Applying green chemistry to the photochemical route to artemisinin


Artemisinin is an important antimalarial drug, but, at present, the environmental and economic costs of its semi-synthetic production are relatively high. Most of these costs lie in the final chemical steps, which follow a complex acid- and photo-catalysed route with oxygenation by both singlet and triplet oxygen. We demonstrate that applying the principles of green chemistry can lead to innovative strategies that avoid many of the problems in current photochemical processes. The first strategy combines the use of liquid CO2 as solvent and a dual-function solid acid/photocatalyst. The second strategy is an ambient-temperature reaction in aqueous mixtures of organic solvents, where the only inputs are dihydroartemisinic acid, O2 and light, and the output is pure, crystalline artemisinin. Everything else—solvents, photocatalyst and aqueous acid—can be recycled. Some aspects developed here through green chemistry are likely to have wider application in photochemistry and other reactions.

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Figure 1: Semi-synthetic production of the potent antimalarial artemisinin, 1.
Figure 2: Our first strategy, the one-pot semi-synthesis of artemisinin in liquid CO2 with a dual-function heterogeneous catalyst.
Figure 3: Our second strategy, photocatalytic oxygenation of 3 dissolved in EtOH + H2O.
Figure 4: 1O2 emission following photo-excitation with a 355 nm pulse.
Figure 5: Proposed acid-catalysed degradation pathways, which occur during or after the reaction and suggest why H2O reduces the extent of degradation.


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The authors acknowledge support from Sanofi, the University of Nottingham, the Bill and Melinda Gates Foundation (grant no. 1070294), and the Engineering and Physical Sciences Research Coucil (EPSRC; grant no. EP/L021889/1, ‘Continuous Chemical Manufacture with Light’). J.F.B.B. thanks the EPSRC for a studentship and M.W.G. thanks the Royal Society for a Wolfson Merit Award. The authors thank L. Hitchen for her contribution to batch studies in scCO2, M. Guyler, P. Fields, R. Wilson and D. Litchfield for technical support, G. Coxhill for MALDI analysis and W. Lewis for obtaining the crystal structure of 1 (shown in Fig. 3c). The authors thank D.B. Amabilino and P. Licence for helpful comments. Note that the production of semi-synthetic 1 at Sanofi is a not-for-profit venture, its development being supported in part by the Bill and Melinda Gates Foundation.

Author information

All authors contributed directly to the project, and all were involved in the writing and revision of the paper. Z.A. led the organic chemistry experimental work and compound characterization. J.F.B.B. focused on the flow chemistry in scCO2. R.H. measured the singlet O2 kinetics, together with A.B., in A.B.'s laboratory in Durham. S.J.M. worked on the reactions in aqueous solvents. A.Bu. and K.R. provided technical advice regarding the overall process, as well as benchmarking against the current commercial process. M.P. and M.W.G. led the project and are responsible for the major part of writing this paper, but all authors discussed the results and commented on the various versions of the manuscript.

Correspondence to Kai Rossen or Martyn Poliakoff or Michael W. George.

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Crystallographic data for compound 1. (CIF 1235 kb)

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Structure factors for compound 1. (CIF 163 kb)

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Amara, Z., Bellamy, J., Horvath, R. et al. Applying green chemistry to the photochemical route to artemisinin. Nature Chem 7, 489–495 (2015).

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