Total Synthesis of Linoxepin through a Palladium‐Catalyzed Domino Reaction

Cascade polycyclizations in natural product synthesis

“…Two examples that epitomize the level of synthetic challenge that can be conquered with this chemistry are shown in Scheme 16. The first, a synthesis of linoexpin (92, Scheme 16a) reported by the Tietze group, 43 involves domino cyclization of an aryl bromide 93 onto an alkyne, with capture of intermediate alkenylpalladium species 94 by an appended allylsilane, which gives a high yield of the pentacyclic product 95. The allylsilane is crucial in controlling the positioning of the exocyclic alkene in 95; among several mechanisms that could be envisaged for this final step, this may suggest a desilylative palladation of 94 (perhaps proceeding via a silicon-stabilized carbocation), prior to rapid reductive elimination; or alkene carbopalladation, followed by an unusual formal b-silyl elimination.…”

Application of the Palladium‐Catalysed Norbornene‐Assisted Catellani Reaction Towards the Total Synthesis of (+)‐Linoxepin and Isolinoxepin

“…The racemic linoxepin was first synthesized by Tietze et al in 2013 through a domino Heck reaction. Tietze et al were able to obtain an X‐ray crystal structure of the unnatural ( S ) enantiomer of linoxepin to support the absolute stereochemistry in the reported structure 6. Shortly after their synthesis, we published an enantioselective synthesis featuring the first use of the Catellani reaction in a complex natural product synthesis 7.…”

Enantioselective Total Synthesis of the Lignan (+)‐Linoxepin

“…Retrosynthetic approach to (+)-linoxepin (1) 4 ] did not lead to the desired compound 9 but instead formed the aromatic congener 10 in 50 % yield (Scheme 2). [6] Mechanistically, one can assume that initially the Sonogashira product 7 is formed, followed by a carbopalladation and a Mizoroki-Heck reaction. However, the desired product 9 seems not to be stable under the reaction conditions and gives 10 by an isomerization of the double bond, probably by readdition of a [PdÀH] species followed by a b-hydride elimination.…”

“…[5] Recently, we reported the first total synthesis of (+)-and (À)-linoxepin (1) and (ent-1), the key step of which featured a Pd-catalyzed domino transformation consisting of a carbopalladation and a silyl-terminated Heck reaction that allowed access to the pentacyclic core of the natural product in a single process. [6] Shortly thereafter, the group of Lautens disclosed an asymmetric approach to the natural product that employed a Catellani reaction and relied on the chiral pool as the source of the target molecule's stereocenter. [7] We hereby report an enantioselective total synthesis of (+)-linoxepin (1) using a new, even more efficient approach, whereby the stereogenic center is introduced by an asymmetric hydroboration (Scheme 1).…”