Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E

Abstract

The annotinolides are one of the most recent additions to the Lycopodium family of alkaloids, with its members possessing challenging, caged structures that include a [3.2.1]-bicyclic core bearing six contiguous stereocenters, including oxa-, aza-, and all-carbon quaternary centers. Herein, we document a concise and stereoselective route that achieves the first total syntheses of three of its members: annotinolides C, D, and E. Key operations include a gold(I)-catalyzed Conia-ene reaction that fashions much of the main core in a single operation, as well as a number of other challenging and chemoselective transformations to generate the remaining elements. Moreover, efforts utilizing the natural products themselves, seeking adjustments in their oxidation states and the rearrangement of individual ring systems, sheds light on their potential biogenesis with some outcomes counter to those originally proposed. Finally, formal enantioenriched syntheses of the target molecules are also presented. File list (2) download file view on ChemRxiv AnnotinolidesTSDraftFinalPreTemplate.pdf (511.47 KiB) download file view on ChemRxiv AnnotinolidesTSSupportingInformationFinalComplete.pdf (8.91 MiB) Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E

Multicomponent Selective Thioetherification of KSAc: Easy Access to Symmetrical/Unsymmetrical 4‐Alkylthio‐3‐halo‐2(5H)‐furanones

“…The 2(5H)-furanone compounds bearing an α,β-unsaturated lactone unit have attracted great attention from chemists in many fields, such as organic synthesis, [24,25] drug design, [26,27] and natural product synthesis [28,29] due to their high antiviral, [30] antitumor [31] and anti-HIV biological activities, [32] making the chemical researches of 2(5H)-furanone more active. [33] Among them, the thioetherified 2(5H)-furanone is a kind of potential drug molecule with good anti-cancer activity as Li's group reported before.…”

Total Syntheses of Polycyclic Diterpenes Phomopsene, Methyl Phomopsenonate, and iso-Phomopsene via Reorganization of C–C Single Bonds

“…We then focused on the enantioselective syntheses of enantioenriched 1 – 3 (Scheme ). Gratifyingly, kinetic resolution of secondary alcohol 13 was efficiently realized by lipase-mediated asymmetric acetylation . Treatment of racemic 13 with the enzyme Novozym 435 and vinyl acetate in TBME produced enantioenriched (−)- 13 in 47% yield (99.7% ee) and acetyl ester (+)- 29 in 49% yield (92% ee).…”

“…Gratifyingly, kinetic resolution of secondary alcohol 13 was efficiently realized by lipase-mediated asymmetric acetylation. 16 Treatment of racemic 13 with the enzyme Novozym 435 and vinyl acetate in TBME produced enantioenriched (−)-13 in 47% yield (99.7% ee) and acetyl ester (+)-29 in 49% yield (92% ee). Based on the synthetic route outlined for 1−3, we achieved the enantioselective syntheses of (−)-phomopsene, (+)-methyl phomopsenonate, and (+)-iso-phomopsene in a divergent manner from (−)-13.…”

Total Synthesis of Mollanol A

“…The presence of an enone within the bicyclic structure 13 suggested its potential formation via an allylic oxidation from 14 . Inspired by Snyder’s total synthesis of chalcitrin and annotinolides as well as several others’ works, − we think that a Conia-ene reaction could potentially fashion the bicyclo[3.2.1]­alkenone of 14 from cyclopentanone precursor 15 , which would be prepared in one step from commercially available material. The successful realization of this convergent strategy would provide a modular route to mollanol A ( 9 ) that we anticipated could ultimately lead to the syntheses of its analogs and other grayanoids.…”