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Can classical and modern chemical C-H oxidation reactions complement biotransformation in the synthesis of drug metabolites? We have surveyed the literature in an effort to try to answer this important question of major practical significance in the pharmaceutical industry. Drug metabolites are required throughout all phases of the drug discovery and development process; however, their synthesis is still an unsolved problem. This Review, not intended to be comprehensive or historical, highlights relevant applications of chemical C-H oxidation reactions, electrochemistry and microfluidic technologies to drug templates in order to access drug metabolites, and also highlights promising reactions to this end. Where possible or appropriate, the contrast with biotransformation is drawn. In doing so, we have tried to identify gaps where they exist in the hope to spur further activity in this very important research area.

Manganese is a non-toxic, inexpensive and earth abundant metal, so is a perfect candidate for catalysis whether as a replacement for precious metals or in the search for novel reactivity. Despite this, manganese catalysis has not undergone the same development of other earth-abundant metals (particularly iron and cobalt). This review details recent synthetic methodologies using manganese catalysts, including C–H activation, late stage fluorination, hydrosilylation and cross-coupling.

We disclose the highly diastereoselective combination of monoamine oxidase-catalyzed oxidation of meso-pyrrolidines and aza-Friedel–Crafts reactions in aqueous buffer to give valuable enantioenriched 2-substituted pyrrolidines in a formal double CH activation process. A range of secondary as well as tertiary amines were shown to be suitable substrates for the biocatalytic oxidation and subsequent addition of a variety of C-nucleophiles.

Allylic chlorides prepared from commercially available trans-1,4-dichloro-2-butene were converted to trans-disubstituted 5- and 6-membered ring systems with perfect diastereoselectivity and high enantioselectivity under chiral ruthenium catalysis. These products contain stereodefined secondary and tertiary alcohols that originate from the trapping of an alkylruthenium intermediate with adventitious water. Key to the success of this transformation was the development of a new BINOL-based phosphoramidite ligand containing bulky substitution at its 3- and 3′-positions. As a demonstration of product utility, diastereoselective Friedel–Crafts reactions were performed on the chiral benzylic alcohols in high yield and stereoselectivity.

A selection of heteroaryl fluorosulfates were readily synthesized using commercial SO2F2 gas. These substrates are highly efficient coupling partners in the Suzuki reaction. Through judicious selection of Pd catalysts the fluorosulfate functionality is differentiated from bromide and chloride; the order of reactivity being: -Br> -OSO2 F> -Cl. Exploiting this trend allowed the stepwise chemoselective synthesis of a number of polysubstituted pyridines, including the drug Etoricoxib.

Catalysts are a vital part of synthetic chemistry. However, there are still many important reactions for which catalysts have not been developed. The use of enzymes as biocatalysts for synthetic chemistry is growing in importance due to the drive towards sustainable methods for producing both bulk chemicals and high value compounds such as pharmaceuticals, and due to the ability of enzymes to catalyse chemical reactions with excellent stereoselectivity and regioselectivity. Such challenging transformations are a common feature of natural product biosynthetic pathways. In this mini-review, we discuss the potential to use biosynthetic pathways as a starting point for biocatalyst discovery. We introduce the reader to natural product assembly and tailoring, then focus on four classes of enzyme that catalyse C─H bond activation reactions to functionalize biosynthetic precursors. Finally, we briefly discuss the challenges involved in novel enzyme discovery.

Novel experimental techniques and computational methods have provided new insight into the behavior of reactive intermediates in solution. The results of these studies show that some of the earlier ideas about how reactive intermediates ought to behave in solution were incomplete or even incorrect. This Perspective summarizes the new experimental and computational methods and draws attention to the shortcomings that their application has brought to light in previous models. Key areas needing further research are highlighted.

Herein some examples of the use of lanthanide ions (f-metal ions) to direct the synthesis of luminescent self-assembly systems (architectures) will be discussed. This area of lanthanide supramolecular chemistry is fast growing, thanks to the unique physical (magnetic and luminescent) and coordination properties of the lanthanides, which are often transferred to the resulting supermolecule. The emphasis herein will be on systems that are luminescent, and hence, generated by using either visibly emitting ions (such as EuIII, TbIII and SmIII) or near infrared emitting ions (like NdIII, YbIII and ErIII), formed through the use of templating chemistry, by employing structurally simple ligands, possessing oxygen and nitrogen coordinating moieties. As the lanthanides have high coordination requirements, their use often allows for the formation of coordination compounds and supramolecular systems such as bundles, grids, helicates and interlocked molecules that are not synthetically accessible through the use of other commonly used templating ions such as transition metal ions. Hence, the use of the rare-earth metal ions can lead to the formation of unique and stable species in both solution and in the solid state, as well as functional and responsive structures.

