Mechanistic Insights on Pd-Catalyzed Three-Component Reactions of Alkynols, Methyl Orthoformate, and Salicylaldehyde Derivatives. Application to the Synthesis of Steroid Chroman Ketals and Spiroketals with Antioxidant Activity.

Contrary to our previous report in which a Pd-catalyzed three-component reaction of a steroid alkynol, trimethyl orthoformate, and salicylaldehyde exclusively produced chroman ketals, the same reaction employing 2,5-dihydroxysalicylaldehyde led to a mixture of a chroman ketal and a spiroketal. Provided that both courses of the reaction imply a 4 + 2 inverse demand cycloaddition between an o-quinone methide and an enol ether, density functional theory calculations revealed that the chroman ketal/spiroketal selectivity is governed by both, the rate of the formation of the o-quinone methide and the isomerization of the initially produced exocyclic enol ether─that led to the spiroketal─to its endocyclic partner that produces the chroman ketal. Remarkably, Lewis catalysis is central to the observed reactivity, and the availability of plausible catalytic species controls the overall chemoselectivity. The methodology herein applied and scrutinized enriches the palette of reactions, leading to increased molecular complexity, as demonstrated in the obtained products, whose antioxidant activity and detailed NMR characterization are presented.

A Visible Light Ru-Catalyzed Photoredox Access to Substituted Dihydrofurans.

An efficient, visible light Ru(bpy)3Cl2-catalyzed method for the preparation of 2,3-dihydrofurans is reported. This approach employs 2-bromoketoesters as radical precursors and alkyl enol ethers as acceptors. The photoredox cycle furnishes an oxonium ion that is captured by an internal nucleophile to render the corresponding dihydrofurans. Moreover, the obtained products contain a versatile acetal moiety at C-2, allowing its transformation into a diverse variety of heteroaromatic and nonaromatic compounds. This method could serve as an important tool in the synthesis of complex tetrahydro- and dihydrofurans as well as heteroaromatic structures.

Dibromo-BODIPY as an Organic Photocatalyst for Radical-Ionic Sequences.

A new dibrominated 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) is reported as a new metal-free photocatalyst. This BODIPY showed similar optoelectronic, electrochemical, and performance properties to those of Ru(bpy)3Cl2, one of the most common photocatalysts in a known radical-ionic transformation, such as the formation of 1,4-dicarbonyl compounds. Moreover, additional sequences in which the generated oxonium ion is trapped by an internal nucleophile were developed using this BODIPY photocatalyst. These new sequences allowed the straightforward preparation of γ-alkoxylactones, monoprotected 1,4-ketoaldehydes, and dihydrofurans. This new catalyst, the methodology, and the forged functional groups could be important tools in organic synthesis.

Stereocontrolled Nucleophilic Addition to Five-Membered Oxocarbenium Ions Directed by the Protecting Groups. Application to the Total Synthesis of (+)-Varitriol and of Two Diastereoisomers Thereof.

A stereodivergent C-glycosidation of carbohydrate-derived lactones can be mediated by the protecting groups and applied to the total synthesis of (+)-varitriol and of two diastereoisomers thereof, which represent an unprecedent use of the protecting groups in the synthesis of a naturally occurring compound. In particular, the stereoselective nucleophile attack for 2,3-trans-substituted five-membered ring oxocarbenium ions is strongly influenced by the presence of aromatic rings in the protecting groups. According to quantum chemical calculations, the stereoselectvity depends on the π-π interactions between the aromatic ring of the C-2 protecting group with the exocyclic triple bond and the oxocarbenium ion. These interactions account for the stabilization of the conformer in which the C-2 and C-3 substituents adopt pseudoaxial orientations. When protecting groups do not contain an aromatic ring, the sterochemical outcome is dictated by stereoelectronic factors established by the Woerpel's model. Based on these findings, a concise total synthesis of the natural product (+)-varitriol and of two diastereoisomers was acomplished.

Gd(OTf)3-catalyzed synthesis of geranyl esters for the intramolecular radical cyclization of their epoxides mediated by titanocene(III).

A selective and mild method for the esterification of a variety of carboxylic acids with geraniol is developed. We demonstrated that the use of triphenylphosphine, I2, 2-methylimidazole or imidazole and a catalytic amount of Gd(OTf)3 resulted to be more active than the previous protocols, providing a 16-membered library of geranyl esters in higher yields and in shorter reaction times. The use of essential oil of palmarosa (Cymbopogon martinii), enriched with geraniol, as a raw material for the synthesis of the target compounds complemented and proved how sustainable and eco-friendly this protocol is. Finally, the selective 6,7-epoxidation of the obtained geranyl esters led us to study their regio-controlled radical cyclization mediated by titanocene(III) for the synthesis of novel (8-hydroxy-9,9-dimethyl-5-methylene cyclohexyl)methyl esters in moderate yields and with excellent stereoselectivities.

Electrospray ionization tandem mass spectrometry of 4-aryl-3,4-dihydrocoumarins.

We have investigated the gas-phase fragmentation reactions of 11 synthetic 4-aryl-3,4-dihydrocoumarins by electrospray ionization tandem mass spectrometry (ESI-MS/MS) on a quadrupole-time-of flight (Q-TOF) hybrid mass spectrometer. We have also estimated thermochemical data for the protonated coumarins (precursor ion A) and product ion structures by computational chemistry at a B3LYP level of theory to establish the ion structures and to rationalize the fragmentation pathways. The most abundant ions in the product ion spectra of coumarins 1-11 resulted from C8H8O2, CO2, C4H4O3, C8H10O3, C8H8O2, and CH3OH eliminations through retro-Diels-Alder (RDA) reactions, remote hydrogen rearrangements (ß-eliminations), and ß-lactone ring contraction. Although the investigated coumarins shared most of the fragmentation pathways, formation of a benzylic product ion and its corresponding tropylium ion was diagnostic of the substituents at ring C. The thermochemical data revealed that the nature and position of the substituents at ring C played a key role in the formation of this product ion and determined its relative intensity in the product ion spectrum. The results of this study contribute to knowledge of the gas-phase ion chemistry of this important class of organic compounds.

Visible-Light Photocatalytic Preparation of 1,4-Ketoaldehydes and 1,4-Diketones from α-Bromoketones and Alkyl Enol Ethers.

A Ru2+-photocatalyzed, visible-light-mediated ATRA reaction for the straightforward preparation of 1,4-ketoaldehydes, 1,4-diketones, and 1,4-ketoesters, which are of difficult access by other means, is reported herein. This method employs readily accessible α-bromoketones and alkyl vinyl ethers as starting materials, allowing the construction of secondary, tertiary, and challenging quaternary centers. In addition, the synthetic usefulness of this method is illustrated by applying it to the construction of substituted pyrroles.