Gold‐ or Silver‐Catalyzed Syntheses of Pyrones and Pyridine Derivatives: Mechanistic and Synthetic Aspects

Abstract

3-Oxo-5-alkynoic acid esters, on treatment with a carbophilic catalyst, undergo 6-endo-dig cyclization reactions to furnish either 2-pyrones or 4-pyrones in high yields. The regiochemical course can be dialed in by the proper choice of the alcohol part of the ester and the π-acid. This transformation is compatible with a variety of acid-sensitive groups as witnessed by a number of exigent applications to the total synthesis of natural products, including pseudopyronine A, hispidine, phellinin A, the radininol family, neurymenolide, violapyrone, wailupemycin and an unnamed brominated 4-pyrone of marine origin. Although the reaction proceeds well in neutral medium, the rate is largely increased when HOAc is used as solvent or co-solvent, which is thought to favor the protodeauration of the reactive alkenyl-gold intermediates as the likely rate-determining step of the catalytic cycle. Such intermediates are prone to undergo diauration as an off-cycle event that sequesters the catalyst; this notion is consistent with literature data and supported by the isolation of the gem-diaurated complexes 12 and 15. Furthermore, silver catalysis allowed access to be gained to 2-alkoxypyridine and 2-alkoxyisoquinoline derivatives starting from readily available imidate precursors.

Polyunsaturated C‐Glycosidic 4‐Hydroxy‐2‐pyrone Derivatives: Total Synthesis Shows that Putative Orevactaene Is Likely Identical with Epipyrone A

“…[19,20] This gratifying result adds another entry to the growing list of exigent pyrone derivatives prepared by this method. [19][20][21] Selective oxidation of the primary hydroxy group in 15 followed by aT akai olefination [22] furnished product 16 as af irst fully functional building block en route to 1.…”

“…To this end, 11 was subjected to hydrogenolysis,w hich left the push-pull alkene site intact;t he resulting product was treated with TBSOTf/pyridine to give 12 in excellent yield, leaving the C32 hydroxy group (orevactaene numbering) uncapped for steric reasons.T he use of an extra equivalent of LDAsufficed to prevent this protic site from intervening in the subsequent directed lithiation/iodination of the enol, whereas the hydroxy group is uncritical anyway in the Sonogashira coupling of the resulting iodide 13 with propargyl alcohol. [19,20] This gratifying result adds another entry to the growing list of exigent pyrone derivatives prepared by this method. [19,20] This gratifying result adds another entry to the growing list of exigent pyrone derivatives prepared by this method.…”

“…Compound 14 was then cyclized with the help of gold complex 19 as a p-acidic catalyst [18] to the desired 2-pyrone 15 according to ap rocedure previously developed by our group. [19][20][21] Selective oxidation of the primary hydroxy group in 15 followed by aT akai olefination [22] furnished product 16 as af irst fully functional building block en route to 1. [19][20][21] Selective oxidation of the primary hydroxy group in 15 followed by aT akai olefination [22] furnished product 16 as af irst fully functional building block en route to 1.…”

Gold Catalysis for Heterocyclic Chemistry: A Representative Case Study on Pyrone Natural Products

“…[40,49] Theu se of ac arbophilic p-acid catalyst would likely enable the alkyne unit to be activated under conditions that are largely orthogonal to activation of the flanking carbonyl groups (or any other heteroatom present in the substrate) by conventional Lewis acids.I ntramolecular attack of the ester carbonyl onto the resulting h 2 -alkyne complex L was expected to trigger a6 -endo-dig cyclization (Scheme 9): the additional polarization induced by complexation reinforces the pattern inherent to the ynone unit and, hence,e nsures high regioselectivity.I ft he primarily formed intermediate M releases ap roton that then engages in the kinetically competent protodeauration of N,t he 4-pyrone O will ensue.Byproper choice of the substituent R, however, it should be possible to favor heterolytic cleavage of the OÀR bond in M with release of as tabilized carbocation [R + ]; subsequent elimination would again provide the proton necessary to close the catalytic cycle with formation of the 2-pyrone Q.Under this premise,the new approach might not only excel in terms of functional-group tolerance,b ut could also provide ah andle to control the cyclization mode such that either a2 -pyrone or a4 -pyrone ring could be formed in areliable and predictable manner. [40,49] In line with these expectations,e xposure of model compound 8 to catalytic amounts of complexes of type LAuCl, after ionization with AgNTf 2 , [50] furnished product 9 in virtually quantitative yield (Scheme 10). [40] Taking advantage of the ß-cation stabilizing effect of silicon, substrate 11 was found to react equally well; [49] as trimethylsilylethyl esters are often easier to make than the corresponding tert-butyl counterparts,v aluable synthetic flexibility is gained, which is most welcome when working with elaborate target compounds.Inline with the mechanistic rationale,the corresponding benzyl or methyl esters 13 a,b cyclized to form the isomeric 2alkoxy-4-pyrone derivatives 14 a,b,r espectively.…”

“…[40] Taking advantage of the ß-cation stabilizing effect of silicon, substrate 11 was found to react equally well; [49] as trimethylsilylethyl esters are often easier to make than the corresponding tert-butyl counterparts,v aluable synthetic flexibility is gained, which is most welcome when working with elaborate target compounds.Inline with the mechanistic rationale,the corresponding benzyl or methyl esters 13 a,b cyclized to form the isomeric 2alkoxy-4-pyrone derivatives 14 a,b,r espectively. [40,49] Av ariety of gold species proved effective,b ut complexes endowed with Buchwald-type ligands [51] usually give the best results.T he reactions can be performed in chlorinated solvents,M eCN,o rM eNO 2 with similarly high yields.M echanistically significant, however,isthe observation that the rate of cyclization is strongly dependent on the medium. Specifically,the use of HOAc as the solvent or cosolvent allows the reactions to proceed within minutes and the catalyst loading to be significantly lowered.…”