The first direct asymmetric Mannich reaction by using α-branched ketones as nucleophilic partners is presented and gives an enantio- and diastereoselective access to various β-amino ketones.

The synthesis of densly functionized α-silyl-β-hydroxyl vinylsilanes via ruthenium-catalyzed multicomponent reaction (MCR) is reported herein. Exceptionally high regio- and diastereoselectivity was achieved by employing an unprecedented hydrosilylation of bifunctional silyl-propargyl boronates. The simple protocol, mild reaction conditions, and unique tolerability of this method make it a valuable tool for the synthesis of highly elaborated building blocks. The one-pot synthesis of stereodefined olefins, the generation of a valuable cyclohexene building block through a four-component MCR, and further functionalization in an abundance of diastereoselective reactions is disclosed herein.

A new method for ozonolysis of alkenes using a continuous flow film-shear reactor was developed. The reactor uses a shearing microfluidic mixing chamber to provide biphasic mixing of an organic phase and aqueous phase with ozone gas. The H2O acts as an in situ reducing agent for the carbonyl oxide intermediate, providing ketones and aldehydes directly from the reaction mixture. Flow rates of up to 1.0 mmol/min (alkene) with an ozone reaction efficiency of >70% were achieved. Aryl conjugated olefins reacted to form carbonyl species in good yields on a multi-gram scale; however, alkyl olefins reacted with ozone to predominantly form secondary ozonides. The discrepancy in product distributions between alkyl and aryl olefins likely originates from the electronic stability of the carbonyl oxide intermediate, which is longer lived for aryl derivatives due to conjugation.

The metal-catalyzed coupling of alkynes is a powerful method for the preparation of 1,3-enynes, compounds that are of broad interest in organic synthesis. Numerous strategies have been developed for the homo- and cross coupling of alkynes to enynes via transition metal catalysis. In such reactions, a major issue is the control of regio-, stereo-, and, where applicable, chemoselectivity. Herein, we highlight prominent methods for the selective synthesis of these valuable compounds. Further, we illustrate the utility of these processes through specific examples of their application in carbocycle, heterocycle, and natural product syntheses.

Chemical vapour deposition (CVD) and atomic layer deposition (ALD) are attractive techniques for depositing a wide spectrum of thin solid film materials, for a broad spectrum of industrial applications. These techniques rely on volatile, reactive, and thermally stable molecular precursors to transport and deposit growth materials in a kinetically controlled manner, resulting in uniform, conformal, high purity films. Developments in these fields depend on careful precursor design. We discuss the qualities that make successful CVD or ALD precursors (low melting point, high volatility, stability and specific reactivity) and the widely applicable design principles used to achieve them, through examples of group 11 and 13 precursors including amidinates, guanidinates and iminopyrrolidinates. We highlight the most valuable techniques that we use to asses potential precursors on the basis of the discussed qualities, and to elucidate relevant mechanisms of decomposition and surface reactivity. There is a strong focus on thermogravimetric analysis (TGA), and solid state (SS) and solution NMR studies.

Alkynyl ketones are attractive but challenging nucleophiles in enolate chemistry. Their susceptibility to other reactions such as Michael additions and the difficulty of controlling the enolate geometry make them difficult substrates. Mannich-type reactions, which previously have not been reported using N-carbamoyl-imines with simple ketone enolates, became our objective. In this report, we describe the first direct catalytic Mannich-type reaction between various ynones and N-Boc imines, whose stereocontrol presumably derives from catalyst control of enolate geometry. This method produces α-substituted β-amino ynones with excellent chemo-, diastereo-, and enantioselectivity. The products can be readily transformed into a broad range of molecular scaffolds upon further one-step transformations, demonstrating the utility of ynones as masked synthetic equivalents for a variety of unsymmetrically substituted acyclic ketones. In particular, alkynyl alkyl ketones resolve the long-standing problem of the inability to use the enolates of unsymmetrical dialkyl ketones lacking α-branching for regio- and stereoselective reactions.

