Enantioselective Michael Addition of the 2‐(1‐Ethylpropoxy)acetaldehyde to N‐[(1Z)‐2‐Nitroethenyl]acetamide – Optimization of the Key Step in the Organocatalytic Oseltamivir Synthesis

Abstract

Organocatalytic Michael addition of alkoxyacetaldehyde 1 to N‐protected 2‐nitroethene‐1‐amine 2 (Scheme 2) is a key step in the synthesis of an important antiviral agent, oseltamivir. Screening of a large array of structurally diverse acids as potential promoters led to the identification of several useful acidic additives for this reaction (Tables 1–4). Also other reaction parameters were investigated with the aim of improving the diastereoselectivity of the Michael addition, while maintaining high enantiomer purity and yield (Tables 5 and 6).

One‐Pot Synthesis of (−)‐Oseltamivir and Mechanistic Insights into the Organocatalyzed Michael Reaction

“…used CHCl 3 /H 2 O as the solvent system and chloroacetic acid as an additive to obtain good yield (88 %) and diastereoselectivity ( 15 / 16 =81:19) 8a. Recently, the addition of rac ‐mandelic acid and 2,4‐dinitrophenol was also found to be effective 8b. Lu et al.…”

Asymmetric Organocatalysis at the Service of Medicinal Chemistry

“…By this approach, disclosed in 2010 [ 148 ], the target oseltamivir 84 could be obtained after a few more steps based on the previous synthesis. Due to its importance, this organocatalytic reaction and the subsequent steps were then the subject of thorough studies directed at their generalisation [ 149 , 150 ] and careful optimisation [ 151 ], which culminated very recently in the disclosure of a synthesis of oseltamivir proceeding in one-pot from the aldehyde and this nitroalkene [ 152 ]. Compared to the previous sequence reported in Scheme 31 , this synthesis ( Scheme 32 ) not only obviates the need of introducing the acetamide functionality with azide chemistry, but also avoids evaporation steps and the usage of toxic chlorinated solvents, allowing the obtainment of oseltamivir even on gram scale with a remarkable 28% yield over the five steps without any intermediate work-up or isolation.…”

Synthetic Advancement of Neuraminidase Inhibitor “Tamiflu”

“…Impact of organic acids on organocatalysed-Michael reaction for Tamiflu synthesis: Diatereomeric ratio of 242 has been optimized by Hajzer and other researchers (Scheme 69). [113] Organocatalytic Michael addition of alkoxyacetaldehyde (222) to N-protected 2-nitroethene-1-amine ( 283) gave diastereomers syn-242 and anti-368 among which syn isomer led to Tamiflu. The ratio of these diastereomers is influenced by acidic additives are shownin Table 1.…”

“…2012 Oh synthesis [111] * Amano Lipase PS induced desymmetrisation * Zn-mediated allylation * Grubbs second-generation catalyst for RCM and opening of the aziridine ring 2012 Hajzer synthesis [113] * Chloroacetic acid, (�)-mandelic acid, bromoacetic acid, and 2,4-dinitrophenol for organocatalysed-Michael addition step 65.…”