New Methodology for the Synthesis of Highly Functionalized Nitrogen Heterocycles

Pelkey, Erin

Abstract

The majority of pharmaceutical agents contain at least one heterocyclic ring due to their tunable electronic properties, conformational rigidity, and bioavailability. Developing efficient (high yielding;low step count;atom economic) and selective (chemo-;regio-;stereo-) methods to heterocycles from simple starting materials is an important goal in organic chemistry. Aryl-substituted 3-pyrrolin-2-one heterocycles are attractive targets given their structural simplicity and wide range of biological activity, but literature methods to this compound class are limited by linear sequences involving acyclic precursors. Three parallel strategies are proposed herein for the preparation of aryl-substituted 3-pyrrolin-2-ones that offer either complete regiocontrol or site selectivity. The proposed methods differ significantly from literature methods as they each produce the nitrogen heterocycle early in the sequence and can be described as follows: (1) synthesis of pyrrole Weinreb amides followed by their two-step conversion to 3-pyrrolin-2-ones;(2) cross-coupling reactions of tetramic acid sulfonates;and (3) site selective cross-coupling reactions of 3,4-difunctionalized 3-pyrolin-2-ones. An advantage of the first method is the commercial availability of the arene starting materials (benzaldehydes and arylboronic acids) that facilitates the synthesis of different analogs. Advantages of the latter two methods include the relative ease of synthesis of the tetramic acid and 3,4-dihalo-3-pyrrolin-2-one starting materials and flexibility for the synthesis of compound libraries and novel analogs as aryl groups are introduced late in the sequence. The utility of the proposed methods will be demonstrated by the total synthesis of biologically active targets including staurosporinone (PKC inhibitor), novel heterocyclic analogs of staurosporinone, and 3,4-diaryl-3-pyrrolin-2-ones (e.g., VEGF-R and COX-II inhibitors). Additionally, we will investigate the conversion of 3,4-diaryl-3-pyrrolin-2-ones into 2,3,4-triarylpyrroles including novel analogs of the lamellarin natural products. These methods should find wide applicability to medicinal chemists seeking to evaluate 3-pyrrolin-2-one and polyarylpyrrole scaffolds and should advance the field of organic chemistry by enhancing the understanding of site selective cross-coupling reactions.

Public Health Relevance

The primary goal of this project is to develop new, efficient methods for the construction of small nitrogen-containing compounds that have demonstrated biological activity or have the potential to be biologically active. The heterocyclic targets described in the proposal have displayed anti-cancer, anti-inflammatory, anti-HIV activity. This work will contribute fundamental knowledge to the science of making molecules and could lead to the discovery of novel therapeutic agents that would not readily be accessible using the current state-of-the-art synthetic methods.