Systematic Asymmetric Synthesis of All Diastereomers of (−)-Talaumidin and Their Neurotrophic Activity

Abstract

(-)-Talaumidin (1), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan isolated from Aristolochia arcuata Masters, shows significant neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in NGF-differentiated PC12 cells. The four stereogenic centers on the tetrahydrofuran moiety in 1 result in the presence of seven diastereomers except for their enantiomers. In order to investigate the stereochemistry-activity relationships of the stereoisomers, the systematic synthesis of all stereoisomers of 1 was accomplished by employing Evans aldol, diastereoselective hydroboration, reductive deoxygenation, and Mitsunobu reactions as key steps. The ability of all of the synthesized stereoisomers to promote neurite-outgrowth in PC12 and neuronal cells was evaluated. All stereoisomers exhibited moderate to potent neurotrophic activities in NGF-differentiated PC12 cells at 30 μM and in primary cultured rat cortical neuronal cells at 0.01 μM. In particular, 1e bearing all cis substituents resulted in the most potent neurite-outgrowth promotion.

Chemistry and Neurotrophic Activities of (–)-Talaumidin and Its Derivatives

“…In this review, we focus and summarize neuriteoutgrowth promotion activities in primary cultured rat cortical neurons (Zhai et al, 2004) and in NGF-differentiated PC12 cells. Additionally, we describe the synthesis of 1 and all stereoisomers of 1 (Esumi et al, 2006;Fukuyama et al, 2008), and discuss structure-activity relationships between 1 and its analogs on PC12 cells (Harada et al, 2015). Furthermore, we report their regenerative activity toward mouse optic nerves as a neurotrophic activity in vivo, reinforcing their potential as therapeutic agents for neurodegenerative disease (Harada et al, 2018).…”

“…The successful control of the four contiguous stereocenters in an asymmetric synthesis of all seven diastereomers would be crucial for the elucidation of the relationship between stereochemistry and neurotrophic activity, and likewise be an important achievement from the viewpoint of organic synthetic chemistry. In 2015, we published the systematic synthesis of talaumidin diastereomers and their evaluation of neurotrophic activity (Scheme 3) (Harada et al, 2015).…”

“…Once the synthesis of all diastereomers was complete, their neurotrophic activity was compared with that of natural talaumidin (Harada et al, 2015). Talaumidin (1) and isomers 1a-1g were assessed their neurite-outgrowth promoting activity together with enantiomer of (-)-talaumidin.…”

Total Synthesis, Stereochemical Assignment, and Divergent Enantioselective Enzymatic Recognition of Larreatricin

“…If we assume that the reaction proceeds via the oxacarbenium ion 9 , the preferred trajectory for attack of the incoming nucleophile should be anti to the C‐3 methyl group for both conformers and thus deliver the desired configuration. The formation of multiple isomers instead suggests that either (a) the oxacarbenium 9 quickly epimerizes (via the enol ether) competitively with nucleophilic addition, or (b) the tetrahydrofuran 10 undergoes further loss of configurational purity and/or destruction initiated by the formation of the p ‐quinone methide through Lewis acid‐mediated ring‐opening …”

“…The formation of multiple isomersi nsteads uggests that either (a) the oxacarbenium 9 quickly epimerizes (via the enol ether) competitively with nucleophilic addition, or (b) the tetrahydrofuran 10 undergoes furtherl oss of configurational purity and/ord estruction initiated by the formation of the p-quinonem ethide through Lewis acid-mediated ring-opening. [20] The need to prevent epimerization and side reactions suggested structurally modifying the leaving group at carbon C-2, to avoid the need for as trong Lewis acid. After some experimentation (Scheme 4), we found that the conversion of lactol 7 to as ulfone acetal 11, [21] followed by the addition of the Grignardr eagent 4 in the presence of zinc(II) bromide gratifyingly generated the tetrasubstituted tetrahydrofuran 10 [13] as the main diastereomeric species in 70-80 %y ield from lactol 7.…”