In literature, the synthesis of bicyclic amino acid  is reported from pyroglutamic acid  (involving nine steps) or (+)-3-carene7 (involving eleven steps). The proposed synthesis of key bicyclic fragment 4 commenced from Boc-trans-4-hydroxy L-proline benzyl ester 8 which was obtained from commercially available trans 4-hydroxy L-proline, using literature protocol . The hydroxy group was mesylated using methanesulfonyl chloride, triethylamine and DMAP to get 9 in quantitative yield. Compound 9 was treated with diphenyldiselenide and sodium borohydride to afford phenylselenyl derivative 10 in 78% yield. The oxidation of intermediate selenide 10, with hydrogen peroxide and subsequent elimination with pyridine smoothly gave the alkene 11 in 75% yield. This compound upon cobalt(II)-catalyzed dimethylcyclopropanation using 2,2-dichloropropane, zinc metal, zinc bromide and Co(II)-complex gave target bicyclic dimethylcyclopropyl amino acid fragment 4 in 68% yield. Thus, the synthesis of bicyclic amino acid 4 was achieved from Boc trans-4-hydroxy L-proline benzylester 8 in four steps in 40% overall yield. To facilitate peptide coupling on either side, the amino acid residue 4 was treated with either 4 N hydrochloric acid to give free amine benzyl ester as HCl salt 12 or Pd/C–H2 to give Boc-protected free acid 13 (Scheme 2). The amine hydrochloride of bicyclic fragment 12 was coupled with N-trifluoroacetyl L-tert-leucine 14 (obtained from N-trifluoro acetylation on L-tert-leucine)  using HATU, in presence of NMM, DMAP to give dipeptide 15 in 71% yield (Scheme 3).

The synthesis of cyano amine 7 was achieved from protected L-glutamic acid 16 (Scheme 4). L-Glutamic acid was silylated with TMSCl, esterified using methanol and the amine group was protected with FmocCl in presence of sodium carbonate as a base to yield protected glutamic acid 16. The diester 16 was subjected to mono-alkylation with bromoacetonitrile using LiHMDS in THF to give cyano compound 17. The cyano diester 17 was cyclized to lactam 18 using CoCl2.6H2O and sodium borohydride . The ester functionality in lactam 18 was reduced to alcohol 6 using sodium borohydride in THF:MeOH (2:1). Alcohol 6, upon oxidation with Dess-Martin periodinane (DMP), afforded aldehyde 19. A one-pot conversion of aldehyde 19 to nitrile 20 was achieved by the treatment of aldehyde with iodine and ammonia solution . Finally, the Fmoc-deprotection of compound 20 using diethylamine resulted in the formation of cyano amine fragment 7.

Dipeptide 15 on debenzylation using Pd/C, H2 in methanol gave dimer acid 5 in 93% yield. The dimer acid (5) is ready to be coupled with amine 7 to give Nirmatrelvir . The amine 7 was coupled with dimer acid 5, using HATU in presence of NMM and DMAP, to afford the target molecule nirmatrelvir 1 (Scheme 5). The spectral data of compound 1.

From Tetrahedron Chem 4 (2022) 100033