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Synthesis 2023; 55(10): 1507-1516
DOI: 10.1055/a-2029-0015
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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
,
Thanos Andreou 
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 AffiliationsThis 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).
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Abstract

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.

Key words

sacubitril - hetero-Diels–Alder reaction - nitrosoalkenes - oxazinanes - chiral auxiliary

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2029-0015.
  • 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

© 2023. Thieme. All rights reserved

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