Discovery and bioinspired total syntheses of unprecedented sesquiterpenoid dimers unveiled bifurcating [4 + 2] cycloaddition and target differentiation of enantiomers.

[4 + 2] cycloaddition has led to diverse polycyclic chiral architectures, serving as novel sources for organic synthesis and biological exploration. Here, an unprecedented class of cadinane sesquiterpene [4 + 2] dimers, henryinins A-E (1-5), with a unique 6/6/6/6/6-fused pentacyclic system, were isolated from Schisandra henryi. The divergent total syntheses of compounds 1-5 and their enantiomers (6-10) were concisely accomplished in eight linear steps using a protection-free approach. Mechanistic studies illustrated the origin of selectivity in the key [4 + 2] cycloaddition as well as the inhibition of reaction pathway bifurcation via desymmetrization. The chemical proteomics results showed that a pair of enantiomers shared common targets (PRDX5 C100 and BLMH C73) and had unique targets (USP45 C588 for 4 and COG7 C419 for 9). This work provides experimental evidence for the discovery of unprecedented cadinane dimers from selective Diels-Alder reaction and a powerful strategy to explore the biological properties of natural products.

Reductive Catalytic Difluorocarbene Transfer via Palladium Catalysis.

A palladium-catalyzed reductive difluorocarbene transfer reaction that tames difluorocarbene to couple with two electrophiles has been developed, representing a new mode of difluorocarbene transfer reaction. The approach uses low-cost and bulk industrial chemical chlorodifluoromethane (ClCF2 H) as the difluorocarbene precursor. It produces a variety of difluoromethylated (hetero)arenes from widely available aryl halides/triflates and proton sources, featuring high functional group tolerance and synthetic convenience without preparing organometallic reagents. Experimental mechanistic studies reveal that an unexpected Pd0/II catalytic cycle is involved in this reductive reaction, wherein the oxidative addition of palladium(0) difluorocarbene ([Pd0 (Ln )]=CF2 ) with aryl electrophile to generate the key intermediate aryldifluoromethylpalladium [ArCF2 Pd(Ln )X], followed by reaction with hydroquinone, is responsible for the reductive difluorocarbene transfer.

Theoretical Study on the Origin of Abnormal Regioselectivity in Ring-Opening Reaction of Hexafluoropropylene Oxide.

That nucleophiles preferentially attack at the less sterically hindered carbon of epoxides under neutral and basic conditions has been generally accepted as a fundamental rule for predicting the regioselectivity of this type of reaction. However, this rule does not hold for perfluorinated epoxides, such as hexafluoropropylene oxide (HFPO), in which nucleophiles were found to attack at the more hindered CF3 substituted ß-C rather than the fluorine substituted α-C. In this contribution, we aim to shed light on the nature of this intriguing regioselectivity by density functional theory methods. Our calculations well reproduced the observed abnormal regioselectivities and revealed that the unusual regiochemical preference for the sterically hindered ß-C of HFPO mainly arises from the lower destabilizing distortion energy needed to reach the corresponding ring-opening transition state. The higher distortion energy required for the attack of the less sterically hindered α-C results from a significant strengthening of the C(α)-O bond by the negative hyperconjugation between the lone pair of epoxide O atom and the antibonding C-F orbital.

Enzymatic α-Ketothioester Decarbonylation Occurs in the Assembly Line of Barbamide for Skeleton Editing.

The decarbonylation reaction has been developed significantly in organic chemistry as an effective approach to various synthetic applications, but enzymatic precedents for this reaction are rare. Based on investigations into the hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly line of barbamide, we report an on-line α-ketothioester decarbonylation reaction that leads to one-carbon truncation of the elongating skeleton. This enzymatic editing reaction occurs in the first round of lipopeptide extension and modification involving the multienzymes BarE and BarF, which successively house an NRPS module to initiate the biosynthesis and a PKS module to catalyze the first round of chain extension. Starting with processing a leucine-derived α-ketoacyl starter, the ketosynthase domain in BarE displays an unusual dual activity that results in net one-carbon chain elongation. It extrudes carbon monoxide from α-keto-isocaproyl thioester and then mediates decarboxylative condenses of the resultant isovaleryl thioester with malonyl thioester to form a diketide intermediate, followed by BarF-based O-methylation to stabilize the enol form of the ß-carbonyl and afford an unusual E-double bond. Biochemical characterization, chemical synthesis, computational analysis, and the experimental outcome of site-directed mutagenesis illustrate the extraordinary catalytic capability of this ketosynthase domain. This work furthers the appreciation of assembly line chemistry and opens the door to new approaches for skeleton editing/engineering of related molecules using synthetic biology approaches.

