Organocatalytic Asymmetric Tandem Cyclization/Michael Addition via Oxazol-5(2H)-One Formation: Access to Perfluoroalkyl-Containing N,O-Acetal Derivatives

Abstract

Herein, we report a convenient organocatalytic asymmetric tandem cyclization/Michael addition protocol for the synthesis of diastereomerically pure and highly enantioenriched perfluoroalkyl-containing N,O-acetal derivatives starting from racemic N-perfluoroacyl amino acids under mild conditions. This efficient atom economic reaction leads to highly enantioselective and diastereoselective construction of N,O-acetal derivatives containing oxazolone and perfluoroalkyl moieties containing vicinal quaternary and tertiary stereocenters (up to 97% yield, up to 96% ee, and up to >20:1 dr).

A 1-Pot Synthesis of the SARS-CoV-2 Mpro Inhibitor Nirmatrelvir, the Key Ingredient in Paxlovid

“…Intermediates formed using this coupling reagent present no regioselectivity issues, and along with its easy handling during aqueous workup qualifies this reagent from both a practical and sustainable perspective. 13 Thus, following treatment of 1 with T3P (1.2 equiv) for 1 h, bicyclic proline was added (as its Na salt, 2; 1.2 equiv) at the same subzero temperatures, along with dilution by addition of EtOAc. The reaction mixture was then allowed to slowly warm to rt with stirring for a period of 20 h. 21 An in f lask acidic aqueous workup afforded crude carboxylic acid 3 in 80% isolated yield (see the SI, Table S2 for more information on yield) as a single diastereomer (Table 1, entry 6).…”

“…Unfortunately, after several attempts at optimization, the yields of 3 were consistently low (see SI, Table S1) and several impurities could be detected by 1 H NMR. Aside from the difficulty associated with handling this highly activated acid chloride due to its sensitivity to moisture, especially on a smaller, academic scale, the potential for the acid chloride to cyclize to form an oxazolone intermediate was also appreciated. , Moreover, the possibility that residual M–OH (M = Li or Na) was present from hydrolysis of the precursor methyl ester en route to the bicyclic proline salt further encouraged investigation into an alternative strategy. Consideration of the numerous peptide coupling reagents in terms of both cost and “greenness” turned our focus to alkyl chloroformates, which have been widely used on scale for this purpose.…”

Total synthesis of antiviral drug, nirmatrelvir (PF-07321332)

“…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) [ 13 ] using HATU, in presence of NMM, DMAP to give dipeptide 15 in 71% yield ( Scheme 3 ).

Scheme 3 Synthesis of dipeptide 15 .

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A 1-pot synthesis of the SARS-CoV-2 Mpro Inhibitor Nirmatrelvir, the key ingredient in Paxlovid

“…Aside from the difficulty associated with handling this highly activated acid chloride due to its sensitivity to moisture, especially on a smaller academic scale, the potential for the acid chloride to cyclize to form an oxazolone type intermediate was also appreciated. 11,12 The possibility that residual LiOH was present from hydrolysis of the precursor methyl ester en route to the bicyclic proline lithium salt further encouraged investigation into an alternative strategy. Consideration of the numerous peptide coupling reagents in terms of both cost and "greenness" turned our focus to alkyl chloroformates, which have been widely used on scale for this purpose.…”