Synthesis of Spirolactones via a BF₃·Et₂O-Promoted Cascade Annulation of α-Keto Acids and 1,3-Enynes

Abstract

A novel and effective method for the synthesis of spirolactones from readily available α-keto acids and 1,3-enynes is developed via a BF 3 •Et 2 O-promoted cascade annulation. This sequential process is conducted at room temperature, and it provides the functionalized spirolactones in good to excellent yield under metal-free conditions.The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c01827.Full experimental details and characterization data for all products (PDF)Accession CodesCCDC 2036731 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk

Direct synthesis of fluorene-based spirolactones through a BF3-promoted spiroannulation of α-keto acids and o-alkynylbiaryls

“…Based on our experimental results as well as previous reports, 12 a plausible reaction pathway for the BF 3 -promoted spiroannulation is suggested in Scheme 6. Initially, the regioselective addition/cyclization of α-keto acid 1a with o -alkynyl biaryl 2a generated a hydroxylactone I in the presence of BF 3 .…”

BF3·Et2O-Mediated annulation of α-keto acids with aliphatic ketones for the synthesis of γ-hydroxy-butenolides and γ-alkylidene-butenolides

“…To delineate the mechanism, control experiment was conducted with 3aa as substrate in the presence of excess amount Based on the results and previous reports, [10][11][12][13][14][15] we proposed a plausible pathway accounting for the formation of 3aa and 4aa (Scheme 5). Initially, the enolized cyclohexanone A from 2a underwent nucleophilic attack with a-keto acid (1a) with the assistance of Lewis acid to afford intermediate B.…”

“…Following the preliminary report, the annulation of α-keto acid with internal 11 or terminal alkynes 12 to afford γ-hydroxybutenolides or multiply substituted butenolides was also reported by the same group (Scheme 1b). The strategy was then extended to the annulation reaction of α-keto acids with functionalized alkynes by Wang 13 and Cui group. 14 In 2018, Fan and coworkers 15 reported an elegant synthesis of furan-2(5 H )-one fused N , O -containing bicyclic compounds via the annulation reaction of N -aryl substituted saturated cyclic amines with α-keto acids (Scheme 1c).…”

Synthesis of Indolyl-Tethered Spiro[cyclobutane-1,1′-indenes] through Cascade Reactions of 1-(Pyridin-2-yl)-1H-indoles with Alkynyl Cyclobutanols

“…Spirocarbocyclic scaffolds have spurred intensive interest among chemists working in synthetic and pharmaceutical fields owing to their prevalence in natural products, chiral ligands, and clinical drugs. Representative examples in this regard are shown in Figure . In the meantime, compounds bearing a cyclobutyl moiety have been frequently exploited as lead compounds for the discovery of anticancer, human TLF4 agonizing, and neuropathic pain-relieving drugs. , In addition, cyclobutane derivatives are widely used as important building blocks for the preparation of a broad spectrum of fine chemicals due to their inherent ring strain nature and diverse reactivity.…”

“…Representative examples in this regard are shown in Figure . In the meantime, compounds bearing a cyclobutyl moiety have been frequently exploited as lead compounds for the discovery of anticancer, human TLF4 agonizing, and neuropathic pain-relieving drugs. , In addition, cyclobutane derivatives are widely used as important building blocks for the preparation of a broad spectrum of fine chemicals due to their inherent ring strain nature and diverse reactivity. Therefore, how to synthesize spirocarbocyclic compounds containing a cyclobutyl unit constitutes a highly desirable yet still challenging synthetic mission …”