Friedel-Crafts-Type Arylation Strategy for the Conversion of Alkyl 2-((Diphenoxyphosphoryl)oxy)-2-arylacetates to α,α-Diaryl Esters.

An arylation strategy allowing the conversion of alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates to α,α-diaryl esters is reported. This transformation can be promoted by TfOH when the starting organic phosphates do not carry para-alkoxy groups on their aryl rings, but it does not require any additives when such groups are present. These alkyl 2-((diphenoxyphosphoryl)oxy)-2-arylacetates can be readily accessed from the insertion of diphenyl phosphate into aryldiazoacetates.

An aza-Robinson Annulation Strategy for the Synthesis of Fused Bicyclic Amides: Synthesis of (±)-Coniceine and Quinolizidine.

An aza-Robinson annulation strategy is described using a NaOEt-catalyzed conjugate addition of cyclic imides onto vinyl ketones, followed by a TfOH-mediated intramolecular aldol condensation to afford densely functionalized fused bicyclic amides. The potential use of these amides in the synthesis of alkaloids is demonstrated by the sequential conversion of appropriate precursors to (±)-coniceine and quinolizidine in two additional steps, thus allowing their preparation in overall 40 and 44% yields, respectively.

Visible light-mediated photolysis of organic molecules: the case study of diazo compounds.

Considering the recent rapid advancement of synthetic technologies promoted by visible light in the last 15 years, the use of photocatalysts has been rightfully justified based on the fact that organic molecules generally do not absorb visible light. However, an increasing number of different classes of organic molecules is being identified as actually directly absorbing in this region of the electromagnetic spectrum. Among them, diazo compounds are possibly one of these classes whose chemistry has been more explored so far. Indeed, irradiation of these compounds with visible light has been introduced as a mild photolytic strategy generally leading to free carbene intermediates. This strategy not only allows for a more cost-economical approach revealing similar outcomes to some previously reported thermal, metal-catalyzed transformations; but it can also eventually lead to different reactivities. Herein, we will present the contributions of our laboratory and of other groups to this research area, along with some important elements of design behind the development of selected reaction profiles, aiming to provide the reader with an overall view of the current state of the art.

H-F bond insertions into α-diazo carbonyl compounds.

A reaction for H-F bond insertion into α-diazo carbonyl compounds is reported. The protocol describes a simple reaction setup employing commercially available HF·pyr (Olah reagent) as the fluorine source. The method is rapid and practical, and allows access to a broad range of α-fluorinated carbonyl compounds in generally good yields.

A Selective C-C Bond Cleavage Strategy Promoted by Visible Light.

A new visible-light-promoted reaction between aryldiazoacetates and 1,3-diketones allows good yields and selectivities for C-C bond insertions, leading to the corresponding 1,4-dicarbonyl compounds. This transformation is straightforward and highly practical. It tolerates air and moisture and does not require the use of any metals. Mechanistic investigations support the involvement of a key cyclopropanol intermediate derived from an intramolecular rearrangement.

Visible-Light-Mediated Strategies to Assemble Alkyl 2-Carboxylate-2,3,3-Trisubstituted ß-Lactams and 5-Alkoxy-2,2,4-Trisubstituted Furan-3(2H)-ones Using Aryldiazoacetates and Aryldiazoketones.

Two new visible-light-mediated strategies are described starting from aryldiazoacetates. The first approach describes their reaction with azides to afford the corresponding imines, and then reaction with aryldiazoketones produces alkyl 2-carboxylate-2,3,3-trisubstituted ß-lactams. The second approach describes the reaction with sulfoxides to afford the corresponding sulfoxonium ylides, followed by reaction with aryldiazoketones to produce 5-alkoxy-2,2,4-trisubstituted furan-3(2H)-ones. These protocols take advantage of the photolysis of aryldiazoacetates and the photochemically promoted Wolff rearrangement of aryldiazoketones.

Visible-Light-Mediated Strategies for the Preparation of Oxime Ethers Derived from O-H Insertions of Oximes into Aryldiazoacetates.

