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26.9.1.1.8.4 Variation 4: Tandem Michael Addition/Intramolecular Aldol Reaction (Robinson Annulation)

DOI: 10.1055/sos-SD-026-00987

Marsden, S. P.Science of Synthesis, (2005261078.

The annulation of 2-alkylcyclohexanones with alkyl vinyl ketones (Robinson annulation) has proven to be one of the most valuable strategies for the synthesis of bicyclic enones and has been extensively reviewed.[‌155‌,‌156‌] In its simplest form, addition of a ketone enolate to methyl vinyl ketone, the reaction is poor yielding, owing largely to ambiguity at the site of enolate formation.[‌157‌] The reactions work much more efficiently if the initial nucleophile is derived from a more acidic carbonyl compound, such as a β-diketone or β-tetralone.[‌158‌,‌159‌] Even in such cases, base-mediated polymerization of the reactive enone substrates can be problematic. In situ generation of the enone by elimination of ammonium salts provides a convenient solution to this.[‌160‌] For example, direct coupling of tetralone 176 with methyl vinyl ketone yields the annulation product 177 in 45% yield, whereas the use of ammonium salt 178 as a source of electrophile results in a 60% yield of 177 (Scheme 35).[‌161‌] Alternatively, strongly basic conditions can be avoided by the use of enamines as nucleophiles,[‌162‌] allowing the use of simple monoketone equivalents such as 179. The reactions give annulated enamines as the initial products, which can then be hydrolyzed to the enones 180 under mild conditions. Enamine chemistry is believed to underpin an asymmetric variant of the Robinson annulation, whereby the initially formed Michael adduct 181 is treated with catalytic enantiomerically pure proline, giving rise to the enone 183 in excellent optical purity following acid-catalyzed elimination of the initial aldol adduct 182.[‌163‌,‌164‌]

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