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

Stavroula A. Zisopoulou; Thanos Andreou; Theocharis V. Koftis; John K. Gallos; Christos I. Stathakis

doi:10.1055/a-2029-0015

Synthesis, Table of Contents

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

^aDepartment of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece

,

Thanos Andreou

^bPharmathen Industrial S.A., 9^th km Thermi-Thessaloniki, Thessaloniki 57001, Greece

,

Theocharis V. Koftis

^bPharmathen Industrial S.A., 9^th km Thermi-Thessaloniki, Thessaloniki 57001, Greece

,

John K. Gallos∗

^aDepartment of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece

,

Christos I. Stathakis∗

^aDepartment of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece

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Abstract

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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

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References

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