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

Abstract

Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthdayThe 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 b-nitrostyrene and chloral (¼ trichloroacetaldehyde), to give the Michael and aldol adduct, respectively, after aqueous workup (Scheme 5). The reactions occur even at À 758 when catalyzed with bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or EtN(i-Pr) 2 (DIPEA) (10%; Table 1). It is shown by NMR (Figs. 1 and 3) and IR analysis (Figs. 2 and 4) 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 3 ) 2 CHOH; HFIP), AcOH, CF 3 COOH, or in LiBr-saturated THF, the ring of the oxazolidinone from cyclohexanone and proline opens up to the corresponding iminium ion (Tables 2 -4), and when treated with strong bases such as DBU (in (D 8 )THF) the enamino-carboxylate derived from proline and cyclohexanone is formed (Scheme 8). Thus, the two hitherto putative participants (iminium ion and enamine) of the catalytic cycle (Scheme 9) have been characterized for the first time. The commonly accepted mechanism of the stereoselective C,C-or C,X-bond-forming step (i.e., A -D) 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 trans-addition with lactonization; Schemes 11 -14). The stereochemical bias between endo-and exo-space of the bicyclo[3.3.0]octane-type oxazolidinone structure (Figs. 5 and 6) is considered to possibly be decisive for the stereochemical course of events.Helvetica Chimica Acta -Vol. 90 (2007) Finally, the remarkable consistency, with which the diastereotopic Re-face of the double bond of pyrrolidino-enamines (derived from proline) is attacked by electrophiles (Schemes 1 and 15), and the likewise consistent reversal to the Si-face with bulky (Aryl) 2 C-substituents on the pyrrolidine ring (Scheme 16) are discussed by invoking stereoelectronic assistance from the lone pair of pyramidalized enamine N-atoms.1. Introduction. -We would hardly have considered to become engaged in the timely research area of organocatalysis , had not, in the recent literature, the name of one of the present authors (D. S.) been implied in a statement on the mechanism of the stereoselection in proline catalysis (see title) such that this author was incited to ...

A Coherent Mechanistic Rationale for Additive Effects and Autoinductive Behaviour in Proline‐Mediated Reactions

“…Scheme 1 is also in accordance with Seebach and Eschenmoser's [19] interpretation of the rate enhancement we reported in the reactions 1a and 1b, which they suggest may be attributed to acceleration of the transformation of an oxazolidinone to an enamine as the rate-determining step. In the proposal of Scheme 1, identical kinetic consequences result from the accelerated formation of the enamine regardless of the pathway this process takes.…”

Crystal structures of proline-derived enamines

“…Additionally, such structural investigations may reveal the degree of oxazolidinone character in proline enaminones. According to a recent proposal by Seebach et al, the reaction of the proline enamine with an electrophile involves an anionic cyclization of the syn-configured carboxylate into the enamine α-carbon with concomitant bond formation at its β-carbon in the sense of an electrophile-induced lactonization (18). This mechanism has already been discussed by Hajos and Parrish before (24) and leads directly to an oxazolidinone.…”

“…Rather than the enamine, thermodynamics favor the oxazolidinone constitutional isomer, in which one C─O-and one C─H-σ-bond are gained at the expense of one C─C-π-bond and one O─H-σ-bond: [1] In view of the catalytic action of proline, oxazolidinone formations with aldehyde or ketone substrates are best described as parasitic equilibria because they are not leading to product but inhibit its formation (14). Although aldehyde-derived "Seebach oxazolidinones" (15)(16)(17) have long been known, their ketone analogues have only recently been detected and characterized by us (14) and later isolated also by Seebach et al (18). Interestingly, the condensation product of acetone and proline has also been detected by Marquez and Metzger using mass spectrometry (19).…”

“…In light of our previous careful NMR-spectroscopic characterization of this adduct as an oxazolidinone (14), their assignment as an enamine appears to be questionable. In addition, Seebach et al have partially characterized an ammonium salt of the prolyl enamine of cyclohexanone (18). Disappointingly though, crystallographic data on proline enamines are entirely lacking.…”

Unusual Reversal of Enantioselectivity in the Proline-Mediated α-Amination of Aldehydes Induced by Tertiary Amine Additives

“…4 Addition of bases in enamine catalysis has not been been extensively studied, 3a,3h and to our knowledge an inversion of ee in the presence of base such as we observe here has not been reported previously. 5 The most significant conceptual role proposed for base additives comes from the work of Seebach and Eschenmoser, 6 whose studies of preformed oxazolidinones in stoichiometric interactions with bases such as DBU led to their proposal that the enamine carboxylate is a key reaction intermediate. In order to rationalize the observed R-selectivity in the proline-catalyzed reaction, they suggested anti-addition to the syn-enamine rotamer (Scheme 2, TS-B), which leads directly to the more stable, exo-isomer of the product oxazolidinone.…”