Two visible-light-mediated O-H insertion protocols involving oximes and aryldiazoacetates leading to different products depending on the solvent employed are reported. In DCM, direct O-H insertion takes place. In THF, there is the additional incorporation of the ring-opened form of this solvent into the structure of the product. These metal-free protocols are mild and tolerant to air and moisture. The preparation of an acaricide has been developed as an example of synthetic application.

The chemistry and biology of guanidine secondary metabolites.

Covering: 2017-2019Guanidine natural products isolated from microorganisms, marine invertebrates and terrestrial plants, amphibians and spiders, represented by non-ribosomal peptides, guanidine-bearing polyketides, alkaloids, terpenoids and shikimic acid derived, are the subject of this review. The topics include the discovery of new metabolites, total synthesis of natural guanidine compounds, biological activity and mechanism-of-action, biosynthesis and ecological functions.

Visible light-promoted reactions with diazo compounds: a mild and practical strategy towards free carbene intermediates.

Carbenes are important intermediates in organic chemistry and have been widely applied in various types of organic reactions, ranging from cycloaddition reactions and sigmatropic rearrangements to C-H functionalizations, thus allowing the rapid construction of densely functionalized molecules. Over the past decades, remarkable progress has been achieved in metal-catalyzed carbene transfer reactions. Nevertheless, realizing these transformations under milder and/or greener conditions is still highly desirable. Only recently, visible light-promoted carbene transfer reactions of diazo compounds via free carbene intermediates have emerged as a practical, mild and powerful tool. In this tutorial review, we summarize the latest advances in the area, aiming at providing a clear overview on reaction design, mechanistic scenarios and potential future developments.

Nonlinear Biosynthetic Assembly of Alpiniamide by a Hybrid cis/trans-AT PKS-NRPS.

Alpiniamide A is a linear polyketide produced by Streptomyces endophytic bacteria. Despite its relatively simple chemical structure suggestive of a linear assembly line biosynthetic construction involving a hybrid polyketide synthase-nonribosomal peptide synthetase enzymatic protein machine, we report an unexpected nonlinear synthesis of this bacterial natural product. Using a combination of genomics, heterologous expression, mutagenesis, isotope-labeling, and chain terminator experiments, we propose that alpiniamide A is assembled in two halves and then ligated into the mature molecule. We show that each polyketide half is constructed using orthogonal biosynthetic strategies, employing either cis- or trans-acyl transferase mechanisms, thus prompting an alternative proposal for the operation of this PKS-NRPS.

Room Temperature Coupling of Aryldiazoacetates with Boronic Acids Enhanced by Blue Light Irradiation.

A visible-light-promoted photochemical protocol is reported for the coupling of aryldiazoacetates with boronic acids. This photochemical reaction shows great enhancement compared to the same protocol performed in the absence of light. Except for a few cases, the room temperature coupling in the dark (thermal process) generally does not work. When it does, it is likely to also involve free carbenes as key intermediates. Alternatively, photochemical reactions show a broad scope, can be performed under air and tolerate a wide variety of functional groups. Reaction-evolution monitoring, DFT calculations and control experiments have been used to evaluate the main aspects of this intricate mechanistic scenario. Biologically active molecules Adiphenine, Benactyzine and Aprophen have been prepared as examples of synthetic applications.

Activating Imides with Triflic Acid: A General Intramolecular Aldol Condensation Strategy Toward Indolizidine, Quinolizidine, and Valmerin Alkaloids.

A simple, inexpensive, step economic, and highly modular synthetic strategy to access izidine alkaloids is described. The key step is a TfOH-promoted intramolecular aldol condensation between enol and cyclic imide moieties. This cyclization strategy can be employed within an aza-Robinson annulation framework and represents a general tool to build fused bicyclic amines. To illustrate the power of this method, we describe the preparation of (±)-coniceine, (±)-quinolizidine, (±)-tashiromine, (±)-epilupinine, and the core of (±)-valmerins.

Preparation of Organic Nitrates from Aryldiazoacetates and Fe(NO3)3·9H2O.

