DOI: 10.1055/a-2029-0015

Hetero-Diels–Alder Addition of Ethyl 2-Nitrosoacrylate to (Z)-Prop-1-enyl Ethers. Stereoselective Synthesis of a Precursor to Sacubitril

Stavroula A. Zisopoulou
a   Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
b   Pharmathen Industrial S.A., 9th km Thermi-Thessaloniki, Thessaloniki 57001, Greece
Theocharis V. Koftis
b   Pharmathen Industrial S.A., 9th km Thermi-Thessaloniki, Thessaloniki 57001, Greece
John K. Gallos
a   Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
Christos I. Stathakis
a   Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
› Author Affiliations
This research has been co-financed by the European Union and Greek national funds through the Operational Program Competitiveness, Entrepreneurship and Innovation, under the call RESEARCH–CREATE–INNOVATE (project code: T1EDK-01161).


A novel, conceptually distinct synthesis of a key precursor to sacubitril, an antihypertensive drug, is presented. The well-demonstrated hetero-Diels–Alder addition of in situ generated nitrosoalkenes to electron-rich enol ethers was engaged to establish the required functionalities with controllable relative stereochemistry. An asymmetric variant of the enol ether enabled access to the target molecule in enantiopure form.

Supporting Information

Publication History

Received: 09 January 2023

Accepted after revision: 06 February 2023

Accepted Manuscript online:
06 February 2023

Article published online:
15 March 2023

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