The synthesis of vinyl boronates and vinyl silanes was achieved by employing a Ru-catalyzed alkene-alkyne coupling reaction of allyl boronates or allyl silanes with various alkynes. The double bond geometry in the generated vinyl boronates can be remotely controlled by the juxtaposing boron- and silicon groups on the alkyne substrate. The synthetic utility of the coupling products has been demonstrated in a variety of synthetic transformations, including iterative cross-coupling reactions, and a Chan-Lam-type allyloxylation followed by a Claisen rearrangement. A sequential one-pot alkene-alkyne-coupling/allylation-sequence with an aldehyde to deliver a highly complex α-silyl-β-hydroxy olefin with a handle for further functionalization was also realized.

Reported herein is a Zn/Prophenol-catalyzed Mannich reaction using fluorinated aromatic ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of β-fluoroamine motifs featuring a fluorinated tetrasubstituted carbon. The reaction can be run on a gram scale with a low catalyst loading without impacting its efficiency. Moreover, a related aldol reaction was also developed. Together, these reactions provide a new approach for the preparation of pharmaceutically relevant products possessing tetrasubstituted C-F centers.

The aldol reaction represents an important class of atom-economic carbon-carbon bond-forming reactions vital to modern organic synthesis. Despite the attention this reaction has received, issues related to chemo- and regioselectivity as well as reactivity of readily enolizable electrophiles remain. To help overcome these limitations, a new direct approach toward aldol products that does not rely upon carbonyl substrates is described. This approach employs room-temperature contemporaneous lanthanum/vanadium dual catalysis, whereby a vanadium-catalyzed 1,3-transposition of allenols is coupled with a lanthanum-catalyzed Meinwald rearrangement of epoxides in situ to directly form aldol products.

Cell signaling via inositol phosphates, in particular via the second messenger myo-inositol 1,4,5-trisphosphate, and phosphoinositides comprises a huge field of biology. Of the nine 1,2,3,4,5,6-cyclohexanehexol isomers, myo-inositol is pre-eminent, with "other" inositols (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro-, and scyllo-) and derivatives rarer or thought not to exist in nature. However, neo- and d-chiro-inositol hexakisphosphates were recently revealed in both terrestrial and aquatic ecosystems, thus highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some "other" inositols are medically relevant, for example, scyllo-inositol (neurodegenerative diseases) and d-chiro-inositol (diabetes). It is timely to consider exploration of the roles and applications of the "other" isomers and their derivatives, likely by exploiting techniques now well developed for the myo series.

α-Trifluoromethyl-styrenes, trifluoromethyl-enynes, and dienes undergo palladium-catalyzed trimethylenemethane cycloadditions under mild reaction conditions. The trifluoromethyl group serves as a unique σ-electron-withdrawing group for the activation of the olefin toward the cycloaddition. This method allows for the formation of exomethylene cyclopentanes bearing a quaternary center substituted by the trifluoromethyl group, compounds of interest for the pharmaceutical, agrochemical, and materials industries. In the diene series, the cycloaddition operates in a [3 + 4] and/or [3 + 2] manner to give rise to seven- and/or five-membered rings. This transformation greatly improves the scope of the TMM cycloaddition technology and provides invaluable insights into the reaction mechanism.

The communesin alkaloids are a diverse family of Penicillium-derived alkaloids. Their caged-polycyclic structure and intriguing biological profiles have made these natural products attractive targets for total synthesis. Similarly, the ascidian-derived alkaloid, perophoramidine, is structurally related to the communesins and has also become a popular target for total synthesis. This review serves to summarize the many elegant approaches that have been developed to access the communesin alkaloids and perophoramidine. Likewise, strategies to access the communesin ring system are reviewed.

Starting from 2-bromo(hetero)aryl aldehydes, diverse terminal acetylenes and 1-chloropropargyl(hetero)arenes an access to ortho-fused cycloocta-2,5-dien-1-ones is developed which tolerates various functional groups.

The development and application of a new generation of non-C2-symmetric ProPhenol ligands is reported herein. Rational design of the ProPhenol ligand paved the way to the first catalytic and asymmetric vinylation of N-Boc imines via hydrozirconation giving rise to valuable allylic amines in excellent yields and enantioselectivities. The utility of this method was demonstrated by developing the shortest reported asymmetric synthesis of the selective serotonine reuptake inhibitor (SSRI) (−)-dapoxetine.

Hydrogenation of readily available pyrido[1,2-a]pyrimidinium salts (I) over a Rh-catalyst forms title compounds (II) in high yields, providing a general route to this little-studied class of compounds.

