Dihydrooxazine Oxides as Key Intermediates in Organocatalytic Michael Additions of Aldehydes to Nitroalkenes

Abstract

Pause and play: dihydrooxazine oxides are stable intermediates that are protonated directly, without the intermediacy of the zwitterions, in organocatalytic Michael additions of aldehydes and nitroalkenes (see scheme, R=alkyl). Protonation of these species explains both the role of the acid co-catalyst in these reactions, and the observed stereochemistry when the reaction is conducted with α-alkylnitroalkenes.

ChemInform Abstract: Recent Advances in Organocatalytic Kinetic Resolution for the Synthesis of Functionalized Products

“…[18] The high diastereoselectivity of tetrahydropyranols 29 could be attributable to the slow irreversible protonation step of the Michael addition of the aldehydes to the nitroolefins. [19] Recovered (S)-28a was ac riticalp recursor in the synthesis of (2S,3R)-3-amino-2-hydroxy-4-phenylbutyric acid (AHPA) and its epimer (2S,3S)-AHPA, which are key intermediates for the total synthesis of numerous biologically active skeletons such as Bestatin, Probestin, Phebestin, KNI-227,a nd JE-2178 (Scheme 5). [20] McGarraugh and Brenner-Moyerw ere the first to report an organocascade kinetic resolution that involved ar eversible intramolecular oxa-Michal and Michael sequence through combination of chirali minium/enamine catalysis (Scheme 6).…”

Dekonstruktion kovalenter Organokatalyse

“…[78] Eine kombinierte experimentelle und theoretische Analyse der Reaktion durch Pihko und Mitarbeiter kam zu der Schlussfolgerung, dass die Dihydrooxazinoxide 20 wichtige Bestandteile des Katalysezyklus sind, während die Cyclobutane als Ruhezustand des Katalysators oder als Reservoir betrachtet werden kçnnen (Abbildung 3). [79] Bei der Entwicklung einer enantioselektiven organokatalytischen Oxa-Michael-Michael-Tandemreaktion zur Synthese von Chromanen identifizierten Wang und Mitarbeiter ähnliche Aminal-Intermediate. [80] Zudem wurde gezeigt, dass anhaltende Exposition von bestimmten MacMillan-Imidazolidinonen gegenüber Aldehyden zu Katalysatormodifikationen führt (Abbildung 2, rechts; 22), [81] was ein weiteres Beispiel dafür ist, dass mehr als eine katalytisch kompetente Verbindung in situ generiert werden kann.…”

Organocatalytic Conjugate Addition of Cyclopropylacetaldehyde Derivatives to Nitro Olefins: en Route to β‐ and γ‐Amino Acids

“…[15] The absolute stereochemistry is determined by a sterically less hindered nucleophilic attack from the Re-face of the enamine onto the Si-face of the nitrostyrene to give the product with a 2R,3S configuration. Based on previous studies of the mechanism of the Michael addition of aldehydes to nitro olefins [16] (most recently by Pihko et al), [17] the key intermediate in the reaction is a six-membered dihydrooxazine oxide (OO). Although according to Pihko et al the OO species are in equilibrium with cyclobutanes, only the OO intermediates can be protonated in the rate-determining step, thus leading to the expected Michael adducts.…”