Enantioselective Catalysis by the Umpolung of Conjugate Acceptors Involving N-Heterocyclic Carbene or Organophosphine 1,4-Addition.

ConspectusConjugate acceptors are one of the most common electrophilic functional groups in organic synthesis. While useful in a diverse range of transformations, their applications are largely dominated by the reactions from which their name is derived (i.e., as an acceptor of nucleophiles in the conjugate position). In 2014, we commenced studies focused on their ability to undergo polarity inversion through the conjugate addition of Lewis base catalysts. The first step in this process provides an enolate, from which the well-developed Rauhut-Currier (RC) and Morita-Baylis-Hillman (MBH) reactions can occur; however, tautomerization to provide a species in which the ß-carbon of the conjugate acceptor can now act as a donor is also possible. When we commenced studies on this topic, reaction designs with this type of species, particularly when accessed using N-heterocyclic carbenes (NHCs), had been reported on only a handful of occasions. Despite a lack of development, conceptually it was felt that reactions taking advantage of polarity switching by Lewis base conjugate addition have a number of desirable features. Perhaps the most significant is the potential to reimagine a ubiquitous functional group as an entirely new synthon, namely, a donor to electrophiles from the conjugate position.Our work has focused on catalysis with both simple conjugate acceptors and also those embedded within more complicated substrates; the latter has allowed a series of cycloisomerizations and annulation reactions to be achieved. In most cases, the reactions have been possible using enantioenriched chiral NHCs or organophosphines as the Lewis base catalysts thereby delivering enantioselective approaches to novel cyclic molecules. While related chemistry can be accessed with either family of catalyst, in all cases reactions have been designed to take advantage of one or the other. In addition, a fine balance exists between reactions that exploit the initially formed enolate and those that involve the polarity-inverted ß-anion. In our studies, this balance is addressed through substrate design, although catalyst control may also be possible. We consider the chemistry discussed in this Account to be in its infancy. Significant challenges remain to be addressed before our broad aim of discovering a universal approach to the polarity inversion of all conjugate acceptors can be achieved. These challenges broadly relate to chemoselectivity with substrates bearing multiple electrophilic functionalities, reliance upon the use of conjugate acceptors, and catalyst efficiency. To address these challenges, advances in catalyst design and catalyst cooperativity are likely required.

Asymmetric Ene-Reduction of α,ß-Unsaturated Compounds by F420-Dependent Oxidoreductases A Enzymes from Mycobacterium smegmatis.

The stereoselective reduction of alkenes conjugated to electron-withdrawing groups by ene-reductases has been extensively applied to the commercial preparation of fine chemicals. Although several different enzyme families are known to possess ene-reductase activity, the old yellow enzyme (OYE) family has been the most thoroughly investigated. Recently, it was shown that a subset of ene-reductases belonging to the flavin/deazaflavin oxidoreductase (FDOR) superfamily exhibit enantioselectivity that is generally complementary to that seen in the OYE family. These enzymes belong to one of several FDOR subgroups that use the unusual deazaflavin cofactor F420. Here, we explore several enzymes of the FDOR-A subgroup, characterizing their substrate range and enantioselectivity with 20 different compounds, identifying enzymes (MSMEG_2027 and MSMEG_2850) that could reduce a wide range of compounds stereoselectively. For example, MSMEG_2027 catalyzed the complete conversion of both isomers of citral to (R)-citronellal with 99% ee, while MSMEG_2850 catalyzed complete conversion of ketoisophorone to (S)-levodione with 99% ee. Protein crystallography combined with computational docking has allowed the observed stereoselectivity to be mechanistically rationalized for two enzymes. These findings add further support for the FDOR and OYE families of ene-reductases displaying general stereocomplementarity to each other and highlight their potential value in asymmetric ene-reduction.

Asymmetric Ene-Reduction by F420 -Dependent Oxidoreductases B (FDOR-B) from Mycobacterium smegmatis.

