The Type 2 Intramolecular Diels-Alder Reaction: Synthesis and Chemistry of Bridgehead Alkenes

Abstract

Anti‐Bredt alkenes, bicyclic molecules that contain a bridgehead double bond, were for many years regarded as chemical curiosities. The type 2 intramolecular Diels–Alder (IMDA) reaction provides a one‐step entry into this fascinating class of molecules. The reaction has made available numerous anti‐Bredt alkenes for structural and chemical studies. X‐ray crystallography has revealed the magnitude of the deformations associated with the bridgehead double bond, and rate studies of reactions of bridgehead alkenes have allowed quantification of the kinetic consequences of the torsional distortions. More recently, the type 2 intramolecular Diels–Alder reaction and the resulting anti‐Bredt alkenes have found application in organic synthesis. The constraints resulting from the connectivity in the Diels–Alder precursor creates a strong regio‐ and stereochemical bias in the cycloaddition step. The end result of this bias is the stereoselective synthesis of highly substituted six‐membered rings. The reaction also achieves a facile synthesis of seven‐ and eight‐membered rings in a single step from acyclic precursors. The utility of this reaction has been verified in recent applications of the type 2 IMDA reaction as a key step in the total synthesis of complex natural products.

Synthetic and Theoretical Investigations on the Construction of Oxanorbornenes by a Michael Addition and Intramolecular Diels–Alder Furan Reaction

“…The requisite Michael acceptors, 2-furyl enones 1a-c, were prepared according to reported aldol condensation methods. [9] These Michael acceptors were then treated with allylmercaptan (2) in the presence of a suitable base to afford Michael adducts 3 (Table 1). For instance, the triethylamine-mediated addition of allylmercaptan (2) to enone 1a provided Michael adduct 3a in 64 % yield (Table 1, Entry 1).…”

“…[9] These Michael acceptors were then treated with allylmercaptan (2) in the presence of a suitable base to afford Michael adducts 3 (Table 1). For instance, the triethylamine-mediated addition of allylmercaptan (2) to enone 1a provided Michael adduct 3a in 64 % yield (Table 1, Entry 1). When 3a was heated in toluene at reflux for 4 d, an IMDAF reaction took place to afford adducts 4a and 5a in 67 % total yield and an 86:14 ratio.…”

“…In a similar fashion, enone 1b was subjected to the conjugate addition of allylmercaptan (2) to afford 1,4-adduct 3b in comparable yield (63 %, Table 1, Entry 2). Subsequently, 3b was transformed into the IMDAF adducts 4b and 5b in 59 % yield and an 87:13 ratio.…”

“…Despite the fact that the IM-DAF reaction time was shorter (3 d), similar reaction conditions were suitable for Michael acceptor 1c possessing two Table 1. Michael addition of allylmercaptan (2) to β-furyl enones 1a-c followed by the IMDAF reaction of the Michael adducts 3a-c. [a] Isolated yield after purification by silica gel column chromatography.…”

“…Intramolecular Diels-Alder (IMDA) reactions have received great attention, as the two bonds formed simultaneously result in two new rings making it an excellent strategy for the synthesis of polycycles including natural products. [1,2] Although various diene components have been employed in IMDA reactions, the furan diene has figured prominently in the literature because of its reactivity and the cleavage options available for the product oxanorbornene. [3,4] However, the requirement of multi-step reactions to obtain suitable precursors is a major impediment to this otherwise attractive synthetic strategy.…”