An Acid-Catalyzed Epoxide Ring-Opening/Transesterification Cascade Cyclization to Diastereoselective Syntheses of (±)-β-Noscapine and (±)-β-Hydrastine

Abstract

An acid-catalyzed stereoselective epoxide ring-opening/intramolecular transesterification cascade cyclization reaction and N-Boc deprotection was found to be a successful strategy to construct the phthalide tetrahydroisoquinoline skeleton in one pot. Based on this strategy, the unified and highly diastereoselective routes for the total syntheses of (±)-β-Noscapine and (±)-β-Hydrastine were exploited.

Construction of Benzo‐Fused Heterocycles by Epoxide–Heteronucleophile Cyclization: Applications in the Synthesis of Natural Products and Designed Molecules

“…In 2019, Zhao and co‐workers accomplished the total synthesis of synthesis of phthalide tetrahydroisoquinoline alkaloids (±)‐β‐noscapine ( 252 ) and (±)‐β‐hydrastine ( 254 b ) (Scheme 60). [74] The researchers performed DMDO‐epoxidation of highly functionalized stilbene derivatives 247 and 248 to generate epoxides 249 and 250 , respectively, in good yields. Remarkably, treatment of epoxide 249 with TFA in CH 2 Cl 2 resulted in a 6‐ exo epoxide–NHBoc cyclization/intramolecular transesterification/ N ‐Boc deprotection cascade, affording phthalide tetrahydroquinoline derivative 251 as a single diastereomer in 76 % yield.…”

“…In 2019, Zhao and co-workers accomplished the total synthesis of synthesis of phthalide tetrahydroisoquinoline alkaloids (�)-β-noscapine (252) and (�)-β-hydrastine (254 b) (Scheme 60). [74] The researchers performed DMDO-epoxidation of highly functionalized stilbene derivatives 247 and 248 to generate epoxides 249 and 250, respectively, in good yields. The century-old nucleophilic aromatic substitution (S N Ar) is frequently used in organic synthesis and stands tall amongst many recent innovative reactions.…”

Synthesis and Biological Evaluation of Phthalideisoquinoline Derivatives

“…1 Structurally, the alkaloids comprise a tetrahydroisoquinoline (THIQ) and a phthalide ring, and these two units are linked together at their C-1 and C-3′ carbons. Due to their intriguing structures and important bioactivities, a series of synthesis routes have been developed, including the reductive coupling of an iminium ion, 2 Bischler−Napieralski cyclization, 3 and epoxide cascade cyclization 4 (Scheme 1b). Despite these important advances, these strategies usually suffer from one or more limitations, such as harsh reaction conditions, prefabrication of complex substrates, and inaccessibility of raw materials.…”

Studies on asymmetric total synthesis of (−)-β-hydrastine via a chiral epoxide ring-opening cascade cyclization strategy

“…Our research group has been exploring a unied acidcatalyzed epoxide ring-opening/intramolecular trans-esterication cascade cyclization strategy for synthesis of phthalide tetrahydroisoquinoline alkaloids, in which the C and D rings are constructed simultaneously in one step. 14 The method was successfully applied to the diastereoselective total synthesis of (AE)-b-hydrastine via an S N 1-like mechanism (Scheme 2a). 14 In order to investigate further applications of this cascade cyclization strategy for enantioselective total syntheses of phthalide tetrahydroisoquinoline alkaloids, we postulated that the chiral epoxide was utilized as a key stereocontrol element in addition to a reactivity control element to enantioselectively construct the phthalide tetrahydroisoquinoline scaffold based on an S N 1-type acid-catalyzed or an S N 2-type base-catalyzed cyclization strategy (Scheme 2b).…”

“…14 The method was successfully applied to the diastereoselective total synthesis of (AE)-b-hydrastine via an S N 1-like mechanism (Scheme 2a). 14 In order to investigate further applications of this cascade cyclization strategy for enantioselective total syntheses of phthalide tetrahydroisoquinoline alkaloids, we postulated that the chiral epoxide was utilized as a key stereocontrol element in addition to a reactivity control element to enantioselectively construct the phthalide tetrahydroisoquinoline scaffold based on an S N 1-type acid-catalyzed or an S N 2-type base-catalyzed cyclization strategy (Scheme 2b). As the Shi ketone catalyst and other variants are synthetically accessible, 15,16 we have the ability to generate epoxide substrate bearing the necessary stereochemistry based on the chosen cascade direction.…”