Oseltamivir is an important antiviral drug, which possess three chirality centers in its structure. From eight possible stereoisomers, only two have been synthesized and evaluated so far. We describe herein the stereoselective synthesis, computational activity prediction and biological testing of another three diastereoisomers of oseltamivir. These isomers have been synthesized using stereoselective organocatalytic Michael addition, cyclization and reduction. Their binding to viral neuraminidase N1 of influenza A virus was evaluated by quantum-chemical calculations and their anti-influenza activities were tested by an in vitro virus-inhibition assay. All three isomers displayed antiviral activity lower than that of oseltamivir, however, one of the stereoisomers, (3S,4R,5S)-isomer, of oseltamivir showed in vitro potency towards the Tamiflu-sensitive influenza viral strain A/Perth/265/2009(H5N1) comparable to Tamiflu.

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).

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The organocatalytic addition of substituted oxyacetaldehydes to 2-acylaminonitroethenes proceeded with good to high diastereoselectivities and enantioselectivities. The resulting adducts reacted with ethyl 2-(diethoxyphosphoryl) acrylate to afford highly functionalized cyclohexenes. A thiol-free protocol for cyclization has been developed that leads to a separable mixture of two diastereoisomers. The unwanted diastereoisomer can be efficiently epimerized. The resulting cyclohexenes are precursors to oseltamivir and its analogues. The synthesis of the key reagent, 3-pentyloxyaldehyde, was also improved.Asymmetric organocatalytic Michael addition is one of the most versatile transformations for enantioselective formation of C-C and C-heteroatom bonds. 1 Organocatalysts has proved to be useful for additions of a range of donors such as enolizable aldehydes and ketones, diketones, ketoesters, and nitroalkanes. In addition, a large variety of Michael acceptors have been utilized such as unsaturated ketones, aldehydes, esters or sulfones. 2 Particular attention has been devoted to nitroalkenes, because the resulting functionalized nitro-derivatives are useful building blocks for the synthesis of many biologically relevant compounds. Successful additions of both aldehydes 3 and ketones 4 to nitroalkenes have already been demonstrated. Interestingly, the simplest enolizable aldehyde, acetaldehyde, poses a special challenge because of its high reactivity. List and co-workers solved the problem by slow addition of an acetaldehyde solution to nitroalkenes. 3a,5 On the other hand, Michael additions of functionalized aldehydes are also challenging. Although, functional groups within the aldehyde offer interesting possibilities for subsequent target-oriented synthesis, only a few examples of functionalized aldehyde additions are known. 6 We showed that alkoxy and aryloxyacetaldehydes can be enantioselectively added to a range of nitroalkenes. 7The organocatalytic Michael addition also serves as an initiating reaction for domino transformations, which lead to a number of structurally or functionally interesting molecules. 8 Already a large number of bioactive compounds have been synthesized through the use of organocatalytic reactions. 9 It was recognized that conjugate addition is also a useful transformation in the synthesis of the antiviral agent oseltamivir. 10 Hayashi and co-workers used the addition of pentyloxyacetaldehyde to tert-butyl nitroacrylate as the key step in a one-pot synthesis of oseltamivir. 11 We envisaged a more direct approach based on the use of 2-acylaminonitroethenes. Recently, Ma and co-workers demonstrated the viability of this approach. 12 In this paper, we present results of our studies on Michael additions of a range of oxyacetaldehydes to 2-acylaminonitroethenes. This reaction is the first step in an organocatalytic synthesis of oseltamivir. Access to its analogues, through structural variations of reaction partners, may become important in view of emerging resistance towards oseltamivir itsel...