Fig. 3 Synthesis of artemisinin from R-(+)-citronellal.

In this article, the history of the art and science of organic and natural products synthesis is briefly reviewed and the state of the art is discussed. The impact of this discipline on biology and medicine is amply demonstrated with examples, and projections for future developments in the field are made.

Fig. 4 Synthesis of artemisinin from R-(+)-pulegone.

Fig. 5 Synthesis of artemisinin from artemisinic acid.

Fig. 6 Synthesis of artemisinin from dihydroartemisinic acid.

One defining feature of terpenoid metabolites is their stereochemical complexity. In order to arrive at an efficient synthesis, the number of stereogenic steps must be minimized, and the level of stereocontrol at each of these steps must be maximized. A logical way to achieve these goals is to prioritize retrosynthetic transforms that efficiently set multiple stereocenters at once (see also ‘Pumilaside aglycon’ section). Furthermore, stereochemical relay from the substrate can be an effective tool to rapidly increase complexity, as long as the appropriate choreography of bond disconnections can be determined. Below, we document several recent examples of terpenoid synthesis and we focus on the stereochemical decisions made during retrosynthetic analysis. In many cases, the actual stereocontrol achieved is not perfect, even though the logic is good and reduces the length of the route. The lessons learned from these syntheses should inform future work in the same or related molecules.

Fig. 2 Synthesis of artemisinin from (-)-isopulegol.

Chain executes his strategy by first reacting the enolate of 6 with citronellal-derived enal 7. A modest 2:1 ratio of 8 to all other isomers is obtained, but this mixture can be subjected to samarium (II) iodide in hexamethylphosphoramide to effect carbonyl-alkene cyclization in 43% yield (maximum 66% yield based on 2:1 diastereomeric mixture of starting material). Keto-alcohol 9 is then elaborated to englerin A in four steps, completing a synthesis of only eight steps from commercial materials in a remarkable 20% overall yield.

A concise stereoselective total synthesis of (+)-artemisinin

So what constitutes the best approach to small molecule synthesis [–]? The answer is simple: it’s complicated. For example, a coarse articulation of the ideal synthesis is one that creates homogeneous material in large scale at low cost, which includes low cost of labor, reactants and reagents, solvents, purification and waste disposal. However, even this rudimentary definition does not always hold: what if you do not know the small molecule structure in advance? If not, then these metrics of synthesis disintegrate. In medicinal chemistry, a synthetic route must be diversifiable and modular, and scalability is not a major issue or even a goal. Nor is yield or purification, which can often be performed rapidly on small scale by HPLC. Similarly, metrics that articulate the need for chemical diversity measure diversity only, even though medicinal chemistry is not a random walk into unknown regions of space, but rather a logical exploration of the relationship between structure and function (SAR) []. All this is to say that for a given molecule, there can be various goals of synthesis – access to bulk material (process), specific modification of structure (optimization of properties, e.g., medicinal chemistry) or diversification of structure (e.g., combinatorial chemistry) – all of which possess competing agendas rather than a grand, unified vision. This means that a synthesis must be tailored to the problem it is trying to solve, and therefore identification of the actual problem is crucial.

Synthesis of (+)-artemisinin and (+)-deoxoartemisinin …

Chemical synthesis may prove an effective strategy to provide 10 in large quantity and at low cost. A general ‘blueprint’ of a potential route to produce 10 from inexpensive building blocks was recently developed by the Cook laboratory at Indiana University (IN, USA) []. Based on knowledge gleaned from the semi-synthetic conversion of 11 to 10, the Cook group realized that three stereocenters (in green) of the stereochemically complex artemisinin core could be immediately cleared to achiral or racemic precursor carbons (). Therefore, the only stereocenter necessary to control in 10 is the tert-alkyl endoperoxide (in blue), which would be favored based on the concavity of octalin 12. This concavity imparted by the ring-fused carbon of 12 (in blue) could be generated by a stereocontrolled annulation of cyclohexanone 13, which in turn might be formed by vicinal difunctionalization of the chemical feedstock, 2-cyclohexenone (14). Thus, seven stereocenters of artemisinin 10 could be relayed from a single stereocenter derived from asymmetric conjugate addition into 14.

the methods of artemisinin synthesis ..

Terpenes (or terpenoids or isoprenoids) constitute a major class of organic molecules produced by diverse organisms to perform an assortment of biological functions in varying ecological contexts. Although all terpenes originate from the same five-carbon building blocks (dimethylallyl pyrophosphate and isopentenyl pyrophosphate), the structures and functions of terpenes vary widely, and are highly tailored to the requirements of the source organism’s environmental pressures and resources. As a consequence of the biological functions of terpenes (in humans and other organisms), these molecules have led to six major drug classes over the last century, namely steroids, tocopherols, taxanes, artemisinins, ingenanes and cannabinoids []. However, optimization of terpene structures for human use requires economical access to not only the carbon scaffold of the terpene class, but also embedded functional groups that allow specific modification of the molecule through a rational medicinal chemistry campaign. Whether a campaign starts from a complex isolate with an essentially intact scaffold (sometimes called semi-synthesis) or several smaller fragments (sometimes called total synthesis, vide infra), this exploration can be costly and lengthy. In this article, we document several strategies to reduce the cost and time of developing terpene-based therapeutics.