Synthesis of (+)-Lineariifolianone and Related Cyclopropenone-Containing Sesquiterpenoids

Abstract

A synthesis of the proposed structure of lineariifolianone has been achieved in eight steps and 9% overall yield starting from (+)-valencene, leading to a reassignment of the absolute configuration of this unusual cyclopropenone-containing natural product. Key steps in the synthetic route include kinetic protonation of an enolate to epimerize the C7 stereocenter and a stereoconvergent epoxide opening to establish the trans-diaxial diol functionality. The syntheses of the enantiomers of two other closely related natural products are also reported, confirming that all three compounds belong to the eremophilane class of sesquiterpenoids.

Novel Electrophilic Warhead Targeting a Triple-Negative Breast Cancer Driver in Live Cells Revealed by “Inverse Drug Discovery”

“…Cyclopropenone, an electrophilic group, is found in natural products such as linearlifolianone, penitricin, and alutacenoic acid A/B . In chemical biology studies, this functional group has been often employed in bio-orthogonal reactions mediated by triarylphosphines (Figure A). , Another familiar application of cyclopropenone is the photo-triggered click reaction with azides or tetrazines for protein bioconjugation (Figure A). − However, the proteome reactivity of the cyclopropenone in live cells has not been explored to date.…”

Monosubstituted 3,3‐Difluorocyclopropenes as Bench‐Stable Reagents: Scope and Limitations

“…Hydrolysis of gem ‐difluorocyclopropenes is one of the attractive methods for preparation of cyclopropenones (Figure 1D) [8] . The approach was used in the total synthesis of (+)‐lineariifolianone, a natural anti‐inflammatory agent (Figure 1C) [9] and functionalized cyclopropenones for metabolic targeting and sequential bioorthogonal labelling [10] . Highly regio‐ and stereoselective hydrostannylation, [11] highly enantioselective copper‐catalyzed hydro‐, bora‐, and carbo‐metalations with Si−H, B−H, B−B and (CH 3 ) 2 Zn, [12] as well as ruthenium‐catalyzed asymmetric transfer hydrogenation [13] of difluorocyclopropenes showcase reactions that utilize reactivity of unsaturated carbon‐carbon bond, leaving fluorine atoms intact.…”

Enantioselective palladium-catalyzed C(sp2)–C(sp2) σ bond activation of cyclopropenones by merging desymmetrization and (3 + 2) spiroannulation with cyclic 1,3-diketones

“…[32][33][34][35][36][37][38][39][40] Although the origin of cyclopropenone ring in nature has not been fully elucidated, several cyclopropenone-contained natural products (Figure 2A) have been isolated, synthesized, and studied on the structure-activity relationships for cytotoxicity and enzyme inhibition. 41 In particular, the transition-metal-catalyzed transformations of cyclopropenones involving the carbon-carbon bond activation have been an active research area in the past years. Among various synthetic approaches based on the chemical reactivity of the cyclopropenones, [42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] enantioselective version of transition-metal-catalyzed carboncarbon bond activation and subsequent ring opening or ring expansion reactions of cyclopropenones remain underexplored.…”