Difluoromethylation of Unactivated Alkenes Using Freon-22 through Tertiary Amine-Borane-Triggered Halogen Atom Transfer.

The application of abundant and inexpensive fluorine feedstock sources to synthesize fluorinated compounds is an appealing yet underexplored strategy. Here, we report a photocatalytic radical hydrodifluoromethylation of unactivated alkenes with an inexpensive industrial chemical, chlorodifluoromethane (ClCF2H, Freon-22). This protocol is realized by merging tertiary amine-ligated boryl radical-induced halogen atom transfer (XAT) with organophotoredox catalysis under blue light irradiation. A broad scope of readily accessible alkenes featuring a variety of functional groups and drug and natural product moieties could be selectively difluoromethylated with good efficiency in a metal-free manner. Combined experimental and computational studies suggest that the key XAT process of ClCF2H is both thermodynamically and kinetically favored over the hydrogen atom transfer pathway owing to the formation of a strong boron-chlorine (B-Cl) bond and the low-lying antibonding orbital of the carbon-chlorine (C-Cl) bond.

Cysteine-Activated Small-Molecule H2Se Donors Inspired by Synthetic H2S Donors.

The importance of selenium (Se) in biology and health has become increasingly clear. Hydrogen selenide (H2Se), the biologically available and active form of Se, is suggested to be an emerging nitric oxide (NO)-like signaling molecule. Nevertheless, the research on H2Se chemical biology has technique difficulties due to the lack of well-characterized and controllable H2Se donors under physiological conditions, as well as a robust assay for direct H2Se quantification. Motivated by these needs, here, we demonstrate that selenocyclopropenones and selenoamides are tunable donor motifs that release H2Se upon reaction with cysteine (Cys) at pH 7.4 and that structural modifications enable the rate of Cys-mediated H2Se release to be tuned. We monitored the reaction pathways for the H2Se release and confirmed H2Se generation qualitatively using different methods. We further developed a quantitative assay for direct H2Se trapping and quantitation in an aqueous solution, which should also be operative for investigating future H2Se donor motifs. In addition, we demonstrate that arylselenoamide has the capability of Cys-mediated H2Se release in cellular environments. Importantly, mechanistic investigations and density functional theory (DFT) calculations illustrate the plausible pathways of Cys-activated H2Se release from arylselenoamides in detail, which may help understand the mechanistic issues of the H2S release from pharmacologically important arylthioamides. We anticipate that the well-defined chemistries of Cys-activated H2Se donor motifs will be useful for studying Se biology and for development of new H2Se donors and bioconjugate techniques.

Cleaving arene rings for acyclic alkenylnitrile synthesis.

Synthetic chemistry is built around the formation of carbon-carbon bonds. However, the development of methods for selective carbon-carbon bond cleavage is a largely unmet challenge1-6. Such methods will have promising applications in synthesis, coal liquefaction, petroleum cracking, polymer degradation and biomass conversion. For example, aromatic rings are ubiquitous skeletal features in inert chemical feedstocks, but are inert to many reaction conditions owing to their aromaticity and low polarity. Over the past century, only a few methods under harsh conditions have achieved direct arene-ring modifications involving the cleavage of inert aromatic carbon-carbon bonds7,8, and arene-ring-cleavage reactions using stoichiometric transition-metal complexes or enzymes in bacteria are still limited9-11. Here we report a copper-catalysed selective arene-ring-opening reaction strategy. Our aerobic oxidative copper catalyst converts anilines, arylboronic acids, aryl azides, aryl halides, aryl triflates, aryl trimethylsiloxanes, aryl hydroxamic acids and aryl diazonium salts into alkenyl nitriles through selective carbon-carbon bond cleavage of arene rings. This chemistry was applied to the modification of polycyclic aromatics and the preparation of industrially important hexamethylenediamine and adipic acid derivatives. Several examples of the late-stage modification of complex molecules and fused ring compounds further support the potential broad utility of this methodology.

