Search Results (12)

For those who did not follow the invention and development of enantioselective catalysis, this review introduces pertinent historical aspects of the field and presents the scientific concepts of asymmetric bio- and organocatalysis. They are powerful technologies applied in organic laboratories and industry. They realize chiral amplification by converting inexpensive achiral substrates and reagents into enantiomerically enriched products using readily recoverable solvents, if any are used. Racemic substrates can also be deracemized catalytically. More sustainable fabrications are now available that require neither toxic metallic species nor costly reaction conditions in terms of energy, atmosphere control, product purification, and safety. Nature has been the source of the first asymmetric catalysts (microorganisms, enzymes, alkaloids, amino acids, peptides, terpenoids, sugars, and their derivatives). They act as temporary chiral auxiliaries and lower the activation free energy of the reaction by altering the reaction mechanism. Reductions, oxidations, carbon-carbon and carbon-heteroatom bond-forming reactions are part of the process panoply. Asymmetric catalyzed multicomponent and domino reactions are becoming common. Typical modes of activation are proton transfers, hydrogen bonded complex formation, charged or uncharged acid/base pairing (e.g., σ-hole catalysts), formation of equilibria between achiral aldehydes and ketones with their chiral iminium salt or/and enamine intermediates, umpolung of aldehydes and ketones by reaction with N-heterocyclic carbenes (NHCs), phase transfer catalysis (PTC), etc. Often, the best enantioselectivities are observed with polyfunctional catalysts derived from natural compounds, but not always. They may combine to form chiral structures containing nitrogen, phosphorus, sulfur, selenium, and iodine functional moieties. Today, man-made enantiomerically enriched catalysts, if not enantiomerically pure, are available in both enantiomeric forms. Being robust, they are recovered and reused readily. Full article

CO₂, an abundant and renewable C1 source, presents significant potential for applications in organic synthesis. Hydrazones, recognized for their distinctive properties, exhibit high versatility in synthetic chemistry, facilitating numerous chemical transformations. Given their crucial roles in organic synthesis, the combination of CO₂ with hydrazones has garnered increasing research interest. This review provides a comprehensive summary of recent progress in reactions involving CO₂ and hydrazones or their derivatives. These include the coupling of amines and N-tosylhydrazones with CO₂, the umpolung-mediated carboxylation of hydrazones/N-tosylhydrazones with CO₂, the cyclization of hydrazones with CO₂, and lactamization reactions incorporating N-tosylhydrazones and CO₂. These transformations utilize the diverse reactivity of hydrazones and their derivatives to capture and convert CO₂, generating valuable organic compounds with both academic and practical relevance. Additionally, the review examines the mechanisms underlying these reactions, offering critical insights for advancing research in this area. Full article

This research investigates the mechanism of the cyanide-type umpolung reaction in benzoin condensation using topological analysis of ELF and catastrophe theory. The study achieves a comprehensive understanding of the evolution of chemical bonds and non-bonding electron density in the reaction of benzaldehyde and cyanide ions. The results reveal that the reaction proceeds through five transition state structures, with the formation of Lapworth’s cyanohydrin being the rate-determining step. The study characterises topological catastrophes in the evolution of the ELF field and provides a detailed description of the evolution of electron density in the mechanism of the reaction. An in-depth analysis of ELF catastrophes confirms the well-established Lapworth mechanism. Full article

Aldehydes constitute a main class of organic compounds widely applied in synthesis. As such, catalyst-controlled enantioselective α-functionalization of aldehydes has attracted great interest over the years. In this context, α-branched aldehydes are especially challenging substrates because of reactivity and selectivity issues. Firstly, the transient trisubstituted enamines and enolates resulting upon treatment with an aminocatalyst or a base, respectively, would exhibit attenuated reactivity; secondly, mixtures of E- and Z-configured enamines/enolates may be formed; and third, effective face-discrimination on such trisubstituted sp² carbon intermediates by the incoming electrophilic reagent is not trivial. Despite these issues, in the last 15 years, several catalytic approaches for the α-functionalization of prostereogenic α-branched aldehydes that proceed in useful yields and diastereo- and enantioselectivity have been uncovered. Developments include both organocatalytic and metal-catalyzed approaches as well as dual catalysis strategies for forging new carbon–carbon and carbon–heteroatom (C-O, N, S, F, Cl, Br, …) bond formation at Cα of the starting aldehyde. In this review, some key early contributions to the field are presented, but focus is on the most recent methods, mainly covering the literature from year 2014 onward. Full article