Asymmetric reduction by ene-reductases has received considerable attention in recent decades. While several enzyme families possess ene-reductase activity, the Old Yellow Enzyme (OYE) family has received the most scientific and industrial attention. However, there is a limited substrate range and few stereocomplementary pairs of current ene-reductases, necessitating the development of a complementary class. Flavin/deazaflavin oxidoreductases (FDORs) that use the uncommon cofactor F420 have recently gained attention as ene-reductases for use in biocatalysis due to their stereocomplementarity with OYEs. Although the enzymes of the FDOR-As sub-group have been characterized in this context and reported to catalyse ene-reductions enantioselectively, enzymes from the similarly large, but more diverse, FDOR-B sub-group have not been investigated in this context. In this study, we investigated the activity of eight FDOR-B enzymes distributed across this sub-group, evaluating their specific activity, kinetic properties, and stereoselectivity against α,ß-unsaturated compounds. The stereochemical outcomes of the FDOR-Bs are compared with enzymes of the FDOR-A sub-group and OYE family. Computational modelling and induced-fit docking are used to rationalize the observed catalytic behaviour and proposed a catalytic mechanism.

Chemoselective Methionine Labelling of Recombinant Trastuzumab Shows High In Vitro and In Vivo Tumour Targeting.

A highly effective 2-step system for site-specific antibody modification and conjugation of the monoclonal antibody Herceptin (commercially available under Trastuzumab) in a cysteine-independent manner was used to generate labelled antibodies for in vivo imaging. The first step contains redox-activated chemical tagging (ReACT) of thioethers via engineered methionine residues to introduce specific alkyne moieties, thereby offering a novel easy way to fundamentally change the process of antibody bioconjugation. The second step involves modification of the introduced alkyne via azide-alkyne cycloaddition 'click' conjugation. The versatility of this 2-step approach is demonstrated here by the selective incorporation of a fluorescent dye but can also be applied to a wide variety of different conjugation partners depending on the desired application in a facile manner. Methionine-modified antibodies were characterised in vitro, and the diagnostic potential of the most promising variant was further analysed in an in vivo xenograft animal model using a fluorescence imaging modality. This study demonstrates how methionine-mediated antibody conjugation offers an orthogonal and versatile route to the generation of tailored antibody conjugates with in vivo applicability.

Cage hydrocarbons as linkers in dimeric drug design: Case studies with trimethoprim and tedizolid.

The looming threat of a "post-antibiotic era" has been caused by a rapid rise in antibacterial resistance and subsequent depletion of effective antibiotic agents in the clinic. An efficient strategy to address this shortfall lies in the reengineering of pre-existing and commercially available antibiotic drugs. This is exemplified by dimerization, a design concept in which two pharmacophores are covalently linked to form a new chemical entity. The cage hydrocarbons cubane (1), bicyclo[2.2.2]octane (BCO) (2), adamantane (3), and bicyclo[1.1.1]pentane (BCP) (4) present themselves as an attractive family of linkers in this regard. In this report, all four hydrocarbon cages were employed as linkers in a series of dimers based on the commercially available antibiotics trimethoprim and tedizolid. A detailed synthetic roadmap for the protection and deprotection of each pharmacophore is outlined. Several members of the trimethoprim series showed activity on par with that of their trimethoprim progenitor, although this was not the case for the tedizolid series. The design strategy outlined herein highlights the utility of the group as a platform for the rapid and modular construction of future novel antibiotics.

Radical Coupling Initiated by Organophosphine Addition to Ynoates.

Dual nucleophilic phosphine photoredox catalysis is yet to be developed due to facile oxidation of the phosphine organocatalyst to the phosphoranyl radical cation. Herein, we report a reaction design that avoids this event and exploits traditional nucleophilic phosphine organocatalysis with photoredox catalysis to allow the Giese coupling with ynoates. The approach has good generality, while its mechanism is supported by cyclic voltametric, Stern-Volmer quenching, and interception studies.

Lewis Base Catalyzed Synthesis of Sulfur Heterocycles via the C1-Pyridinium Enolate.

While the addition of C1-Lewis base enolates to carbonyls and related structures are well established, the related addition to thiocarbonyls compounds are unknown. Herein, we report a reaction cascade in which a C1-pyridinium enolate undergos addition to dithioesters, trithiocarbonates and xanthates. The reaction provides access to a range of dihydrothiophenes and dihydrothiopyrans (28-examples). Mechanistic investigations, including isolation of intermediates, electronic correlation, and kinetic isotope effect studies support the viability of an activated acid intermediate giving rise to the C1-pyridinium enolate which undergoes turnover limiting cyclization. Subsequent formation of a ß-thiolactone regenerates the catalyst with loss of carbon oxysulfide providing the observed products.

