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

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.