Hypervalent iodine reagents are in high current demand due to their exceptional reactivity in oxidative transformations, as well as in diverse umpolung functionalization reactions. Cyclic hypervalent iodine compounds, known under the general name of benziodoxoles, possess improved thermal stability and synthetic versatility in comparison with their acyclic analogs. Aryl-, alkenyl-, and alkynylbenziodoxoles have recently received wide synthetic applications as efficient reagents for direct arylation, alkenylation, and alkynylation under mild reaction conditions, including transition metal-free conditions as well as photoredox and transition metal catalysis. Using these reagents, a plethora of valuable, hard-to-reach, and structurally diverse complex products can be synthesized by convenient procedures. The review covers the main aspects of the chemistry of benziodoxole-based aryl-, alkynyl-, and alkenyl- transfer reagents, including preparation and synthetic applications. Full article

An efficient general method for the synthesis of a wide family of α-aminophosphonate analogs of aspartic acid bearing tetrasubstituted carbons is reported through an aza-Reformatsky reaction of α-iminophosphonates, generated from α-aminophosphonates, in an umpolung process. In addition, the α-aminophosphonate substrates showed in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines A549 (carcinomic human alveolar basal epithelial cell) and SKOV3 (human ovarian carcinoma). In view of the possibilities in the diversity of the substituents that offer the synthetic methodology, an extensive profile structure–activity is presented, measuring IC₅₀ values up to 0.34 µM in the A549 and 9.8 µM in SKOV3 cell lines. Full article

For a long time, the organic chemistry of sulfur dioxide (SO₂) consisted of sulfinates that react with carbon electrophiles to generate sulfones. With alkenes and other unsaturated compounds, SO₂ generates polymeric materials such as polysulfones. More recently, H-ene, sila-ene and hetero-Diels–Alder reactions of SO₂ have been realized under conditions that avoid polymer formation. Sultines resulting from the hetero-Diels–Alder reactions of conjugated dienes and SO₂ are formed more rapidly than the corresponding more stable sulfolenes resulting from the cheletropic additions. In the presence of a protic or Lewis acid catalyst, the sultines derived from 1-alkoxydienes are ionized into zwitterionic intermediates bearing 1-alkoxyallylic cation moieties which react with electro-rich alkenes such as enol silyl ethers and allylsilanes with high stereoselectivity. (C–C-bond formation through Umpolung induced by SO₂). This produces silyl sulfinates that react with carbon electrophiles to give sulfones (one-pot four component asymmetric synthesis of sulfones), or with Cl₂, generating the corresponding sulfonamides that can be reacted in situ with primary and secondary amines (one-pot four component asymmetric synthesis of sulfonamides). Alternatively, Pd-catalyzed desulfinylation generates enantiomerically pure polypropionate stereotriads in one-pot operations. The chirons so obtained are flanked by an ethyl ketone moiety on one side and by a prop-1-en-1-yl carboxylate group on the other. They are ready for two-directional chain elongations, realizing expeditious synthesis of long-chain polypropionates and polyketides. The stereotriads have also been converted into simpler polypropionates such as the cyclohexanone moiety of baconipyrone A and B, Kishi’s stereoheptad unit of rifamycin S, Nicolaou’s C₁–C₁₁-fragment and Koert’s C₁₆–C_I fragment of apoptolidin A. This has also permitted the first total synthesis of (-)-dolabriferol. Full article

A facile and sustainable electrochemical umpolung of bromide ion protocol was developed under mild reaction conditions. Transition metal catalysts and exogenous chemical oxidants were obviated for the bromination of C–H bond. Notably, graphite rod, which is commercially available at supermarkets and is inexpensive, was employed as the electrode material. This operationally easy and environmentally friendly approach accomplished the synthesis of 3-bromoindole in excellent yield and regioselectivity. Full article

