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Exploiting the Reactivity of Arynes in the Total Synthesis of Natural Products


Tadross, Pamela Michele (2012) Exploiting the Reactivity of Arynes in the Total Synthesis of Natural Products. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/0HAZ-QF41.


Within 14 years of the seminal experiments of J. D. Roberts leading to the first proposal of the structure of benzyne, synthetic organic chemists recognized the potential to exploit this highly reactive intermediate (and its substituted variants) in the synthesis of natural products. More specifically, it was recognized that arynes offered the strategic advantage of rapidly functionalizing an aromatic ring by forming multiple carbon–carbon or carbon–heteroatom bonds in a single operation, often in a regioselective manner. Herein are reported three separate efforts aimed at constructing natural products by aryne-based methodologies. In each of the studies described in the following chapters, the implementation of new aryne technologies developed in our group to natural product synthesis has resulted in concise, convergent, and general strategies to our targets.

The first project discussed in this work is the enantioselective total synthesis of (–)-curvularin by an acyl-alkylation reaction of a protected resorcinylic silyl aryl triflate aryne precursor with a β-ketolactone. Application of this strategic disconnection resulted in a six-step convergent synthesis of the polyketide natural product, the shortest to date. These efforts also resulted in the syntheses of curvulin and diplodialide C.

In our efforts toward the total synthesis of two naturally occurring HIV integrase inhibitors, integrastatins A and B, we attempted to utilize a sequence involving an acyl-alkylation followed by an ortho-Fries-type rearrangement to access the tetracyclic core of the natural products. However, this proved to be a significant challenge and led to the development of an alternative route to the tetracyclic integrastatin core by a Wacker cyclization of a diol onto a pendant olefin.

Finally, ongoing progress toward the synthesis of the bis-tetrahydroisoquinoline natural product jorumycin is detailed. In a departure from the efforts toward curvularin and the integrastatins, jorumycin has been targeted through the application of a combination of aryne annulation and acyl-alkylation/condensation methodologies aimed at the synthesis of a functionalized bis-isoquinoline intermediate. Reduction of this key bis-isoquinoline to a bis-tetrahydroisoquinoline and subsequent lactamization provided the pentacyclic core of jorumycin and related natural products in only two steps from simple isoquinoline building blocks.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Arynes, Benzyne, Natural Products, Total Synthesis, Curvularin, Integrastatin, Jorumycin, Isoquinolines, Oxidative Cyclization
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Stoltz, Brian M.
Thesis Committee:
  • Dervan, Peter B. (chair)
  • Reisman, Sarah E.
  • Goddard, William A., III
  • Virgil, Scott C.
  • Stoltz, Brian M.
Defense Date:4 November 2011
Funding AgencyGrant Number
California HIV/AIDS Research ProgramUNSPECIFIED
Record Number:CaltechTHESIS:11092011-100634353
Persistent URL:
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6732
Deposited By: Pamela Tadross
Deposited On:06 Jan 2012 22:28
Last Modified:08 Nov 2023 00:39

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