Total Synthesis of (+)‐Linoxepin by Utilizing the Catellani Reaction

Abstract

Molekulare Intelligenz: Das strukturell neuartige Lignan (+)‐Linoxepin wurde in acht Stufen erhalten, wobei die palladiumkatalysierte Catellani‐Reaktion als Schlüsselschritt identifiziert wurde. In dieser hoch konvergenten Mehrkomponentenreaktion werden zwei neue C‐C‐Bindungen gebildet, eine davon infolge einer C‐H‐Funktionalisierung.

Intermolecular Domino Reaction of Two Aryl Iodides Involving Two CH Functionalizations

“…For this reason, domino reactions represent a powerful strategy for the rapid formation of multiple bonds in a single flask. [6] The key to success of the norbornene-facilitated transformation is the lack of suitable syn-b-hydrogen atoms in the carbopalladated intermediate, which prompts the CÀH activation and initiates the subsequent steps. Metals, including palladium, rhodium, and iridium, have been used to access a variety of ortho-or meta-directed C À H activations.…”

“…The power of this reaction was recently demonstrated in the total syntheses of two distinct classes of natural products. [6] The key to success of the norbornene-facilitated transformation is the lack of suitable syn-b-hydrogen atoms in the carbopalladated intermediate, which prompts the CÀH activation and initiates the subsequent steps. The utilization of other olefins following similar principles was rarely reported, and in most cases an incorporation of the double-bond scaffold in the final product structure was observed.…”

Catellani Reaction: An Enabling Technology for Vicinal Functionalization of Aryl Halides by Palladium(0)/Norbornene Cooperative Catalysis

“…In addition, a recent strategy on the use of two distinct electrophiles for the trifunctionalization of aryl halides offers a complementary approach for the typical difunctionalization at two or three adjacent sites. Overall, these unique protocols have considerably expanded to diverse fields such as the total synthesis of natural products [79,84,102,[120][121] and the development of new materials. [122][123] Moreover, it should be mentioned that the Pd(II)/NBE-catalyzed reactions have also gained very remarkable achievements by Bach, Dong, Yu, Zhou and others.…”

Advances in Palladium‐Catalyzed Cascade Cyclizations

“…Lautens used the Catellani reactionf or his synthesis of (+ +)-linoxepin( Scheme 144). [200] Most of the steps in the strategy are in fact requiredf or the construction of aryl iodide 500.T he key Catellani reaction between aryl iodide 500,a lkyl iodide 501 and tert-butyl acrylate 502 producest he desired product 507 in excellent yield. Subsequently,t he olefin was oxidatively cleaved to the aldehyde,w hich was then condensed with the lactone moiety to give dihydronaphthofuranone 508.AfinalH eck cyclization was envisioned to complete the synthesiso f( + +)-linoxepin.…”

“…However, palladium-catalyzed cascade reactions offer unique reactivity and astounding synthetic efficiency,m aking them of high potential utility in natural product total synthesis.A sashowcase,w ew ill presenttwo different approaches to the total synthesis of the lignane natural product linoxepin reported by Tietze and Lautens in 2013 (Scheme 142). [47,200] Althoughb oth groups used ap alladium-catalyzed cascade reactiona st he key step,t he approaches are conceptually completelyd istinct,b oth providing valuable insightint he field.…”