A Double Ring Closing Metathesis Reaction in the Rapid, Enantioselective Synthesis of NK-1 Receptor Antagonists

Abstract

[structure: see text]. The NK-1 receptor antagonist 1 has been prepared in seven steps from phenylglycine methyl ester. The key steps are a double ring closing metathesis reaction of tetraene 7 to prepare spirocycle 6 and a reductive Heck reaction to introduce the aryl moiety. This latter reaction discriminates the olefins of compound 6 and proceeds in a highly regio- and stereoselective manner.

Mizoroki–Heck Reactions with 4‐Phenoldiazonium Salts

“…[5] Apart from photochemical and radical reactions, additions of polar organometallics to carbonyl compounds and transition metal-catalyzed coupling and cross-coupling reactions [6] are commonly used synthetic methods in this field. [7] In this context, the Mizoroki-Heck reaction [8] is one of the most important transformations.…”

Diastereoselective Desymmetrization of Symmetric Dienes and its Synthetic Application

“…They also applied this reaction to the enantioselective synthesis of the NK-1 receptor antagonist in 3 steps from 24 (R = Ph) [16] (Scheme 9). Recently, they revealed the reaction mechanism [17,18].…”

Metathesereaktionen in der Totalsynthese

“…[154] 2. 4 [155,156] Der charakterische Spirocyclus dieser Therapeutika wurde zuvor schrittweise aufgebaut, wobei unter anderem der Tetrahydrofuranring an das Piperidin-Gerüst einer enantiomerenreinen Vorstufe angeknüpft wurde. [157] Daher wurden ein direkteres Konzept gesucht, bei dem das bicyclische Templat in einem einzigen Schritt aus einer acyclischen Vorstufe gebildet Schema 30.…”

“…Eine diastereoselektive doppelte Ringschlussmetathese mit anschließender reduktiver Heck-Reaktion in der Synthese des NK-1-Rezeptorantagonisten 174 (Merck, 2001). [155] K. C. Nicolaou et al …”