CH Bond Arylation in the Synthesis of Aryltetralin Lignans: A Short Total Synthesis of Podophyllotoxin

Abstract

A short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported. Key to the success of this synthetic pathway is a Pd-catalyzed C(sp(3))-H arylation reaction enabled by a conformational biasing element to promote C-C reductive elimination over an alternative C-N bond-forming pathway. This strategy allows for access to the natural product in five steps from commercially available bromopiperonal, and sheds light on subtle conformational effects governing reductive elimination pathways from high-valent palladium centers.

Palladium-Catalyzed Transformations of Alkyl C–H Bonds

“…143 Subsequently, Maimone reported a short total synthesis of podophyllotoxin via Pd(II)-catalyzed arylation of cyclohexyl C(sp 3 )–H bonds. 145 Very recently, Reisman and co-workers accomplished the first enantioselective total synthesis of (+)-psiguadial B. 146 The directed C(sp 3 )–H alkenylation of a chiral cyclobutane 142 could provide the key intermediate 143 in 72% yield on a gram scale (Scheme 33).…”

Recent Applications of Rh‐ and Pd‐Catalyzed C(sp3)–H Functionalization in Natural Product Total Synthesis

“…In 2014, Maimone and co‐workers reported a concise synthesis of (±)‐podophyllotoxin ( 87 ) using a Pd‐catalyzed C(sp 3 )–H arylation as the key step (Scheme ) . Commercially available 6‐bromopiperonal ( 88 ) was transformed into benzocyclobutanol 89 in two steps.…”

“…In 2014, Maimone and co-workers reported a concise synthesis of (±)-podophyllotoxin (87) using a Pd-catalyzed C(sp 3 ation as the key step (Scheme 15). [44] Commercially available 6bromopiperonal (88) was transformed into benzocyclobutanol 89 in two steps. Base-promoted thermal cycloaddition between 89 and fumarate-derived amide 90 readily afforded the desired cycloadduct 91, which -after in situ reduction with LiEt 3 BH and subsequent ketalization -afforded arylation precursor 92 as a single diastereomer in good yield.…”

Recent Accomplishments in the Total Synthesis of Natural Products Through C–H Functionalization Strategies

“…The method used highlights the importance of C-H activation in preparing a family of different analogs by modifying the arene coupling counterpart [45]. The method used highlights the importance of C-H activation in preparing a family of different analogs by modifying the arene coupling counterpart [45].…”