Malaria infects over 200 million people each year with up to one million, mostly children, perishing from the infection [1]. Currently, the most effective treatment against malaria-causing Plasmodium parasites is artemisinin-based combination therapy (ACT). The key ingredient for the production of ACTs, artemisinin (1), is a natural product extracted on industrial scale from the sweet wormwood plant, Artemisia annua. Unfortunately, artemisinin is currently too expensive to meet the distribution needs of the world. Moreover, crop disruptions caused by natural disasters, poor planning and geopolitical events have led to shortages and price fluctuations. In the decade leading to 2012, there have been two primary approaches to combat these problems: using synthetic biology to produce a chemical precursor of artemisinin in microbes [2, 3], or breeding new varieties of Artemisia annua with improved growth and/or production traits [4]. While advances have been made in both areas, these strategies have yet to make a contribution to the world's artemisinin supply. Interestingly, the literature over the last decade reveals a disappointing lack of effort focused on discovering a de novo synthesis of 1 and its derivatives from inexpensive, readily available chemicals—a significantly more affordable and timely research proposition.
Soon after the initial report of the structure and anti-malarial activity of artemisinin (1), chemists began working towards a feasible chemical synthesis of the unprecedented endoperoxide-containing natural product [7]. This work culminated in several total syntheses of artemisinin (1) between 1979 and 1996 [6, 8-15]. While impressive from a chemical “proof-of-principle” perspective, these early syntheses have done little to address the supply problems of artemisinin (1) because of the high costs inherent to long reaction sequences, excessive protecting group schemes and expensive terpene-based starting materials (FIG. 1). Even modern syntheses of artemisinin (1) cannot compete on price with isolation from natural sources [16]. These problems have driven the perception that a laboratory synthesis of artemisinin (1) is untenable [17].
USPTO Backgrounds
USPTO Backgrounds