Asymmetric Formal Carbonyl-Ene Reactions of Formaldehyde tert-Butyl Hydrazone with α-Keto Esters: Dual Activation by Bis-urea Catalysts

Abstract

The dual activation of α-keto esters and formaldehyde tert-butyl hydrazone by BINAM-derived bis-ureas is the key to achieve high reactivity and excellent enantioselectivities in nucleophilic addition (formal carbonyl-ene reaction) to functionalized tertiary carbinols. Ensuing high-yielding diazene-to-aldehyde tranformations and subsequent derivatizations provides a direct entry to a variety of densely functionalized products.

Ambidente Reaktivität von Formaldehyd‐N,N‐dialkylhydrazonen

“…B. Enone (E % À18), Aldehyde (E % À19) oder schwach aktivierte Imine (E % À14), eine Aktivierung durch Brønsted-oder Lewis-Säuren, um mit Hydrazonen zu reagieren. [5,6] Eingegangen am …”

“…Diese Art der "Umpolung" [4] der Carbonylreaktivität (Schema 1) [1a-d] wurde vielfach bei Synthesestrategien unter Verwendung chiraler Auxiliare [3c, 5] und bei asymmetrischen organokatalytischen Reaktionen angewendet. [6] Trotz des häufigen Einsatzes von Hydrazonen in der organischen Synthese ist ihre ambidente Nucleophilie bisher noch nicht quantitativ untersucht worden. In früheren Arbeiten haben wir gezeigt, dass das HSAB-Modell [7] wie auch das damit verwandte Klopman-Salem-Konzept ladungs-und orbitalkontrollierter Reaktionen [8] nicht einmal zur Deutung der ambidenten Reaktivität von Cyanid-, Nitrit-, Cyanat-, Thiocyanat-oder Nitronatanionen, also der Prototypen ambidenter Nucleophile, geeignet sind.…”

Organocatalyzed synthesis of optically active cyanohydrins starting from alpha-ketoesters

“…The BINAM-derived bis-urea IV, that has been also successfully employed in the formaldehyde tert-butylhydrazone addition to aromatic α-ketoesters [13], did not catalyze the cyanosilylation at -30ºC even after 72 hours. By this reason, we have prepared a BINAM-monourea containing a tertiary amine in its structure (catalyst Va) [14].…”

Organocatalytic Nucleophilic Addition of Hydrazones to Imines: Synthesis of Enantioenriched Vicinal Diamines

“…[2] In this umpolung strategy, [3] theinitial azomethine carbon remains sp 2 hybridized after the addition reaction. Concurrently,L assaletta et al [5] reported abisurea-catalyzed reaction of formaldehyde Ntert-butyl hydrazone with aryl glyoxylates to afford b-hydroxy diazenes in excellent yields and ee values (Scheme 1b). One obvious way to keep the stereochemical integrity of the a-carbon of the diazene would be the use of N-monoalkyl hydrazones,a ssuming that the tautomerization of diazene to hydrazone would be slow enough to be suppressed.…”