title: Cyclobutenes: At a Crossroad between Diastereoselective Syntheses of Dienes and Unique Palladium-Catalyzed Asymmetric Allylic Substitutions.
abstract: The rich chemistry of cyclobutanes is underpinned by a large body of synthetic literature devoted to their synthesis and decoration. This is motivated by the widespread representation of cyclobutane moieties in biologically active natural products and man-made molecules. Surprisingly, this vast array of knowledge finds no parallel in the chemistry of cyclobutenes, their unsaturated analogues. In particular, a dearth of methods to synthesize enantioenriched cyclobutenes is apparent upon cursory investigation of the literature. As a leading example, the photocycloaddition of maleic anhydride to acetylene or dichloroethylene, probably a benchmark of cyclobutene synthesis, delivers a meso cyclic anhydride which can be further converted to a cyclobutene product by enantioselective desymmetrization by ring opening. Nonetheless, such an approach delivers products with a rather inflexible substitution pattern around the four-membered ring. The lack of general approaches has motivated our group and others to develop novel routes to cyclobutene scaffolds, leading to the development of a strategy that combines photochemistry and catalysis. Indeed, we have coupled the simple and efficient photochemical isomerization of 2-pyrone into a strained bicyclo[2.2.0] lactone with palladium-catalyzed allylic alkylation as a simple and versatile access to functionalized cyclobutenes. Several nucleophiles can be added to the activated, strained intermediate, including malonate anions and azlactones. The products are mono- and bicyclic building blocks richly decorated with functional groups. Importantly, they are formed with high levels of diastereoselectivity as expected by the tenets of palladium-catalyzed allylic alkylation, which posit that the oxidative addition and nucleophilic capture steps proceed with inversion of configuration, resulting in overall retention (inversion + inversion). However, the transposition of the methodology to an asymmetric version subsequently led to the surprising discovery of a family of highly enantioselective, diastereodivergent catalytic processes. Indeed, we observed a ligand-dependent stereochemical outcome for a range of palladium-catalyzed allylic alkylations affording either overall retention or overall inversion of configuration, and that with very high levels of enantio- and diastereoselectivity. The new family of diastereodivergent reactions enables the conversion of the aforementioned racemic bicyclo[2.2.0] lactone into each of 4 stereoisomeric products, at will. Although the mechanistic details at the origin of this unusual stereodivergence are not yet fully elucidated, it became clear through our studies that unique Pd-allyl complexes, residing preferentially as their σ-(monohapto)-bound isomers, are at the heart of the process. The cyclobutenes prepared can also engage in electrocyclic ring-opening reactions (often spontaneous depending on the substitution pattern) that link this chemistry with that of diene and polyene frameworks. Using the strategies laid out above, our group was then able to harness the high stereospecificity of electrocyclic reactions and design modular syntheses of several natural products and natural product fragments. We believe that the methods presented herein shall soon pave the way for the streamlined synthesis of more complex polyenic natural products.
authors: University of Vienna , Institute of Organic Chemistry, Währinger Straße 38, 1090 Vienna, Austria.
authors: Antonio
authors: A
authors: Misale
authors: University of Vienna , Institute of Organic Chemistry, Währinger Straße 38, 1090 Vienna, Austria.
authors: Supaporn
authors: S
authors: Niyomchon
authors: University of Vienna , Institute of Organic Chemistry, Währinger Straße 38, 1090 Vienna, Austria.
authors: Nuno
authors: N
authors: Maulide
mesh_terms: D000466:Alkadienes / Q000138:chemical synthesis*; D000478:Alkylation; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D002384:Catalysis; D056831:Coordination Complexes / Q000737:chemistry; D003503:Cyclobutanes / Q000138:chemical synthesis* / Q000737:chemistry*; D007783:Lactones / Q000737:chemistry; D008024:Ligands; D010165:Palladium / Q000737:chemistry*; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry
chemical_list: D000466:Alkadienes; D019086:Bridged Bicyclo Compounds, Heterocyclic; D056831:Coordination Complexes; D003503:Cyclobutanes; D007783:Lactones; D008024:Ligands; D010165:Palladium; D015032:Zinc