Redox Isomerization/(3+2) Allenoate Annulation by Auto-Tandem Phosphine Catalysis.

A phosphine-catalyzed approach to pyrrolines has been developed that involves two mechanistically unlinked catalytic processes. The first involves the redox isomerization of amino crotonates to provide access to aliphatic tosyl imines, which then engage in a (3+2) annulation with various allenoates. The reaction shows generality, with 24 examples established, along with a low yielding and moderately enantioselective variant. Mechanistic studies indicate that the viability of the process is linked to the selection of catalysts with similar propensity to add to the two coupling partners.

Para-Selective Cyanation of Arenes by H-Bonded Template.

The significance of site selective functionalization stands upon the superior selectivity, easy synthesis and diverse product utility. In this work, we demonstrate the para-selective introduction of versatile nitrile moiety, enabled by a detachable and reusable H-bonded auxiliary. The methodology holds its efficiency irrespective of substrate electronic bias. The conspicuous shift in the step energetics was probed by both experimental and computational mechanistic tools, which heralds the inception of para-deuteration. The synthetic impact of the methodology was highlighted with reusability of directing group and post synthetic modifications.

Enantioselective N-Heterocyclic Carbene Catalyzed Bis(enoate) Rauhut-Currier Reaction.

While the enantioselective Rauhut-Currier reaction is established with bis(enone) substrates, it is yet to be reported with less electrophilic bis(enoate) substrates. By exploiting high-nucleophilicity N-heterocyclic carbenes, it is possible to achieve Rauhut-Currier reactions with these substrates. The reaction is demonstrated with a range of intramolecular reactions (20 examples) and six esterification/RC reaction cascades, which all proceed with high enantioselectivity (most >93:7 er).

Enantioselective N-Heterocyclic Carbene Catalysis that Exploits Imine Umpolung.

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza-Stetter reaction that proceeds via imine umpolung using N-heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover-limiting addition of the NHC to the imine.

N-Heterocyclic Carbene Catalyzed (5+1) Annulations Exploiting a Vinyl Dianion Synthon Strategy.

Direct polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N-heterocyclic carbene (NHC) catalyzed reactions, in which ß-unsubstituted conjugate acceptors undergo homoenolate formation and C-C bond formation twice, have been developed. Specifically, the all-carbon (5+1) annulations give a range of mono- and bicyclic cyclohexanones (31 examples). In the first family of annulations, ß-unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.

Enantioselective N-Heterocyclic Carbene Catalysis via the Dienyl Acyl Azolium.

Herein we report the enantioselective N-heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio- and diastereo-enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6-addition/ß-lactonization.

Enantioselective N-Heterocyclic Carbene Catalyzed Cyclopentene Synthesis via the ß-Azolium Ylide.

Herein we report the cycloisomerization of electron-poor 1,5-dienes via the ß-azolium ylide to give enantioenriched cyclopentenes. The reaction is mediated by a chiral N-heterocyclic carbene (NHC) catalyst, exploits readily available substrates, has good generality (17 examples), and displays excellent enantioselectivity (mostly >94:6). Studies demonstrating the viability of a related dynamic kinetic resolution are reported, as are those with alternate tethers and derivatizations.

Auxiliary-Directed C(sp3 )-H Arylation by Synergistic Photoredox and Palladium Catalysis.

Herein we describe the auxiliary-directed arylation of unactivated C(sp3 )-H bonds with aryldiazonium salts, which proceeds under synergistic photoredox and palladium catalysis. The site-selective arylation of aliphatic amides with α-quaternary centres is achieved with high selectivity for ß-methyl C(sp3 )-H bonds. This operationally simple method is compatible with carbocyclic amides, a range of aryldiazonium salts and proceeds at ambient conditions.

Enantioselective N-Heterocyclic Carbene Catalysis by the Umpolung of α,ß-Unsaturated Ketones.

