Thiol-Free Synthesis of Oseltamivir and Its Analogues via Organocatalytic Michael Additions of Oxyacetaldehydes to 2-Acylaminonitroalkenes

Abstract

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...