Synfacts 2016; 12(09): 0887
DOI: 10.1055/s-0035-1561891
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Letermovir by an Asymmetric Aza-Michael Reaction

Philip Kocienski
Humphrey GR, * Dalby SM, * Andreani T, Xiang B, Luzung MR, Song ZJ, Shevlin M, Christensen M, Belyk KM, Tschaen DM. Merck & Company, Rahway, USA
Asymmetric Synthesis of Letermovir Using a Novel Phase-Transfer-Catalyzed Aza-Michael Reaction.

Org. Process Res. Dev. 2016;
20: 1097-1103
Further Information

Publication History

Publication Date:
18 August 2016 (online)



Letermovir is a DNA terminase inhibitor that has entered phase III clinical trials for the treatment of cytomegalovirus infections. The seven-step synthesis depicted delivered over one ton of the target molecule in 60% overall yield without recourse to chromatography. The key step is the phase-transfer-catalyzed aza-Michael reaction (GI) that installs the single stereogenic center. The stability of the carbodiimide E and the nucleophilicity of the piperazine F underpinned the success of this approach and the use of toluene as solvent prevented premature cyclization of G.



The aza-Michael cyclization revealed a number of features that suggest an atypical PTC-type mechanism. Both reaction rate and enantio­selectivity were sensitive to (i) agitation rate; (ii) the concentration and equivalents of aqueous base, where superstoichiometric amounts of ­K3PO4 proved optimal; and (iii) PTC/base counterions, where deviation from Br or PO4 3– respectively were detrimental.