Synthetic Opportunities Research Articles

Catalytic functionalization of tertiary alcohols to fully substituted carbon centres.

The catalytic nucleophilic substitution of tertiary alcohols using carbon or heteroatom based nucleophiles is a versatile methodology for the efficient, diverse and atom economical construction of fully substituted carbon centres, including both quaternary carbons and heteroatom substituted tetrasubstituted carbons, which only produces water as the by-product. This review summarizes the recent progress in this field, including the catalytic asymmetric studies and their application in the natural product synthesis, briefly discusses the reaction mechanism and challenges, and outlines synthetic opportunities that are still open.

Alkynes in Organocatalysis

AbstractIn this Focus Review, a selection of organocatalyzed reactions in which alkynes have been used are presented. Catalysis by tertiary and secondary amines, by phase‐transfer catalysis, by phosphines and carbenes, as well as bifunctional and multiple catalysis are discussed. Alkynes are versatile intermediates which can open novel synthetic opportunities as their reactivity is enhanced with respect to the corresponding alkenes and further elaboration to develop domino processes is possible.

Underpotential Co-deposition of Au–Cu Alloys: Switching the Underpotentially Deposited Element by Selective Complexation

Underpotential deposition and monolayer replacement processes are widely used for the synthesis of core/shell catalysts and heterointerfaces. Conventionally, only the more noble metal can be underpotentially deposited on or replace the less noble metal, limiting the number of accessible material configurations. We show here that the reverse process is possible, using the Au-Cu pair as a model system. By tuning the redox potentials of the two components via use of strong, selective metal ion complexes, Au-Cu alloys could be synthesized at will by (i) conventional underpotential co-deposition, whereby Cu is reduced at underpotential in parallel with the overpotential deposition of Au, or (ii) the reverse process, where Au is reduced at underpotential, while Cu is deposited at overpotential. Selective complexation also draws the redox potential of Au and Cu closer, resulting in co-deposition under activation control for the noble metal and precise alloy composition control by the applied potential, enabling in principle the formation of arbitrary metal or alloy interfaces. The alloys resulting from the two processes exhibit distinct enthalpy of mixing, suggesting different degrees of short-range order and dissimilar atomic configurations. These findings open new perspectives on underpotential deposition phenomena and possibly new synthetic opportunities in electrodeposition.

Rhodium(III)-catalyzed olefinic C-H alkynylation of enamides at room temperature.

Rh(III)-catalyzed C-H olefinic alkynylation of enamides for the stereospecific construction of synthetically useful Z-type enynamides is reported. This protocol displays good functionality tolerance and operational simplicity thus providing an alternative synthetic opportunity for the ease of access to specific 1,3-enyne derivatives.

ChemInform Abstract: Synthesis of Fluorine‐Containing α‐Amino Acids in Enantiomerically Pure Form via Homologation of Ni(II) Complexes of Glycine and Alanine Schiff Bases

AbstractReview: 144 refs.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: Aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids

This review provides a comprehensive treatment of literature data dealing with asymmetric synthesis of α-amino-β-hydroxy and α,β-diamino acids via homologation of chiral Ni(II) complexes of glycine Schiff bases using aldol and Mannich-type reactions. These reactions proceed with synthetically useful chemical yields and thermodynamically controlled stereoselectivity and allow direct introduction of two stereogenic centers in a single operation with predictable stereochemical outcome. Furthermore, new application of Ni(II) complexes of α-amino acids Schiff bases for deracemization of racemic α-amino acids and (S) to (R) interconversion providing additional synthetic opportunities for preparation of enantiomerically pure α-amino acids, is also reviewed. Origin of observed diastereo-/enantioselectivity in the aldol, Mannich-type and deracemization reactions, generality and limitations of these methodologies are critically discussed.