I am highly honored to be the co-recipient of the Tetrahedron Prize for 2014 with Professor Jiro Tsuji for our work on metal catalyzed allylic alkylation, notably that using palladium. In the context of this award, this report deals only with the evolution of our work. Nevertheless, it is important to note that innumerable groups around the world have and are playing essential roles metal catalyzed allylic alkylations. The reader can find citations to such work in the references to our work that appears in this report. My involvement with this field derived from work in my laboratory dealing with the structure determination and synthesis of the insect juvenile hormone.1 The juvenile hormone is one of three hormones that control the stages of insect development from the pupae to the larvae and finally to the adult. Thus, these hormones, most notably the juvenile hormone that prevented molting was targeted as a potentially more environmentally benign insecticide. The structural relationship of the insect juvenile hormone and methyl farnesoate suggests a possible biosynthetic pathway may be involving the homologation of two of the olefinic methyl groups to ethyl groups. Such an approach, if feasible, would be very attractive, short, and potentially very practical. Unfortunately, such a synthetic protocol did not exist – a fact that intrigued me. While the reactions of the oxygen analog wherein alkylation at the carbon adjacent to the π-unsaturated carbonyl group is one of the most important synthetic reactions, the inability of the all carbon analog to undergo a similar transformation was very attractive.

The practical, cost-effective and operationally simple two-step transformation is applied to a range of dimethylamine-containing pharmaceuticals including clomipramine (I) and diltiazem (IV).

The oxidative addition of cyano substituted esters (II) and (IV) to allylic imines proceeds at the imine carbon to yield 1-aza-1,3-dienes (III) and (V).

Crystals of [YbCl2(H2O)6]Cl are obtained by slow evaporation of MeCN solutions of the compound also containing di-2-pyridyl ketone oxime (dpko) in the attempt to prepare the Yb-dpko complex.

Starting from protected propargyl imines an efficient one-pot approach to 1,2-dihydropyridines is elaborated.

An atom-economic route to benzo[f]-1-indanone frameworks is developed starting from readily available gem-dialkylthio trienynes by intramolecular annulations.

Easily prepared aryl fluorosulfates are used as coupling partners in the Suzuki—Miyaura reaction.

Nitrogen-, phosphorus-, and oxygen-based ligands with chiral backbones have been the historic workhorses of asymmetric transition-metal-catalyzed reactions. On the contrary, sulfoxides containing chirality at the sulfur atom have mainly been used as chiral auxiliaries for diastereoselective reactions. Despite several distinct advantages over traditional ligand scaffolds, such as the proximity of the chiral information to the metal center and the ability to switch between S and O coordination, these compounds have only recently emerged as a versatile class of chiral ligands. In this Review, we detail the history of the development of chiral sulfoxide ligands for asymmetric catalysis. We also provide brief descriptions of metal–sulfoxide bonding and strategies for the synthesis of enantiopure sulfoxides. Finally, insights into the future development of this underutilized ligand class are discussed.

Carbamates are investigated as directing groups in the title process and -NH-Boc is found to be the optimal one.

The asymmetric key step of the new protocol is the molybdenum-catalyzed allylic alkylation of the oxindole (II) to give (III) with high enantioselectivity.

Enantiomerically enriched [3.1.0] bicycles containing vicinal quaternary centers are synthesized from [1,6]-enynes using a ruthenium catalyst with a tethered chiral sulfoxide.

ConspectusThe development of catalytic enantioselective transformations has been the focus of many research groups over the past half century and is of paramount importance to the pharmaceutical and agrochemical industries. Since the award of the Nobel Prize in 2001, the field of enantioselective transition metal catalysis has soared to new heights, with the development of more efficient catalysts and new catalytic transformations at increasing frequency. Furthermore, catalytic reactions that allow higher levels of redox- and step-economy are being developed. Thus, alternatives to asymmetric alkene dihydroxylation and the enantioselective reduction of α,β-unsaturated ketones can invoke more strategic C–C bond forming reactions, such as asymmetric aldol reactions of an aldehyde with α-hydroxyketone donors or enantioselective alkynylation of an aldehyde, respectively. To facilitate catalytic enantioselective addition reactions, including the aforementioned aldol and alkynylation reactions, our lab has devel...

Optimal conditions are elaborated for the preparation of a broad spectrum of intermediate ammonium sulfinates [cf.

The title reaction proceeds without subsequent rearomatization and can be applied on a broad range of heterocyclic and benzoid substrates.

Pd-catalyzed asymmetric desymmetrization of the meso 1,4-dibenzolate produces the common intermediate (III) in excellent yield and enantioselectivity.

