The Science of Total Synthesis

The landmark synthesis of strychnine was reported by Woodward and coworkers in 1954,6 years after its structure determination [58], 

Since then, many synthetic chemists have been confronted with strychnine, which is a classic among the classics of total synthesis. Overall, 18 total syntheses of strychnine have been reported so far [58a-r], the shortest one in only 7 linear steps from tryptamine by Vanderwal [58r], to be compared with the earliest total synthesis of Woodward in 29 linear steps from phenylhydrazine [53a], The efficiency of these works can be evaluated by looking at the overall yields, from 0.00014% [58a] to nearly 10% yield [58e]. For sure, these improvements not only took benefits from Corey s retrosyn-thetic Logic of Chemical Synthesis but also from those famous chemists s creativity and from new achievanents in synthetic and catalytic methodologies. Indeed, new methodological concepts have arisen by the last 20 years, such as those of ideal synthesis [59], atom economy, step economy, redox economy, and sustainable approaches [60]. 

The efficiency of total synthesis should then benefit to the growing research efforts in chemical biology and drug discovery in the future, in connection with recently designed strategies like diversity-oriented synthesis (DOS) and function-oriented synthesis (FOS). 

SCHEME 1.13 The FOS strategy toward a simplified but still potent analog of the antimalarial artemisinin. 

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It is striking that Diels and Alder finally received the Nobel Prize in chemistry in 1950, more than two decades after their initial publication. The science of total synthesis of natural products was slow to advance and was hindered by World War II. These factors perhaps explain the delay in fuUy appreciating the impact of the Diels-Alder reaction. The modem era of total organic synthesis is generally considered to have started during the 1940s. In 1952, Robert Bums ( R. B. ) Woodward (1917-79) at Harvard would employ the Diels-Alder reaction to brilliant effect en route to total syntheses of the steroids cortisone and cholesterol. 

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