BIOLOGICAL CONTROL OF POSTHARVEST DISEASES: HURDLES, SUCCESSES AND PROSPECTS

Research has accelerated recently on biological control of postharvest diseases and has resulted in the development of several commercial products for controlling decays of temperate and subtropical fruits. The demand for alternatives to synthetic fungicides is much greater than the supply provided by these new technologies, including biological control. The development of a postharvest disease biocontrol product is a lengthy process involving many steps. The need for alternatives to synthetic fungicides and opportunities for biological control under controlled environmental conditions in storage have been the driving forces for research in this area. Research around the world has proven the effectiveness of biological control of postharvest diseases and, at the same time, identified its limitations. Many of these limitations result from knowledge gaps that can be addressed by additional research to better understand the mechanisms of biocontrol on fruit, microbial ecology of the fruit surfaces, and the survival of antagonists under adverse conditions. Additional research is also needed to prolong the shelf life of antagonists, determine the compatibility of biocontrol with other alternative treatments, and adapt biocontrol to various postharvest handling practices, and to new production technologies, such as mechanical harvesting, that may predispose fruit to decay. The greater use of biological control of postharvest diseases can be achieved by expanding the application of available products to new commodities and different pathogens. The products currently available were developed to control decays originating from wound infections; however, significant postharvest losses on various fruits may also occur from decays originating from latent infections that develop before harvest. Controlling these decays has become the new frontier for biological control. New approaches utilizing natural fruit wax and artificial membranes were developed to find antagonists effective in controlling latent infections under laboratory conditions. The high cost of tests required for registration prohibited the commercial development of several effective biocontrol agents. A new framework is needed for streamlining the registration of low risk biocontrol agents without known deleterious effects to human health. This is especially relevant for those agents that are consumed with foods in large quantities (e.g., in apple cider, fruit juices, or with various cultured food products (probiotics)). Biological control of postharvest diseases has been accepted by the fruit industry as a viable alternative to synthetic fungicides, and products registered in the United States can be used on organically-labeled fruit.

Visible‐Light Photocatalytic Radical Alkenylation of α‐Carbonyl Alkyl Bromides and Benzyl Bromides

Through the use of [Ru(bpy)3Cl2] (bpy=2,2'-bipyridine) and [Ir(ppy)3] (ppy=phenylpyridine) as photocatalysts, we have achieved the first example of visible-light photocatalytic radical alkenylation of various α-carbonyl alkyl bromides and benzyl bromides to furnish α-vinyl carbonyls and allylbenzene derivatives, prominent structural elements of many bioactive molecules. Specifically, this transformation is regiospecific and can tolerate primary, secondary, and even tertiary alkyl halides that bear β-hydrides, which can be challenging with traditional palladium-catalyzed approaches. The key initiation step of this transformation is visible-light-induced single-electron reduction of C-Br bonds to generate alkyl radical species promoted by photocatalysts. The following carbon-carbon bond-forming step involves a radical addition step rather than a metal-mediated process, thereby avoiding the undesired β-hydride elimination side reaction. Moreover, we propose that the Ru and Ir photocatalysts play a dual role in the catalytic system: they absorb energy from the visible light to facilitate the reaction process and act as a medium of electron transfer to activate the alkyl halides more effectively. Overall, this photoredox catalysis method opens new synthetic opportunities for the efficient alkenylation of alkyl halides that contain β-hydrides under mild conditions.

Enantioselective Organocatalytic Michael Addition of Cyclobutanones to Nitroalkenes

AbstractSynthetic applications of cyclobutanones other than ring expansion and fragmentation reactions are rare. Herein, highly efficient diastereo‐ and enantioselective organocatalytic Michael additions of 2‐substituted cyclobutanone derivatives to nitroalkenes are reported allowing the stereocontrolled creation of ‘all‐carbon’ quaternary centers. The approach relies on both the use of Brønsted base/hydrogen‐bond donor bifunctional organocatalysts, and importantly, the specific stabilization and activation of cyclobutanone with a secondary amide moiety. The reaction was found to nicely accommodate a broad scope of substrates, allowing the control of up to three contiguous stereogenic centers. This work has opened new synthetic opportunities.

