Enantioselective Total Synthesis of Pentacyclic Proaporphine Alkaloid (−)‐Misramine

Abstract

An enantioselective total synthesis of pentacyclic proaporphine alkaloid (−)‐misramine has been achieved. The synthetic route features a Pictet‐Spengler cyclization to construct the fused B and C rings and a sequence of Baeyer‐Villiger oxidation, Pinnick oxidation, and pinacol‐type cyclization to install the α‐hydroxy ketal moiety. The absolute configuration of the pentacyclic framework was elucidated by X‐ray single‐crystal analyses of (−)‐11‐demethoxymisramine.

Development of TfOH‐Catalyzed Spirocyclization by Intramolecular Friedel‐Crafts‐type 1,4‐Addition: Application to the Total Synthesis of the Unusual Proaporphine Alkaloid (±)‐Misrametine

“…In 2018, we achieved the first total synthesis of unusual proaporphine alkaloid (−)‐misramine 3 [16] . Later, Xie, Zhou and co‐workers also reported the total synthesis of 3 [20] . Here, we attempted the total synthesis of (±)‐misrametine 4 by using the TfOH‐catalyzed intramolecular Friedel‐Crafts‐type 1,4‐addition and O ‐demethylation based on the hypothesized biosynthesis.…”

Baeyer–Villiger oxidation: a promising tool for the synthesis of natural products: a review

“…(−)-Misramine 26 is a pentacyclic proaporphine alkaloid, 52 a member of isoquinoline alkaloids. 60 The former is a biologically active compound and was found in Roemeria hybrida and R. dodecandra. 61 In 2018, Yoshida and Takao et al synthesized Lamellarins are marine alkaloids isolated from mollusk Lamellaria species.…”

“…(−)-Misramine 26 is a pentacyclic proaporphine alkaloid, 52 a member of isoquinoline alkaloids. 60 The former is a biologically active compound and was found in Roemeria hybrida and R. dodecandra . 61 In 2018, Yoshida and Takao et al synthesized the (−)-misramine with overall 2.0% yield (in twenty four steps) from 2,4,6-tribromoanisole by employing asymmetric Friedel–Crafts 1,4-addition.…”

“…However, Pu et al in 2021 presented the enantioselective total synthesis of the natural product, (−)-misramine 26 in 11.4% overall yield (in nine steps) by utilizing Baeyer–Villiger oxidation as a significant step. 60 The synthesis was commenced with the reaction of chiral intermediate (−)-19 with TFA and methyl chloroformate in DCM to afford a pentacyclic intermediate 20 in 66% yield. Compound 20 underwent Baeyer–Villiger oxidation with m -CPBA in DCM to generate a lactone 21 in 80% yield.…”

Pictet–Spengler-Based Multicomponent Domino Reactions to Construct Polyheterocycles

“…The Pictet–Spengler reaction, discovered in 1911 by Amé Pickett and Theodore Spengler, is originally a cyclization of a phenethylamine 1 and a formaldehyde dimethyl acetal 2 to produce 1,2,3,4-tetrahydroisoquinoline 3 in the presence of hydrochloric acid ( Scheme 1 ). 1 After that, a variety of modified reaction systems for the Pictet–Spengler reaction have been developed for the construction of valuable heterocyclic scaffolds, 2 such as Brønsted acids, 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Lewis acids, 39 40 41 transition metal catalysts, 42 43 44 45 46 organocatalysts, 26 27 47 48 and enzyme strictosidine synthases. 13 49 Meanwhile, the use of suitably substituted amine derivatives such as β-arylethylamines, tryptamines, or functionalized aromatic amines with an aldehyde or ketone is essential for the progress of the Pictet–Spengler reaction.…”