Nitromethane → 3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-4-nitro-butyric acid ethyl ester

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Reaction Steps

WO03/022853 in Example I provides a Wittig route which employs triethyl phosphono acetate (TEPA) to obtain 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid ethyl ester. The subsequent Michael addition to 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-acrylic acid ethyl ester, presents limitations in that it produces a nitromethane adduct, i.e. 3-(2,2-dimethyl-[1,3]dioxolan-4-yl)-4-nitro-butyric acid ethyl ester, with a syn:anti ratio of approximately 8:2. Subsequent reduction followed by Nef/cyclization reactions yields the (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol seriously contaminated with its exo-diastereoisomer, i.e. (3R,3aR,6aS) hexahydro-furo[2,3-b]furan-3-ol, with a ratio endo:exo of around 8:2. Although this process does not possess several of the disadvantages attached to the Knoevenagel process, it does not produce pure endo-diastereoisomer since there is no purification step available, such as crystallization, to remove the undesired exo-diastereoisomers that have been formed during the Michael addition in the anti configuration.

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