Are Oxazolidinones Really Unproductive, Parasitic Species in Proline Catalysis? – Thoughts and Experiments Pointing to an Alternative View

<jats:title>Abstract</jats:title><jats:p>The N,O‐acetal and N,O‐ketal derivatives (oxazolidinones) formed from proline, and aldehydes or ketones are well‐known today, and they are detectable in reaction mixtures involving proline catalysis, where they have been considered ‘parasitic dead ends’. We disclose results of experiments performed in the early 1970's, and we describe more recent findings about the isolation, characterization, and reactions of the oxazolidinone derived from proline and cyclohexanone. This oxazolidinone reacts (THF, room temperature) with the electrophiles <jats:italic>β</jats:italic>‐nitrostyrene and chloral (=trichloroacetaldehyde), to give the <jats:italic>Michael</jats:italic> and aldol adduct, respectively, after aqueous workup (<jats:italic>Scheme 5</jats:italic>). The reactions occur even at −75° when catalyzed with bases such as 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) or EtN(i‐Pr)<jats:sub>2</jats:sub> (DIPEA) (10%; <jats:italic>Table 1</jats:italic>). It is shown by NMR (<jats:italic>Figs. 1</jats:italic> and <jats:italic>3</jats:italic>) and IR analysis (<jats:italic>Figs. 2</jats:italic> and <jats:italic>4</jats:italic>) that the primarily detectable product (before hydrolysis) of the reaction with the nitro‐olefin is again an oxazolidinone. When dissolved in hydroxylic solvents such as MeOH, ‘hexafluoroisopropanol’ ((CF<jats:sub>3</jats:sub>)<jats:sub>2</jats:sub>CHOH; HFIP), AcOH, CF<jats:sub>3</jats:sub>COOH, or in LiBr‐saturated THF, the ring of the oxazolidinone from cyclohexanone and proline opens up to the corresponding iminium ion (<jats:italic>Tables 2–4</jats:italic>), and when treated with strong bases such as DBU (in (D<jats:sub>8</jats:sub>)THF) the enamino‐carboxylate derived from proline and cyclohexanone is formed (<jats:italic>Scheme 8</jats:italic>). Thus, the two hitherto putative participants (iminium ion and enamine) of the catalytic cycle (<jats:italic>Scheme 9</jats:italic>) have been characterized for the first time. The commonly accepted mechanism of the stereoselective C,C‐ or C,X‐bond‐forming step (<jats:italic>i.e.</jats:italic>, <jats:bold>A</jats:bold>–<jats:bold>D</jats:bold>) of this cycle is discussed and challenged by thoughts about an alternative model with a pivotal role of oxazolidinones in the regio‐ and diastereoselective formation of the intermediate enamino acid (by elimination) and in the subsequent reaction with an electrophile (by <jats:italic>trans</jats:italic>‐addition with lactonization; <jats:italic>Schemes 11–14</jats:italic>). The stereochemical bias between <jats:italic>endo</jats:italic>‐ and <jats:italic>exo</jats:italic>‐space of the bicyclo[3.3.0]octane‐type oxazolidinone structure (<jats:italic>Figs. 5</jats:italic> and <jats:italic>6</jats:italic>) is considered to possibly be decisive for the stereochemical course of events. Finally, the remarkable consistency, with which the diastereotopic <jats:italic>Re</jats:italic>‐face of the double bond of pyrrolidino‐enamines (derived from proline) is attacked by electrophiles (<jats:italic>Schemes 1</jats:italic> and <jats:italic>15</jats:italic>), and the likewise consistent reversal to the <jats:italic>Si</jats:italic>‐face with bulky (Aryl)<jats:sub>2</jats:sub>C‐substituents on the pyrrolidine ring (<jats:italic>Scheme 16</jats:italic>) are discussed by invoking stereoelectronic assistance from the lone pair of pyramidalized enamine N‐atoms.</jats:p>