University of Tasmania
whole_NgSarahManYee2010_thesis.pdf (10.75 MB)

Regioselective modification of pyrroles : applications towards lamellarins & pyrrolidine analogues

Download (10.75 MB)
posted on 2023-05-26, 18:20 authored by Ng, SMY
In the past few decades, an extensive family of structurally intriguing and biologically active pyrrolic natural products were recognised. Many of these compounds were isolated from marine organisms and show potent biological activity, and as such have been the focus of much synthetic effort. The synthetic approaches involve the synthesis of substituted pyrroles, as well as using the reactive parent pyrrole as a flexible building block for construction. Herein, by using pyrrole as the core of the construction, the syntheses developed will be reported in two parts: (1) Regioselective synthesis towards aryl pyrroles. (2) The reduction of pyrroles via catalytic hydrogenation, dissolving metals reduction, and by borohydrides. Part I - Regioselective synthesis towards aryl pyrroles Pyrrole is a unique aromatic molecule as it can readily undergo substitution at all five positions. However, obtaining the desired regioisomer can be difficult to control. If the regioselectivity of the substitution reactions at any given position could be controlled, then pyrrole would be useful as a template for the synthesis of substituted pyrroles. The controlled substitution of the pyrrole nucleus and the elaboration of these products into selectively substituted pyrrole containing natural products can now be reported. The key to regioselective introduction of substituents is the selective halogenation of the ring. Chloride acts as a blocking group at the most nucleophilic site while iodide can be introduced at less active sites. Selective substitutions of the iodide through the Suzuki-Miyaura reaction, followed by removal of the chloride, allow the preparation of C3-, C4- and CS-aryl derivatives. We have applied this methodology to the synthesis of lamellarin Q dimethyl ether (22), an intermediate in the synthesis of lukinol A (5) and other diaryl-substituted pyrroles. Part II - Reduction of Pyrroles Methodologies for reduction of pyrroles have been reported previously, but have not been applied widely in synthesis. Pyrrole is a potential building block for the synthesis of pyrrolidine alkaloids and structural analogues. For example, if pyrrole can be reduced to a pyrroline via catalytic hydrogenation. This exploits regioselective pyrrole synthesis, followed by catalytic hydrogenation to form the saturated praline derivatives. Partial reduction of these relatively electron rich pyrroles is not possible via typical Birch reductions. We now report a method for reduction of pyrroles to pyrrolines for the generation of a small compound library of pyrrolidine and praline analogues. Further N-sulfonyl derivatives can be chemoselectively reduced under mildly acidic conditions with hydride reagents to generate pyrroline building blocks. From these substrates, structural analogues of anisomycin (99) with two and three carbons between the pyrrolidine and an aromatic ring can be generated in good yields over a few short steps. These methods can also be applied towards natural products of codonoposinine (100) and preussin (101)


Publication status

  • Unpublished

Rights statement

Copyright 2010 the author - The University is continuing to endeavour to trace the copyright owner(s) and in the meantime this item has been reproduced here in good faith. We would be pleased to hear from the copyright owner(s). Thesis (PhD)--University of Tasmania, 2010. Includes bibliographical references

Repository Status

  • Open

Usage metrics

    Thesis collection


    No categories selected


    Ref. manager