Nitrogen heterocycles represent vital structural motifs in biologically-active natural products and pharmaceuticals. As a result, the development of new, convenient and more efficient processes to N-heterocycles is of great interest to synthetic chemists. Samarium(II) iodide (SmI₂, Kagan’s reagent) has been widely used to forge challenging C–C bonds through reductive coupling reactions. Historically, the use of SmI₂ in organic synthesis has been focused on the construction of carbocycles and oxygen-containing motifs. Recently, significant advances have taken place in the use of SmI₂ for the synthesis of nitrogen heterocycles, enabled in large part by the unique combination of high reducing power of this reagent (E_1/2 of up to −2.8 V) with excellent chemoselectivity of the reductive umpolung cyclizations mediated by SmI₂. In particular, radical cross-coupling reactions exploiting SmI₂-induced selective generation of aminoketyl radicals have emerged as concise and efficient methods for constructing 2-azabicycles, pyrrolidines and complex polycyclic barbiturates. Moreover, a broad range of novel processes involving SmI₂-promoted formation of aminyl radicals have been leveraged for the synthesis of complex nitrogen-containing molecular architectures by direct and tethered pathways. Applications to the synthesis of natural products have highlighted the generality of processes and the intermediates accessible with SmI₂. In this review, recent advances involving the synthesis of nitrogen heterocycles using SmI₂ are summarized, with a major focus on reductive coupling reactions that enable one-step construction of nitrogen-containing motifs in a highly efficient manner, while taking advantage of the spectacular selectivity of the venerable Kagan’s reagent. Full article

Catalysis fulfills the promise that high-yielding chemical transformations will require little energy and produce no toxic waste. This message is carried by the study of the evolution of molecular catalysis of some of the most important reactions in organic chemistry. After reviewing the conceptual underpinnings of catalysis, we discuss the applications of different catalysts according to the mechanism of the reactions that they catalyze, including acyl group transfers, nucleophilic additions and substitutions, and C–C bond forming reactions that employ umpolung by nucleophilic additions to C=O and C=C double bonds. We highlight the utility of a broad range of organocatalysts other than compounds based on proline, the cinchona alkaloids and binaphthyls, which have been abundantly reviewed elsewhere. The focus is on organocatalysts, although a few examples employing metal complexes and enzymes are also included due to their significance. Classical Brønsted acids have evolved into electrophilic hands, the fingers of which are hydrogen donors (like enzymes) or other electrophilic moieties. Classical Lewis base catalysts have evolved into tridimensional, chiral nucleophiles that are N- (e.g., tertiary amines), P- (e.g., tertiary phosphines) and C-nucleophiles (e.g., N-heterocyclic carbenes). Many efficient organocatalysts bear electrophilic and nucleophilic moieties that interact simultaneously or not with both the electrophilic and nucleophilic reactants. A detailed understanding of the reaction mechanisms permits the design of better catalysts. Their construction represents a molecular science in itself, suggesting that sooner or later chemists will not only imitate Nature but be able to catalyze a much wider range of reactions with high chemo-, regio-, stereo- and enantioselectivity. Man-made organocatalysts are much smaller, cheaper and more stable than enzymes. Full article

The mechanism of the N-heterocyclic carbene (NHC)-catalyzed intramolecular Stetter reaction of salicylaldehyde 1 to yield chromanone 3 has been theoretically studied at the B3LYP/6-31G** level. This NHC-catalyzed reaction takes place through six elementary steps, which involve: (i) formation of the Breslow intermediate IN2; (ii) an intramolecular Michael-Type addition in IN2 to form the new C-C s bond; and (iii) extrusion of the NHC catalyst from the Michael adduct to yield chromanone 3. Analysis of the relative free energies in toluene indicates that while formation of Breslow intermediate IN2 involves the rate-determining step of the catalytic process, the intramolecular Michael-type addition is the stereoselectivity determining step responsible for the configuration of the stereogenic carbon a to the carbonyl of chromanone 3. An ELF analysis at TSs and intermediates involved in the Michael-type addition allows for the characterization of the electronic changes along the C-C bond-formation. Full article