Inverse‐Electron‐Demand Diels–Alder Reactions of 2‐Pyrones: Bridged Lactones and Beyond

Abstract

Inverse‐electron‐demand Diels–Alder (IEDDA) reactions of electron‐poor 2‐pyrones as electrophilic dienes have been extensively studied in the past fifty years. These reactions provide an efficient access to bridged bicyclic lactones and their derivatives, such as densely functionalized 1,3‐cyclohexadienes after CO2 extrusion and polysubstituted aromatic compounds through elimination. This reaction has been used for the synthesis of many biologically active natural products and drug candidates. In this review, the developments of these IEDDA reactions including non‐catalytic, Lewis acid‐catalyzed and organocatalytic IEDDA reactions, and their applications in total synthesis are discussed in detail.

tert-Butyl(2-oxo-2H-pyran-5-yl)carbamate as the First Chameleon Diene Bearing an Electron-Donating Substituent

“…Ring substituents play a critical role in the cycloadditions of 2( H )pyran-2-ones. Generally speaking, the unsubstituted ring 2( H )pyran-2-one, 18 ( Figure 2 ), undergoes cycloadditions only under harsh conditions and with alkynes to afford benzenes following the tandem loss of CO 2 [ 1 , 2 , 3 , 4 , 5 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. Examples of cycloadditions of 2( H )pyran-2-one, 18, with alkenes to afford bridged bicyclic lactones do exist, but are rare [ 65 , 66 , 67 , 68 , 69 , 70 ].…”

“…The Diels–Alder (DA) cycloaddition of 2( H )pyran-2-ones [ 1 , 2 , 3 , 4 , 5 ], e.g., 1 , is a powerful and versatile methodology in synthetic organic chemistry and is widely used in the preparation of complex molecules [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. In particular, cycloadditions of 2( H )pyran-2-one dienes to alkene dienophiles affords bridged bicyclic lactones, e.g., 2 which can then be transformed in few steps to highly substituted, six-membered rings, e.g., 3 ( Scheme 1 ) [ 1 , 2 , 3 , 4 , 5 ,…”

Skeletal Editing: Interconversion of Arenes and Heteroarenes

“…[66,86,98] Similar in concept, 2-pyrones are able to undergo IEDDA reactions to exchange a C-and O-atom for two C-atoms with release of CO 2 . [99,100] Atom exchanges of dibenzothiophenes have been reasonably well developed, [101] as described in recent reviews. [102,103] For example, Yorimitsu and co-workers have reported a series of methods that rely on oxidation of a dibenzothiophene to the corresponding S,S-dioxide to enable sequential S N Ar displacement of the S-atom (Scheme 13,D-i).…”

Enantioselective construction of cis-hydroindole scaffolds via an asymmetric inverse-electron-demand Diels–Alder reaction: application to the formal total synthesis of (+)-minovincine

“…Due to the hemi-aromatic and adjustable electronic properties, electron-deficient 2-pyrone has become a favored diene component in the IEDDA reaction with a wide range of applications in aromatic compounds and complex natural product synthesis. 19,20 Particularly, the Cai group demonstrated the enantioselective IEDDA reaction of 3-carboalkoxyl-2-pyrone with electron-rich dienophiles, such as 2,2-dimethyl-1,3-dioxole, 20 g silyl cyclohexadienol 20 i and 1-naphthyl acetylenes, 20 j affording the products in high yield, excellent ee, and high dr. In spite of the above achievements, catalytic asymmetric synthesis of cis -hydroindoles via the enantioselective IEDDA reaction of 2-pyrones with cyclic enamines is still in its infancy so far.…”