Organohalogenite‐Catalyzed Spiroketalization: Enantioselective Synthesis of Bisbenzannulated Spiroketal Cores

Abstract

An ew core structure-motivated strategy for the intramolecular aromatic spiroketalization process wasf ound and used for the enantioselective synthesis of bisbenzannulated spiroketals,t he bioactive core of rubromycins,w ith high levels of enantioselectivity (up to 98% ee) via an organohalogenite-mediated asymmetric intramolecular aromatic spiroketalization. This is the first organocatalytic method for the construction of opticallyp ure bisbenzannulated spiroketals.Keywords: asymmetric synthesis; organocatalysis; organohalogen;spiroketalization Core-scaffold-lead synthesist hrough rapid construction of chiral molecular complexity around the biologically relevant framework using ah ighly efficient strategyisakey goal of organic andmedicinal synthesis.B enzannulated spiroketals,a saprivileged structural moietyf ound in al arge series of bioactive naturally occurring alkaloids andp harmaceutically relevant assays, such as Lysidicin [1] and rubromycins [2] ( Figure 1), exhibit ar ange of biological and pharmaceutical activities.[3] Although many strategies were designed to construct spiroketals [4] and related natural products, [5] the direct asymmetric catalytic approaches to access them are stillscarce.Recently,List [6] and Nagorny [7] developed the asymmetricc atalytic construction of aliphatic spiroketals by chiral phosphorica cid-catalyzed spiroketalizations (a,S cheme 1), respectively.H owever, comparedt o the asymmetric formation of aliphatic spiroketals,t he enantioselective construction of aromatic spiroketals represents ac onsiderable challenge because the aromatic hydroxy groups have less nucleophilicity.T herefore,itisnot surprising that the catalytic enantioselective synthesis of aromatics piroketals hasb een rarely

A Green and Versatile Route to Highly Functionalized Benzofuran Derivatives Using Biomimetic Oxygenation

“…As far as we are aware, dimer 3 is new and might be an interesting structure for benzofuran based pharmaceuticals . A search using the structures of products 4 a , 4 b , 5 , 5 a , 6 , 6 a , 6 b and 7 indicated that these compounds have also not been previously characterized although some bioactive compounds such as Arundinone B, or the drug Griseofulvin (Figure ) contain the core structure of compound 4 a .…”

Iodine-Catalyzed Cascade Annulation of 4-Hydroxycoumarins with Aurones: Access to Spirocyclic Benzofuran–Furocoumarins

“…The design and synthesis of biologically active spiro-heterocycles have attracted the attention of many pharmacologists and chemists [14,15]. In particular, the spiro-heterocycles that contain benzofuran have become one of the most interesting classes of molecules due to their notable biological activities [ [16][17][18]. For example, griseofulvin A is one of the earliest spirocyclic drugs to exhibit antifungal activity [19], while spiro-benzofuran B, with isobenzofuranone and benzofuranone motifs, has been found to be a core chemical skeleton for antivirals against influenza viruses [20].…”

Synthesis of Benzannulated [6,6]-Spiroketals by a One-Pot Carbonylative Sonogashira Coupling/Double Annulation Reaction

“…Despite these advances, the development of more atom- and step-economic methods starting from easily available substrates under mild conditions is still highly desirable for the synthesis of benzannulated [6,6]-spiroketals. Our group has a longstanding interest in this field and has developed a series of efficient methods for the syntheses of benzannulated [5,6]-spiroketals . In accordance with our interest in developing synthetic tools for the synthesis of natural products containing benzannulated [6,6]-spiroketal motifs, we wish to develop a new and efficient method for the stereocontrolled synthesis of this skeleton.…”