N-Heterocyclic carbene-catalyzed formation of ß-anionic intermediates from enones has been employed in the enantioselective synthesis of 2-aryl propionates. The reaction was achievable using a homochiral 4-MeOC6H4 morpholinone catalyst allowing the first example of enantioselective catalysis by umpolung of α,ß-unsaturated ketones. The reaction is high yielding, and shows robustness with reasonable generality. A mechanism is proposed in which the enantiodetermining protonation is achieved using either hexafluoroisopropanol or the formed naphthol product.

Enantioselective (4+2) Annulation of Donor-Acceptor Cyclobutanes by N-Heterocyclic Carbene Catalysis.

Herein we report the enantioselective (4+2) annulation of donor-acceptor cyclobutanes and unsaturated acyl fluorides using N-heterocyclic carbene catalysis. The reaction allows a 3-step synthesis of cyclohexyl ß-lactones (25 examples) in excellent chemical yield (most ≥90 %) and stereochemical integrity (all >20:1 d.r., most ≥97:3 e.r.). Mechanistic studies support ester enolate Claisen rearrangement, while derivatizations provide functionalized cyclohexenes and dihydroquinolinones.

N-Heterocyclic Carbene Catalyzed Synthesis of δ-Sultones via α,ß-Unsaturated Sulfonyl Azolium Intermediates.

A limited array of reactive intermediates have enabled a wealth of discoveries in N-heterocyclic carbene organocatalysis. In this study, the viability of α,ß-unsaturated sulfonyl azoliums as double electrophiles in new reactions is examined. Specifically, the (3+3) annulation of such species with the trimethylsilyl enol ethers of various 1,3-dicarbonyl compounds has been developed. This reaction provides access to a range of novel unsaturated δ-sultones (18 examples) in good yields (40-88 %) under mild reaction conditions. Mechanistic studies and the development of an enantioselective variant (55 % yield, 73:27 e.r.) support the intermediacy of an α,ß-unsaturated sulfonyl azolium species.

Enantioselective all-carbon (4+2) annulation by N-heterocyclic carbene catalysis.

The enantioselective vinylogous Michael/aldol cascade is an underdeveloped approach to cyclohexenes. Herein we describe a highly enantioselective (most ≥ 98:2 er) and diastereoselective (all ≥ 15:1 dr) N-heterocyclic carbene catalyzed cycloisomerization of acyclic dienyl esters to cyclohexyl ß-lactones. Derivatizations avail cyclohexenes bearing four contiguous stereogenic centers, while mechanistic studies support olefin isomerization prior to cyclization.

Solvate-dependent spin crossover and exchange in cobalt(II) oxazolidine nitroxide chelates.

Two oxazolidine nitroxide complexes of cobalt(II), [Co(II)(L(•))2](B(C6F5)4)2·CH2Cl2 (1) and [Co(II)(L(•))2](B(C6F5)4)2·2Et2O (2), where, L(•) is the tridentate chelator 4,4-dimethyl-2,2-bis(2-pyridyl)oxazolidine N-oxide, have been investigated by crystallographic, magnetic, reflectivity, and theoretical (DFT) methods. This work follows on from a related study on [Co(II)(L(•))2](NO3)2 (3), a multifunctional complex that simultaneously displays magnetic exchange, spin crossover, and single molecule magnetic features. Changing the anion and the nature of solvation in the present crystalline species leads to significant differences, not only between 1 and 2 but also in comparison to 3. Structural data at 123 and 273 K, in combination with magnetic data, show that at lower temperatures 1 displays low-spin Co(II)-to-radical exchange with differences in fitted J values in comparison to DFT (broken symmetry) calculated J values ascribed to the sensitive influence of a tilt angle (θ) formed between the Co(dz(2)) and the trans-oriented O atoms of the NO radical moieties in L(•). Spin crossover in 1 is evident at higher temperatures, probably influenced by the solvate molecules and crystal packing arrangement. Complex 2 remains in the high-spin Co(II) state between 2 and 350 K and undergoes antiferromagnetic exchange between Co-radical and radical-radical centers, but it is difficult to quantify. Calculations of the magnetic orbitals, eigenvalue plots, and the spin densities at the Co and radical sites in 1 and 2 have yielded satisfying details on the mechanism of metal-radical and radical-radical exchange, the radical spins being in π*NO orbitals.