A unified strategy toward total syntheses of lindenane sesquiterpenoid [4 + 2] dimers

Abstract

The dimeric lindenane sesquiterpenoids are mainly isolated from the plants of Chloranthaceae family. Structurally, they have a crowded molecular scaffold decorated with more than 11 stereogenic centers. Here we report divergent syntheses of eight dimeric lindenane sesquiterpenoids, shizukaols A, C, D, I, chlorajaponilide C, multistalide B, sarcandrolide J and sarglabolide I. In particular, we present a unified dimerization strategy utilizing a base-mediated thermal [4 + 2] cycloaddition between a common furyl diene, generated in situ, and various types of dienophiles. Accordingly, all the three types of lindenane [4 + 2] dimers with versatile biological activities are accessible, which would stimulate future probing of their pharmaceutical potential.

Atypical Lindenane-Type Sesquiterpenes from Lindera myrrha

“…The determined A/B ring substitution pattern of myrrhalindenane A is common among lindenane sesquiterpenes, falling into the lindenane sesquiterpenoid subtype I, as defined by Du and co-workers [9]. Conversely, the occurrence of oxygenated substituents at C-5 is rather uncommon among lindenane sesquiterpenes, since this position is often substituted by an α-disposed hydrogen atom, or is unsaturated due to either a Δ 4,5 or a Δ 5,6 function [13].…”

“…The chemical shift of C-4 (δ C 80.1) defined the presence of a hydroxy group on it. Such B-ring structures are recurrent within lindenane sesquiterpenes, falling into the third subtype defined by Du [9]. The tetracyclic core of 2, and the unchanged chemical shifts of both C-8 and C-9 left no possibility but to introduce an additional α-methyl-∆ α,β -γ lactone fused ring at C-6/C-7.…”

“…Having in mind, i) the consensual trans arrangement of the hydrindane system in lindenane sesquiterpenes, and ii) the antifacial orientations of H-5 and H-6, only left the configuration of C-4 pending assignment [12,13]. A preferred configuration for C-4 prevails with a β-OH group and an α-oxygenated methylene moiety, so that Du's lindenane sesquiterpene subtypes define the absolute configuration of this stereocenter [9]. Nevertheless, exceptions were reported throughout literature [11,14,15], so assigning the configuration of these positions based solely on biosynthetic considerations is not a relevant approach to reliably establish the configuration of such compounds.…”

“…The biosynthesis of dimeric lindenane sesquiterpenes is deemed to proceed via a Diels-Alder reaction with ∆ 4,15 and ∆ 5,6 representing the diene reactive unit [34]. Furyldiene lindenanes and, more generally speaking, molecules displaying these structural features rendering them prone to undergoing Diels-Alder addition, seem to be too unstable to be isolable [9]. This inherent reactivity towards dimerization most likely accounts for 1 being the first reported seco d-lindenane monomer, which can be readily related to its ∆ 6,7 function that prevents it from dimerizing.…”

Spirolindemers A and B, Lindenane Sesquiterpenoid Oligomers Equipped with Oxaspiro[4.5]decane from Chloranthus henryi

“…Lindenane sesquiterpenoid (LDS), the characteristic secondary metabolites of plants from Chloranthaceae family, possessing highly conjugated olefinic bonds and α , β ‐unsaturated ketones, are promising precursors for diverse polymerization reactions. [ 1 ] As diverse LDS polymers with peculiar structural skeletons are becoming the hot spot of natural products research, [ 2 ] more than 140 congeners with a similar polycyclic core have been discovered so far. [ 1 ] Their structural diversities are normally expanded by the intermolecular Diels‐Alder reaction between Δ 15(4),5(6) and Δ 8′(9′) , which was the most common pattern for dimerization, [ 3‐4 ] and subsequent skeletal rearrangement, [ 5‐6 ] oxidation, and acylation.…”