Aryl sulfonyl chlorides (e.g. Ts-Cl) are beloved of organic chemists as the most commonly used S(VI) electrophiles, and the parent sulfuryl chloride, O2 S(VI) Cl2 , has also been relied on to create sulfates and sulfamides. However, the desired halide substitution event is often defeated by destruction of the sulfur electrophile because the S(VI) Cl bond is exceedingly sensitive to reductive collapse yielding S(IV) species and Cl(-) . Fortunately, the use of sulfur(VI) fluorides (e.g., R-SO2 -F and SO2 F2 ) leaves only the substitution pathway open. As with most of click chemistry, many essential features of sulfur(VI) fluoride reactivity were discovered long ago in Germany.6a Surprisingly, this extraordinary work faded from view rather abruptly in the mid-20th century. Here we seek to revive it, along with John Hyatt's unnoticed 1979 full paper exposition on CH2 CH-SO2 -F, the most perfect Michael acceptor ever found.98 To this history we add several new observations, including that the otherwise very stable gas SO2 F2 has excellent reactivity under the right circumstances. We also show that proton or silicon centers can activate the exchange of SF bonds for SO bonds to make functional products, and that the sulfate connector is surprisingly stable toward hydrolysis. Applications of this controllable ligation chemistry to small molecules, polymers, and biomolecules are discussed.

An asymmetric Pd-catalyzed [3 + 2] cycloaddition of alkynyl substituted trimethylenemethane donors is developed to allow the synthesis of highly functionalized cyclopentanes having three contiguous stereocenters.

Chromatography is routinely used in drug discovery as a means to isolate intermediates and final compounds. From a sustainability perspective, it is one of the largest contributors of solvent waste in the drug discovery process. The medicinal chemistry subgroup within the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective aimed at providing chemists with practical tools and easily implemented techniques to improve the sustainability of drug discovery through reduction of the waste generated during chromatography. This perspective also offers alternatives to traditional, silica gel-based chromatography as well as information on how to avoid chromatography completely through use of crystallization and reaction telescoping.

The palladium-catalyzed oxidative desymmetrization of meso-dibenzoates yields γ-benzoyloxy cycloalkenones in good yields and with excellent levels of enantioselectivity. These compounds serve as precursors to a broad range of substituted cycloalkenones, including well-established synthetic building blocks and elaborated cycloalkanone derivatives. The ability to prepare both enantiomers of the oxidative desymmetrization products enables a unified strategy toward stereochemically diverse epoxyquinoid natural products.

2,2,6,6-Tetramethylpiperidine (TMP)-catalyzed (1–10%) chlorinations of phenols by SO2Cl2 in aromatic solvents are more ortho selective than with primary and less hindered secondary amine catalysts. Ortho-selective chlorination is successful even with electron deficient phenols such as 2-hydroxybenzaldehyde and 2′-hydroxyacetophenone. Notably, ortho selectivity increases with the reaction temperature. On the other hand, tetraalkylammonium chloride-catalyzed chlorinations are moderately para selective.

This reaction proceeds with good regio- and enantioselectivity yielding preferably the branched products.

The title reaction provides a synthesis of marcofortines, which are potent anthelmintic active metabolites.

The three-component palladium-catalyzed coupling of aryl lithium compounds, sulfur dioxide, and aryl, heteroaryl, and alkenyl halides yields a diverse library of sulfones.

The thermolysis of metal compounds incorporating amidinate-type ligands (RN(H)C(X)NR, where R is any alkyl and X is an alkyl or an amido) show a great complexity and diversity. Amidinates and guanidinates of copper(I), aluminium(III) and gallium(III) can undergo thermal decomposition by two main routes: elimination of carbodiimide (here called “deinsertion”) and by abstraction of a β-hydrogen. In general terms carbodiimide deinsertion tends to be a low temperature and solution-based thermolysis route, and β-hydrogen elimination tends to be a high temperature and gas phase thermolysis path. There is little difference between amidinates and guanidiantes in this respect: both ligands show these decomposition pathways on a variety of metal centres. The iminopyrrolidinate (ip) ligand can be designed without β-hydrogens, and so the ligand tert-butyl-imino-2,2-dimethylpyrrolidinate ( t Bu-ip) was used on copper(I) to successfully show that this compound does not undergo these two thermolyses, but undergoes a much higher thermolysis through loss of the iminotertbutyl group and subsequent decomposition of the five-membered ring. This “redesigned” ligand boosts the thermal stability of the copper(I) dimer from 225 °C for [CuI{(iPrN)2CNMe2}] 2 to 350 °C for [Cu I (Me 2 - t Bu-ip)] 2 .