Highly γ-Selective Arylation and Carbonylative Arylation of 3-Bromo-3,3-difluoropropene via Nickel Catalysis.

A nickel-catalyzed highly γ-regioselective arylation and carbonylative arylation of 3-bromo-3,3-difluoropropene has been developed. The reaction proceeds under mild reaction conditions, providing the gem-difluoroalkenes with high efficiency and good functional group tolerance. The resulting gem-difluoroalkenes can serve as versatile building blocks for diversified synthesis. Preliminary mechanistic studies and density functional theory calculations reveal that both non-radical and radical pathways are possible for the reaction, and the radical pathway is more likely. The high γ-regioselectivity results from the ß-bromide elimination of alkylnickel(II) species or from the reductive elimination of nickel(III) species [(aryl)(CF2 =CHCH2 )NiIII (Ln )X]. The γ-selective carbonylation of 3-bromo-3,3-difluoropropene under 1 atm CO gas also provides a new way for nickel-catalyzed carbonylation.

Biomimetic Total Synthesis of (±)-Carbocyclinone-534 Reveals Its Biosynthetic Pathway.

Carbocyclinone-534 is a new antibiotic produced after the metabolism of tapinarof. We identify a biomimetic total synthesis of carbocyclinone-534 in eight steps by taking advantage of an intermolecular Diels-Alder homodimerization/dehydrogenation/intramolecular Diels-Alder cycloaddition cascade. This synthetic sequence provides direct experimental evidence for revealing the biosynthetic pathway of carbocyclinone-534.

Mechanism and Origins of Enantioselectivities in Spirobiindane-Based Hypervalent Iodine(III)-Induced Asymmetric Dearomatizing Spirolactonizations.

The work of Kita et al. on asymmetric oxidative dearomatization of naphthol carboxylic acids to spirolactones mediated/catalyzed by a novel, conformationally rigid µ-oxo-bridged hypervalent iodine(III) species is a landmark discovery in enantioselective iodine(III) catalysis [Kita, Y.; et al. Angew. Chem., Int. Ed. 2008, 47, 3787. DOI: 10.1002/anie.200800464 ; J. Am. Chem. Soc. 2013, 135, 4558. DOI: 10.1021/ja401074u ]. We have investigated the detailed mechanism of this important transformation using density functional theory. Calculations revealed that proton transfer from the pendant carboxylic acid of naphthols to the bridging oxygen atom or the ligand of iodine(III) species, which enhances the nucleophilicity of the carboxylic oxygen and the nucleofugality of the iodoarene, is crucial for the dearomatizing spirolactonization. Halogen bonding between the resulting carboxylate and the electron-deficient iodine(III) center further stabilizes the dearomatizing spirolactonization transition states. Calculations also revealed a long-neglected cleaved µ-oxo iodine(III) species that is more reactive but less selective than the µ-oxo-bridged hypervalent iodine(III) species itself for the oxidative dearomatization of naphthols. The coexistence of two sequential dearomatizing spirolactonization processes in the reaction system results in a lower enantioselectivity. A new stereochemical model that is able to reproduce and rationalize the observed apparent enantioselectivities is proposed.

Origin of Stereocontrol in Photoredox Organocatalysis of Asymmetric α-Functionalizations of Aldehydes.

The merger of the common photoredox catalyst Ru(bpy)3Cl2 with an imidazolidinone organocatalyst by MacMillan et al. has enabled a series of highly enantioselective α-functionalizations of aldehydes, a landmark discovery in photoredox organocatalysis. Herein, we present the theoretical investigation into the origin of enantioselectivity in asymmetric radical additions to the MacMillan imidazolidinone enamines, the key stereocontrolling step in photoredox organocatalysis of asymmetric α-functionalizations of aldehydes. The calculations reveal a hidden but crucial role of E-cis enamine in enantiocontrol. The enantioselectivity in the radical additions is mainly determined by steric effects. A model based on the pseudo C2-symmetric arrangement of the methyl and tert-butyl moieties on the catalyst is proposed. This rationalizes the stereoselective outcome of these reactions and provides a good model to understand MacMillan's imidazolidinone/photoredox dual catalysis. The insights obtained from this study should be valuable in future efforts toward the design and development of new enantioselective catalytic radical reactions.