Studies Toward The Synthesis Of Strychnos Alkaloids

Author : David Bruce Coakwell Martin
Publisher :
ISBN 13 : 9781267029607
Total Pages : 471 pages
Book Rating : 4.0/5 (296 download)

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Download or read book The Application of Zincke Aldehydes to the Synthesis of Strychnos Alkaloids and Progress Toward the Synthesis of Platencin written by David Bruce Coakwell Martin and published by . This book was released on 2011 with total page 471 pages. Available in PDF, EPUB and Kindle. Book excerpt: In the first part of this dissertation, our studies toward the Strychnos alkaloids are detailed. Previous work in this area is summarized in Chapter 1, including a short description of the biosynthetic pathway, a discussion of the structural challenges of the Strychnos alkaloids, and unique strategies that have been developed to overcome these challenges. An introduction to the use of Zincke aldehydes in natural product synthesis is presented in Chapter 2, including important historical examples and the work developed in the Vanderwal group. In Chapter 3, the development of the anionic bicyclization of tryptamine-derived Zincke aldehydes is outlined, along with substrate scope and preliminary mechanistic discussions. The bicyclization reaction provides tetracyclic products in moderate to high yields and as single diastereomers, matching the ABCE ring system of most indole monoterpene alkaloids. The application of this reaction to the synthesis of norfluorocurarine is discussed. In Chapter 4, a second-generation strategy for gaining general access to more complex tetracyclic compounds is outlined. The allyl group was identified as an easily removed protecting group, allowing the subsequent incorporation of more complex side-chains. A number of strategies for Strychnos D-ring closure were explored, including a propargylsilane cyclization, Heck reaction and Cu-mediated conjugate addition. Concise syntheses of norfluorocurarine (five steps), dehydrodesacetylretuline (six steps), valparicine (seven steps), the Wieland-Gumlich aldehyde (five steps) and strychnine (six steps) are disclosed. Unexpected reactions discovered during our studies include a surprisingly facile dimerization of the products, and an unexpected cycloreversion to regenerate Zincke aldehydes under specific conditions. In the second part of this dissertation, our progress toward the synthesis of platencin, a novel antibiotic, is described. The proposed synthesis incorporates a bicyclization strategy that was explored using a radical cascade reaction, a Heck reaction, and related stepwise approaches. While attempting to photoinitiate an atom-tranfer radical cyclization, a [2+2] adduct was isolated and characterized by X-ray diffraction. A variety of thermally initiated reactions are also described, giving different products, including small quantities of a tricyclic product that closely resembles the desired product, but could not be unambiguously characterized. Using a Heck reaction, cyclization could not complete with ß-hydride elimination. A two-step cyclization sequence was also attempted, without success.