ChemInform Abstract: New Synthetic Opportunities in Miniaturized Flow Reactors with Inductive Heating

AbstractReview: 85 refs.

Cinchona‐based Primary Amine Catalysis in the Asymmetric Functionalization of Carbonyl Compounds

Asymmetric aminocatalysis exploits the potential of chiral primary and secondary amines to catalyze asymmetric reactions. It has greatly simplified the functionalization of carbonyl compounds while ensuring high enantioselectivity. Recent advances in cinchona-based primary amine catalysis have provided new synthetic opportunities and conceptual perspectives for successfully attacking major challenges in carbonyl compound chemistry, which traditional approaches have not been able to address. This Review outlines the historical context for the development of this catalyst class while charting the landmark discoveries and applications that have further expanded the synthetic potential of aminocatalysis.

Isomerizing Olefin Metathesis as a Strategy To Access Defined Distributions of Unsaturated Compounds from Fatty Acids

The dimeric palladium(I) complex [Pd(μ-Br)(t)Bu(3)P](2) was found to possess unique activity for the catalytic double-bond migration within unsaturated compounds. This isomerization catalyst is fully compatible with state-of-the-art olefin metathesis catalysts. In the presence of bifunctional catalyst systems consisting of [Pd(μ-Br)(t)Bu(3)P](2) and NHC-indylidene ruthenium complexes, unsaturated compounds are continuously converted into equilibrium mixtures of double-bond isomers, which concurrently undergo catalytic olefin metathesis. Using such highly active catalyst systems, the isomerizing olefin metathesis becomes an efficient way to access defined distributions of unsaturated compounds from olefinic substrates. Computational models were designed to predict the outcome of such reactions. The synthetic utility of isomerizing metatheses is demonstrated by various new applications. Thus, the isomerizing self-metathesis of oleic and other fatty acids and esters provides olefins along with unsaturated mono- and dicarboxylates in distributions with adjustable widths. The cross-metathesis of two olefins with different chain lengths leads to regular distributions with a mean chain length that depends on the chain length of both starting materials and their ratio. The cross-metathesis of oleic acid with ethylene serves to access olefin blends with mean chain lengths below 18 carbons, while its analogous reaction with hex-3-enedioic acid gives unsaturated dicarboxylic acids with adjustable mean chain lengths as major products. Overall, the concept of isomerizing metatheses promises to open up new synthetic opportunities for the incorporation of oleochemicals as renewable feedstocks into the chemical value chain.

Mild Oxidation of Benzylic Amines into Aldehydes Using an Oxidative Polonovski-Like Process

A chemoselective and environmentally benign oxidation of benzylic amines into aldehydes mediated by a hypervalent iodine reagent has been developed. This mild oxidative version of the ­Polonovski process may be selectively carried out in the presence of several functionalities including a free alcohol and provides new synthetic opportunities as a masked aldehyde segment.

New Synthetic Opportunities in Miniaturized Flow Reactors with Inductive Heating

Abstract Inductive heating has emerged as a new heating technique in the laboratory, particularly when combined with miniaturized flow reactor devices. Traditionally, inductive heating is found in industrial applications like the heating of large metallic objects such as in the bending of pipes, bonding and welding. New fields of application are the preparation of nanotubes as well as hyperthermia in the treatment of cancer. This account specifically addresses the use of heatable materials such as superparamagnetic iron oxide nanoparticles in many areas of organic synthesis and how this enabling technology compares to conventional as well as microwave heating.

Chiral-Sc catalyzed asymmetric Michael addition/protonation of thiols with enones in water

Asymmetric Michael reactions and enantioselective protonations between enones and thiols were catalyzed by a Sc(OTf)(3)-chiral 2,2'-bipyridine complex in water. The remarkable governing of the enantioselectivity for simple introduction of protons despite their abnormally high mobility in water may provide us with new synthetic opportunities as well as significant chemical advances.

