Behaviour of aminoacids and aliphatic aldehydes in dipolar aprotic solvents: Formation of oxazolidinones—behaviour of aminoacids and aliphatic aldehydes in dipolar aprotic solvents

Abstract

Reactions of aliphatic branched aldehydes with proline in dimethyl sulfoxide or acetonitrile solution afford oxazolidin‐5‐ones with high diastereoselection. Linear aldehydes afford aldolic/crotonic condensation products; with short reaction times, the presence of Oxazolidinones can be detected in the pmr spectra. Acyclic aminoacids and branched aldehydes yield a reaction mixture the pmr and ir spectra of which give evidence for iminic‐oxazolidinone equilibria. The structure of (2R,5S)‐2‐trichloromethyl‐1‐aza‐3‐oxabiciclo‐[3.3.0]octan‐4‐one has been confirmed by X‐ray diffraction analysis.

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

“…6.5 ppm [38]), and which would have to arise from 15. Oxazolidinones derived from proline show two distinct spectroscopic features: i) The H-atom at the bridgehead between the two five-membered rings (HÀC(5)) gives rise to a typical sharp dd NMR signal between 3.8 and 4.4 ppm, depending upon the substituent(s) at C(2) and the solvent used for the measurement [5] [7] [8] [16 -19]; as the reaction of oxazolidinone 8 (HÀC (5) (Fig. 3).…”

“…For a dissociative ring-opening of an oxazolidinone to a zwitterionic iminium carboxylate (Fig. 5, d), a process that formally does not follow a 42 ) All pivalaldehyde derivatives have exclusively exo-configuration [16 -19] [55], so has the chloral derivative of proline [7]. In oxazolidinones derived from aldehydes RCHO with smaller R groups, NMR-detectable amounts of a minor diastereoisomer have been reported ([8] and hitherto unpublished results by W. Prikoszovich, B. Linder, Novartis Pharma AG, Basel).…”

“…The assignment of the role of unproductive parasitic species to oxazolidinones [3] presumably has its roots in chemical reasoning according to which either enamine carboxylic acids or their carboxylates of type 1 must constitute the nucleophilic species reacting in prolinecatalyzed reactions of aldehydes or ketones with electrophiles [3] (Scheme 1) 6 ), even though such intermediates have not been detected by NMR spectroscopy in any of a variety of solvents [5], quite in contrast to corresponding oxazolidinones of type 2, which are seen spectroscopically whenever aldehydes or ketones, and proline are mixed in solvents such as DMSO in the presence of molecular sieves. The greater stability of oxazolidinones 7 ) relative to their enamine carboxylic acid isomers is not surprising, while observations such as those of Orsini et al [7] according to which the stability of oxazolidinones derived from aldehydes and proline decreases from chloral (¼ trichloroacetaldehyde) to pivalaldehyde (¼ 2,2-dimethylpropanal) to a-branched aldehydes (cf. 2-methylpropanal) to aldehydes without a-branching (cf.…”

Crystal structures of proline-derived enamines

“…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).…”

Das schwer fassbare Enamin‐Intermediat in prolinkatalysierten Aldolreaktionen: NMR‐Detektion, Entstehungsweg und Stabilisierungstrends

“…[29] Mit in-situ-NMR-spektroskopischen Ansätzen gelang bisher nur die Detektion der isomeren Oxazolidinone, [20,[30][31][32][33][34] angeblich wegen eines "ungewollten und verlangsamenden parasitären Gleichgewichts", [20,35] das auch für die fehlende Enamindetektion verantwortlich gemacht wurde. In der Tat wurden Gleichgewichte unter Beteiligung von Oxazolidinonen beschrieben, [20,[32][33][34] und deren energetische Bevorzugung wurde unlängst berechnet.…”