A thermal protocol is reported for the formal insertion of nitric acid into aryldiazoacetates using Fe(NO3)3·9H2O. This strategy is mild and high yielding and allows the preparation of a large variety of members of an unprecedented family of organic nitrates. The nitrate group can be also readily transformed into other functional groups and heterocyclic moieties and can possibly allow new biological explorations of untapped potential associated with their NO-releasing ability.

Blue light-promoted photolysis of aryldiazoacetates.

Aryldiazoacetates can undergo photolysis under blue light irradiation (460-490 nm) at room temperature and under air in the presence of numerous trapping agents, such as styrene, carboxylic acids, amines, alkanes and arenes, thus providing a straighforward and general platform for their mild functionalization.

Unusual mechanisms in Claisen rearrangements: an ionic fragmentation leading to a meta-selective rearrangement.

A mechanistic investigation of the acid-catalysed redox-neutral oxoarylation reaction of ynamides using electrospray ionisation mass-spectrometry (ESI-MS) and quantum chemical calculations (DFT and MP2) is presented. This study reveals the diversity of pathways and products available from an otherwise deceptively simple-looking, classical transformation: fragmentation, an unusual meta-arylation and competing α-carbonyl cation pathways are some of the alternatives unveiled by ESI-MS and mechanistic experiments. Detailed calculations explain the observed trends and rationalise the results.

General Protocol to Obtain D-Glucosamine from Biomass Residues: Shrimp Shells, Cicada Sloughs and Cockroaches.

A general protocol is developed to obtain D-glucosamine from three widely available biomass residues: shrimp shells, cicada sloughs, and cockroaches. The protocol includes three steps: (1) demineralization, (2) deproteinization, and (3) chitin hydrolysis. This simple, general protocol opens the door to obtain an invaluable nitrogen-containing compound from three biomass residues, and it can potentially be applied to other chitin sources. White needle-like crystals of pure D-glucosamine are obtained in all cases upon purification by crystallization. Characterization data (NMR, IR, and mass spectrometry) of D-glucosamine obtained from the three chitin sources are similar and confirm its high purity. NMR investigation demonstrates that D-glucosamine is obtained mainly as the α-anomer, which undergoes mutarotation in aqueous solution achieving equilibrium after 440 min, in which the anomeric glucosamine distribution is 60% α-anomer and 40% ß-anomer.

An Aminocatalyzed Michael Addition/Iron-Mediated Decarboxylative Cyclization Sequence for the Preparation of 2,3,4,6-Tetrasubstituted Pyridines: Scope and Mechanistic Insights.

A novel, scalable strategy for the preparation of 2,3,4,6-tetrasubstituted pyridines is described. This protocol has two steps: an aminocatalyzed addition of ketones to alkylidene isoxazol-5-ones, followed by an iron-mediated decarboxylative cyclization event. Mechanistic insights for both steps are provided based on HRMS-ESI(+) studies.

Rhodium- and Non-Metal-Catalyzed Approaches for the Conversion of Isoxazol-5-ones to 2,3-Dihydro-6H-1,3-oxazin-6-ones.

Two approaches were developed for the conversion of isoxazol-5-ones to 2,3-dihydro-6H-1,3-oxazin-6-ones. The first involves dirhodium-catalyzed reaction of aryl diazoacetates, leading to rhodium carbene intermediates that undergo insertion into the N-O bond of isoxazol-5-ones. The second approach involves conversion of the aryldiazoacetates to the corresponding tosylates, followed by reaction with the isoxazol-5-one in a metal-free one-pot procedure. These studies illustrate an alternative method to achieve a carbene-like transformation without requiring a metal catalyst.

An Aminocatalyzed Stereoselective Strategy for the Formal α-Propargylation of Ketones.

A two-step reaction sequence is described for the asymmetric formal α-propargylation of ketones. This approach takes advantage of an aminocatalyzed conjugate addition of ketones to alkylidene isoxazol-5-ones, followed by a controlled nitrosative degradation event. The target compounds can be accessed in broad scope, in moderate to good yields, perfect diastereocontrol and good to excellent enantioselectivity.