The I2/Et3SiH system: A versatile combination with multiple applications in carbohydrate chemistry

In this contribution, a brief survey of the multiple synthetic opportunities offered by the I2/Et3SiH combined system is presented. Both reagents are cheap and easy to handle, and their combination allows HI to be quickly formed in situ. A suitable stoichiometry of the mixture can be addressed to a set of very useful transformations of carbohydrate chemistry ranging from glycosidation reactions to functional group manipulation of sugars.

ChemInform Abstract: Tosylhydrazones: New Uses for Classic Reagents in Palladium‐Catalyzed Cross‐Coupling and Metal‐Free Reactions

AbstractReview: 75 refs.

ChemInform Abstract: The Transaldolase Family: New Synthetic Opportunities from an Ancient Enzyme Scaffold

AbstractReview: 122 refs.

Tosylhydrazones: New Uses for Classic Reagents in Palladium‐Catalyzed Cross‐Coupling and Metal‐Free Reactions

Tosylhydrazones are useful synthetic intermediates that have been used in organic chemistry for almost 60 years. The recent discovery of a palladium-catalyzed cross-coupling reaction involving a tosylhydrazone coupling partner has triggered renewed interest in these reagents. This reaction shows nearly universal generality with regard to the hydrazone and can be employed for the preparation of polysubstituted alkenes. In the course of this research, novel metal-free C-C and C-O bond-forming reactions have been discovered. Since tosylhydrazones are readily prepared from carbonyl compounds, these transformations offer new synthetic opportunities for the unconventional modification of carbonyl compounds. This Minireview discusses all of these new reactions of a classic reagent.

Biomedical Applications of Tetrazine Cycloadditions

Disease mechanisms are increasingly being resolved at the molecular level. Biomedical success at this scale creates synthetic opportunities for combining specifically designed orthogonal reactions in applications such as imaging, diagnostics, and therapy. For practical reasons, it would be helpful if bioorthogonal coupling reactions proceeded with extremely rapid kinetics (k > 10(3) M(-1) s(-1)) and high specificity. Improving kinetics would minimize both the time and amount of labeling agent required to maintain high coupling yields. In this Account, we discuss our recent efforts to design extremely rapid bioorthogonal coupling reactions between tetrazines and strained alkenes. These selective reactions were first used to covalently couple conjugated tetrazine near-infrared-emitting fluorophores to dienophile-modifed extracellular proteins on living cancer cells. Confocal fluorescence microscopy demonstrated efficient and selective labeling, and control experiments showed minimal background fluorescence. Multistep techniques were optimized to work with nanomolar concentrations of labeling agent over a time scale of minutes: the result was successful real-time imaging of covalent modification. We subsequently discovered fluorogenic probes that increase in fluorescence intensity after the chemical reaction, leading to an improved signal-to-background ratio. Fluorogenic probes were used for intracellular imaging of dienophiles. We further developed strategies to react and image chemotherapeutics, such as trans-cyclooctene taxol analogues, inside living cells. Because the coupling partners are small molecules (<300 Da), they offer unique steric advantages in multistep amplification. We also describe recent success in using tetrazine reactions to label biomarkers on cells with magneto-fluorescent nanoparticles. Two-step protocols that use bioorthogonal chemistry can significantly amplify signals over both one-step labeling procedures as well as two-step procedures that use more sterically hindered biotin-avidin interactions. Nanoparticles can be detected with fluorescence or magnetic resonance techniques. These strategies are now being routinely used on clinical samples for biomarker profiling to predict malignancy and patient outcome. Finally, we discuss recent results with tetrazine reactions used for in vivo molecular imaging applications. Rapid tetrazine cycloadditions allow modular labeling of small molecules with the most commonly used positron emission tomography isotope, (18)F. Additionally, recent work has applied this reaction directly in vivo for the pretargeted imaging of solid tumors. Future work with tetrazine cycloadditions will undoubtedly lead to optimized protocols, improved probes, and additional biomedical applications.