C₃‐Thioester/‐Ester Substituted Linear Dienones: A Pluripotent Molecular Platform for Diversification via Cascade Pericyclic Reactions

Abstract

Substituted oxabicyclo derivatives bearing two quaternary carbon centers and five contiguous stereocenters have been synthesized from C3‐thioester/‐ester substituted dienones, a simple and linear pluripotent molecular platform. The conversion proceeds from neat reactants, possibly via a thermally‐driven pericyclic cascade manifold involving sequential (E)‐s‐trans to (E)‐s‐cis isomerization, oxa‐6π‐electrocyclization, and intermolecular, regioselective [4π+2π] cycloaddition. The proposed mechanism has been substantiated by intermediate trapping experiments and DFT studies. Such dienones have also been exploited to effect stereoselective cross Diels‐Alder cycloadditions with olefins and sequential Diels‐Alder/retro‐Diels‐Alder reactions with activated alkynes. The reaction is greatly influenced by the substituent effect exerted by the C3‐thioester/‐ester group.

Recent Advances in Oxa-6π Electrocyclization Reactivity for the Synthesis of Privileged Natural Product Scaffolds

“…Aside from these steric factors, the oxa-6π electrocyclic ring-closure is also favored towards 2H-(benzo)pyrans 2 by the presence of either electron-withdrawing groups at the C5 and/or C6 positions (reduced nucleophilicity of the enol ether moiety), or the stabilizing π-aromaticity of arenes (C5-C6) [18,19]. For most oxatriene substrates 1 which do not possess the stereoelectronic characteristics mentioned above, the oxa-6π electrocyclic ring-closure is often reversible unless being funneled through a cascade reaction [20,21]. As such, the total synthesis of (+)-torreyanic acid by Porco involving a oxa-6π electrocyclization/Diels−Alder cycloaddition cascade rapidly became a classic biomimetic reaction demonstrating how a 2H-pyran can be seamlessly transformed into a much more complex natural scaffold (Scheme 2).…”

Recent Advances in the Synthesis and Applications of α‐Ketothioesters

“… [54] The difference in reactivity between Wittig reagents 84 (Scheme 44) and phosphonates 50 (Scheme 28) may be explained on the basis of the presence of a base (NaH) in Horner‐Wadsworth‐Emmons olefination, in which the base may accelerate the E to Z isomerization and subsequent cyclization reaction (Scheme 29). 3‐Thioester substituted 2,4‐dienones and ‐dienals 85 , two pluripotent molecular platforms, are versatile intermediates for generating structural complexity and this has enabled the invention of a wide variety of novel new bond‐forming protocols via a series of activation modes with or without visible light [69–72] …”

“…3-Thioester substituted 2,4-dienones and -dienals 85, two pluripotent molecular platforms, are versatile intermediates for generating structural complexity and this has enabled the invention of a wide variety of novel new bond-forming protocols via a series of activation modes with or without visible light. [69][70][71][72] Harada, Nishida, and co-workers were the first to utilize α-ketothioester 4 bn as a nucleophilic ene moiety in an enantioselective carbonyl-ene-type cyclization catalyzed by 5 mol% chiral copper-BOX complex (Scheme 45). [73] The reaction gave chiral indenol 87 possessing a tetrasubstituted carbon with good yield and moderate enantioselectivity.…”

“…In this section, the selective reactions at the ketone centre with Wittig reagents, copper‐catalyzed carbonyl‐ene‐type cyclization, and triphenylphosphine‐catalyzed cyclization with acetylenedicarboxylates will be addressed (Section 3.3.) [54,69–78] . Reactions involving unsaturated bonds (C=C/C≡C) and carbonyl centres [C(O)/C(O)S] in β,γ‐unsaturated α‐ketothioesters will be discussed in gold‐catalyzed cyclization and ZnI 2 ‐catalyzed hetero Diels‐Alder reactions with olefins (Section 3.4.)…”

“…In this section, the selective reactions at the ketone centre with Wittig reagents, copper-catalyzed carbonyl-ene-type cyclization, and triphenylphosphine-catalyzed cyclization with acetylenedicarboxylates will be addressed (Section 3.3.). [54,[69][70][71][72][73][74][75][76][77][78] Reactions involving unsaturated bonds (C=C/C�C) and carbonyl centres [C(O)/C(O)S] in β,γ-unsaturated α-ketothioesters will be discussed in gold-catalyzed cyclization and ZnI 2 -catalyzed hetero Diels-Alder reactions with olefins (Section 3.4.). [36,79] In the next section, chemoselective reduction of various functionalities such as the keto group, thioester moiety, C=C bond, or the enone moiety of α-keto thioesters or its β,γ-unsaturated analogues in the presence of other reducible functional groups will be reported (Section 3.5).…”