Cyclopiamide A and Speradine E and Progress towards the Total Synthesis of (±)-Isopalhinine A
by Nakhla, Mina Cyril, Ph.D., Baylor University, 2018, 496; 10975389
Abstract (Summary)

In 2001, the total synthesis of (±)-epoxysorbicillinol was completed by Wood and coworkers. This work featured as the key step a Rh(II) catalyzed carbonyl ylide formation and subsequent dipolar cycloaddition of a diazomalonate to yield a highly functionalized oxabicyclic intermediate. In efforts to render the synthesis enantioselective, a method for chemoselective carbonyl ylide formation was devised; this culminated in the formal enantioselective synthesis of (+)-epoxysorbicillinol in 2005. The methodology utilized in this synthesis centered around electronic differentiation of the diazomalonate’s esters to induce chemoselective carbonyl ylide formation. Having established a methodology for chemoselective carbonyl ylide formation, the substrate scope was expanded and steric differentiation of the diazomalonate’s esters explored.

Aspergilline A was isolated from Aspergillus versicolor in 2014 by Hu and Gao and was shown to exhibit moderate biological activity against several human cancer cell lines. The compound bears several intriguing structural features including a 6/5/6/5/5/5 fused ring system which contains an oxindole moiety and a substituted tetramic acid. In synthesizing this compound our strategy relied upon two key steps. The first was a single step conversion of a propargyl amine into to a pyrrolinone through the action of an ammonium enolate and the second was a formal [3+2] dipolar cycloaddition between an imidate and a cyclopropenone derived all carbon 1, 3 dipole. Ultimately this work resulted in the sixteen step total synthesis of (±)-aspergilline A. Additionally, two other related natural products cyclopiamide A and speradine E were synthesized by diverting intermediates accessed during the aspergilline A synthesis.

In 2013, the Lycopodium alkaloid isopalhinine A was isolated from Palhinhaea cernua by Zhao and coworkers. To date, the compound has not been shown to exhibit any biological activity. Despite its lack of known biological activity, the compound does possess a variety of synthetically challenging structural features, including a 5/6/6/6/7 fused ring system which contains an isotwistane and a cycloheptane hemiaminal. In devising a synthetic strategy, we settled upon two key synthetic transformations; an allene Nazarov cyclization to construct the central cyclopentanone core and a late stage titanium mediated 6-exo-trig cyclization and subsequent deoxygenation to complete construction of the isotwistane.

Indexing (document details)
Advisor: Wood, John L.
Commitee: Hockaday, William C., Martin, Caleb D., Pinney, Kevin G., Romo, Daniel, Wood, John L.
School: Baylor University
Department: Chemistry and Biochemistry
School Location: United States -- Texas
Source: DAI-B 80/05(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Chemistry
Keywords: 3+2 dipolar cycloaddition, Aspergilline A, Isopalhinine A, Natural products, Organic chemistry, Total synthesis
Publication Number: 10975389
ISBN: 9780438797468
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