Gram-Scale Enantioselective Synthesis of (+)-Lucidumone

Abstract

The first enantioselective total synthesis of (+)-lucidumone is described through a 13-step synthetic pathway (longest linear sequence). The key steps involve the formation of a bridged bicyclic lactone by an enantioselective inverse-electron-demand Diels–Alder cycloaddition, C–O bond formation to assemble two fragments, and a one-pot retro-[4 + 2]/[4 + 2] cycloaddition cascade. The synthesis is scalable, and more than one gram of natural product was synthesized in one batch.

Total Synthesis of Lucidumone through Convenient One‐pot Preparation of the Tetracyclic Skeleton by Claisen Rearrangement and Subsequent Intramolecular Aldol Reaction

“…The unique structure and intriguing bioactivity inspired us to synthesize 1 . The total synthesis of 1 has previously been reported only by Torre‘s group [2] . In Torre's report, 1 was synthesized on gram‐scale through repeated Diels–Alder cycloadditions.…”

Catalytic Enantioselective Inverse-Electron-Demand Diels–Alder Reaction of 2-Pyrones and Vinyl Selenides

“…The Tang group recently demonstrated that side arms on the bisoxazoline framework have a marked influence on both reactivity and stereocontrol. 29 This strategy was subsequently employed successfully by us [20][21][22] and by de la Torre and co-workers [25][26] in the development of enantioselective IEDDA reactions of 2-pyrones. Inspired by these works, modifications of L6 by installing only one example 91%, 84% ee by Gademann [28] O O PhSe…”

“…Therefore, the development of an efficient asymmetric catalytic system to promote this reaction under mild reaction conditions is highly desirable. Although great achievements have been made very recently for the development of enantioselective IEDDA reactions of 2-pyrones, [18][19][20][21][22][23][24][25][26] the reaction using a cis-phenyl vinyl selenide as the dienophile remains elusive. Only two related examples have been reported.…”

“…Recently, the Tang group has demonstrated that side arms on the bisoxazoline framework have great influence on both the reactivity and stereocontrol. 29 This strategy was then employed successfully by us [20][21][22] and de la Torre [25][26] S2). To our great delight, it was revealed that L11 with a 3,5-bis(trifluoromethyl)benzyl group dramatically improved the enantioselectivity, affording 3a in 95% yield and 88% ee (Table 1, entry 11).…”

“…Therefore, the development of an efficient asymmetric catalytic system to promote this reaction under mild reaction conditions is highly desirable. Although considerable achievements have recently been made in the development of enantioselective IEDDA reactions of 2-pyrones, [18][19][20][21][22][23][24][25][26] the reaction using a cisphenyl vinyl selenide as the dienophile remains elusive: only two related examples have been reported. In 2000, Markó reported the catalytic asymmetric IEDDA reaction of methyl 2-oxo-2H-pyran-3-carboxylate with simple unsubstituted vinyl phenyl selenide, but only a 56% ee was achieved.…”