Rapid and scalable synthesis of chiral bromolactones as precursors to α-exo-methylene-γ-butyrolactone-containing sesquiterpene lactones

Abstract

The sesquiterpene lactones cover a diverse and pharmacologically important diversity space. In particular, the electrophilic α-exo-methylene-γ-butyrolactone moiety that is preponderant in this natural product family has been shown to readily engage in covalent inhibition via conjugate addition of cysteine residues in target proteins. However, the synthetic accessibility of sesquiterpenes or related probes to investigate their mode of action remains laborious. Herein, we present a rapid and scalable route to chiral bromolactones as enabling precursors in the synthesis of sesquiterpene lactones.

Diastereoselective Allylation in the Divergent Total Syntheses of Guaianolides (+)-Ligustrin and (+)-Grosheimin and the Formal Synthesis of (−)-Eupalinilide E

“…(S)-3-(Bromomethyl)-5-(hydroxymethyl)furan-2(5H)-one ( 11). 14 To a stirred solution of aldehyde 16 (50 g, 384.2 mmol, 1.0 equiv) in methyl acrylate (99.2 g, or 104.5 mL, 1152.6 mmol, 3.0 equiv), DABCO (43.1 g, 384.2 mmol, 1.0 equiv) was added at room temperature. After 48 h, the reaction mixture was diluted with CH 2 Cl 2 (100 mL), and the organic layer was separated, washed with water and brine, dried (Na 2 SO 4 ), and concentrated.…”

“…The titled compound was prepared as reported in the literature. 14 1 H NMR (400 MHz, CDCl 3 ) δ = 7.55−7.52 (m, 1H), 4.85 (dd, J = 3.0, 1.5 Hz, 2H), 4.08 (dd, J = 3.3, 1.6 Hz, 2H) ppm; 13 C{ 1 H} NMR (100 MHz, CDCl 3 ) δ = 171. 5, 149.1, 130.8, 70.1, 20.7 ppm.…”

Synthesis of α-exo-Methylene-γ-butyrolactones: Recent Developments and Applications in Natural Product Synthesis

“…Subsequently, our group developed a rapid and scalable route to chiral bromolactones as enabling precursors in the synthesis of -(hydroxymethylalkyl)--exo-methylene--butyrolactones. 46…”

Synthesis and Biological Evaluation of Analogues of Butyrolactone I as PTP1B Inhibitors

“…The metabolites display antibacterial, antiviral, antitumor and other activities [ 9 , 10 , 11 ]. Butenolide, a collective name for α,β-unsaturated lactones with four carbon heterocyclic rings produced by a variety of marine organisms, is drawing increasing attention in drug discovery [ 12 , 13 , 14 , 15 , 16 ]. Butenolide derivatives display an impressive range of pharmacological properties, including anti-inflammatory [ 17 , 18 ], antibacterial [ 19 ], antiviral [ 20 ], and antitumor activities [ 21 , 22 ], while aromatic butenolides were found to have α- and β-glucosidase inhibitory activities [ 23 , 24 ].…”