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Studies on the Stereoselective Synthesis of Sacubitril via a Chiral Amine Transfer Approach. | LitMetric

AI Article Synopsis

  • The text discusses the synthesis of sacubitril, a neprilysin inhibitor combined with valsartan in the drug Entresto™.
  • The initial synthesis used (S)-pyroglutamic acid and Cu(I)-mediated cross-coupling, followed by the development of chiral amine transfer reagents for stereoselective synthesis.
  • Key steps included creating γ-ylidene-butenolide from biphenyl bromide and 4-pentynoic acid, converting it to an ene-lactam, and reducing it with specific reagents, with outcomes analyzed using DFT studies to understand stereochemical results.

Article Abstract

We present a comprehensive account of our efforts directed towards the synthesis of sacubitril, a neprilysin inhibitor used in combination with valsartan and marketed as Entresto™. Our initial approach to the formal synthesis of sacubitril employed a chiral pool strategy, utilizing (S)-pyroglutamic acid as a key building block and Cu(I)-mediated Csp2-Csp3 cross-coupling as a key transformation. Further investigations led to the development of chiral amine transfer (CAT) reagents-based stereoselective synthesis. This involved the E-selective construction of γ-ylidene-butenolide from readily available biphenyl bromide and 4-pentynoic acid, the conversion of this butenolide to its ene-lactam using chiral amine, and substrate-controlled diastereoselective reduction of ene-lactam using Et3SiH or Pd/C, H2 (overall chiral amine transfer) as key transformations. Antipodal lactam intermediates were synthesized using corresponding chiral amines, and the stereochemical outcomes during the ene-lactam reduction with Et3SiH were rationalized by DFT studies.

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http://dx.doi.org/10.1002/asia.202401223DOI Listing

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