Synthetic Approaches To An Indole Alkaloid Precursor

Author : Asuman Durmus
Publisher :
ISBN 13 : 9781303791840
Total Pages : pages
Book Rating : 4.7/5 (918 download)

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Download or read book Concise Synthesis of Indole Natural Products and Rosette Nanotube Forming G-C Base Hybrids, and Efforts Towards the Isolation of an Oxonium Ylide written by Asuman Durmus and published by . This book was released on 2013 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is among the most serious and persistent health hazards known to man, with over 200 million infections leading to ca. 1 million fatalities annually, more than 80% of which being in children under five. It is for this reason that the development of simple routes to effective antimalarials is an urgent priority in the global health arena. Decursivine is an extracyclic indole alkaloid which shows activity (4.4 mg mL−1) against the chloroquinine-resistant malaria parasite Plasmodium falciparum. It was recently isolated from active extracts of Rhaphidophora decursiva, a perennial, evergreen vine native to Vietnam. In this work, the synthesis of (±)-decursivine was achieved in 4 steps from commercially available starting materials. A photoinitiated reaction cascade involving indole radical cation formation, rearrangement, radical recombination, rearomatization, elimination, and diastereoselective auto-acid-catalyzed closure of the dihydrofuran ring combine in a single step in this remarkably efficient synthesis. Following up on this simple approach to (±)-decursivine, a stereocontrolled synthesis of (+)-decursivine was pursued using a BINOL-based strong chiral acid to introduce chirality during the protonation step. A chiral precursor derived from 5-hydroxy-L-tryptophan ethyl ester was also synthesized in another attempt to obtain (+)-decursivine. The synthesis of two other natural products, bufothionin (a toad skin toxin) and discorhabdin C (an indole alkaloid that exhibits high toxicity against tumor cells) was also attempted using Witkop-like cyclizations. N-substituted pyrido[4,3-d]pyrimidines are heterocycles which exhibit the asymmetric hydrogen bonding codes of both guanine and cytosine at 60° angles to each other, such that the molecules self-organize unambiguously into a cyclic hexamer, assembled via 18 intermolecular hydrogen bonds. The synthesis is straightforward and can be concluded in six steps from the commercially available malononitrile dimer. X-ray crystallographic analysis of the supermacrocyclic structure shows an undulating disk with a ca. 10.5 Å cavity, the centers of which do not overlap sufficiently to describe a channel in the solid state. However, AFM, SEM, and TEM imaging in solution reveals the formation of 1D nanostructures in agreement with their self-assembly into rosette supermacrocycles, which then stack linearly to form rosette nanotubes. Oxonium ylides have not, to date, been isolated or even characterized by spectroscopic methods due to their high reactivity. Even though their discrete existence is a matter of speculation, their rearrangement chemistry has led to a rapid growth in the use of oxonium ylides in synthesis in recent years. It has been shown that oxatriquinanes, tricyclic oxonium ions, possess significant solvolytic stability compared to simple alkyl oxonium salts. A potentially stable oxonium ylide that could be generated within the oxatriquiane framework was conceptualized and the precursor for this species had been synthesized previously, albeit in low yield. In this work, three novel synthetic approaches towards a higher yielding route to the precursor were designed and their utility was tested. However, the precursor could not be obtained by any of these approaches.