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A group-III iron containing 1,2-propanediol oxidoreductase, FucO, (also known as lactaldehyde reductase) from Escherichia coli was examined regarding its structure–dynamics–function relationships in the catalysis of the NADH-dependent reduction of (2S)-lactaldehyde. Crystal structures of FucO variants in the presence or absence of cofactors have been determined, illustrating large domain movements between the apo and holo enzyme structures. Different structures of FucO variants co-crystallized with NAD+ or NADH together with substrate further suggest dynamic properties of the nicotinamide moiety of the coenzyme that are important for the reaction mechanism. Modelling of the native substrate (2S)-lactaldehyde into the active site can explain the stereoselectivity exhibited by the enzyme, with a critical hydrogen bond interaction between the (2S)-hydroxyl and the side-chain of N151, as well as the previously experimentally demonstrated pro-(R) selectivity in hydride transfer from NADH to the aldehydic carbon. Furthermore, the deuterium kinetic isotope effect of hydride transfer suggests that reduction chemistry is the main rate-limiting step for turnover which is not the case in FucO catalysed alcohol oxidation. We further propose that a water molecule in the active site – hydrogen bonded to a conserved histidine (H267) and the 2′-hydroxyl of the coenzyme ribose – functions as a catalytic proton donor in the protonation of the product alcohol. A hydrogen bond network of water molecules and the side-chains of amino acid residues D360 and H267 links bulk solvent to this proposed catalytic water molecule.

A group-III iron containing 1,2-propanediol oxidoreductase, FucO, (also known as lactaldehyde reductase) from Escherichia coli was examined regarding its structure–dynamics–function relationships in the catalysis of the NADH-dependent reduction of (2S)-lactaldehyde. Crystal structures of FucO variants in the presence or absence of cofactors have been determined, illustrating large domain movements between the apo and holo enzyme structures. Different structures of FucO variants co-crystallized with NAD⁺ or NADH together with substrate further suggest dynamic properties of the nicotinamide moiety of the coenzyme that are important for the reaction mechanism. Modelling of the native substrate (2S)-lactaldehyde into the active site can explain the stereoselectivity exhibited by the enzyme, with a critical hydrogen bond interaction between the (2S)-hydroxyl and the side-chain of N151, as well as the previously experimentally demonstrated pro-(R) selectivity in hydride transfer from NADH to the aldehydic carbon. Furthermore, the deuterium kinetic isotope effect of hydride transfer suggests that reduction chemistry is the main rate-limiting step for turnover which is not the case in FucO catalysed alcohol oxidation. We further propose that a water molecule in the active site — hydrogen bonded to a conserved histidine (H267) and the 2′-hydroxyl of the coenzyme ribose — functions as a catalytic proton donor in the protonation of the product alcohol. A hydrogen bond network of water molecules and the side-chains of amino acid residues D360 and H267 links bulk solvent to this proposed catalytic water molecule.

Environmental behavior and toxicity of chiral compounds is a topic of great interest in environmental chemistry. In recent years, the evolution of the stereochemistry of organic compounds has highlighted the importance of considering separately stereoisomers of chiral herbicides when studying their fate and behavior in the environment. As many as 40% of all plant protection products currently used contain chiral active ingredients. Not only the effects on the biological target, but also their biodegradation, environmental fate and toxicity of stereoisomers of the same herbicide may be also different. As such, chiral compounds should be evaluated by using enantiomer-specific techniques and analytical tools. In this sense, stereoselective separation and analysis with HPLC-MS/MS is one of the most effective and powerful technique for investigate the enantioselective behavior of the isomers. Most of the chiral separation are performed by means of columns based on derivatized amylose or cellulose due to their wide analyte coverage and compatibility with reverse phase and sensitive detection techniques such as mass spectrometry. For sure, research in this field will continue growing due to the necessity of assessing the risks related to exposure to chiral herbicides, which can be considered as emerging environmental contaminants.

We have investigated the stereoselectivity and reactivity of the sodium borohydride reduction of 2-X-cyclohexanones (X=H, Cl, Br) using a combined approach of competitive experiments and density functional theory calculations. Our results show that the hydride addition proceeds via a late transition state in which the C–H bond is nearly formed, consistent with the mild reducing power of NaBH4. The reaction barrier decreases from the 2-halocyclohexanones to the unsubstituted cyclohexanone, in line with relative reactivities observed in the competitive experiments. Furthermore, we provide a protocol to solve the longstanding issue of properly modelling the axial–equatorial facial selectivity of hydride addition to the carbonyl group substituted with a vicinal polar group. The inclusion of implicit solvation in combination with an explicit solvent molecule is crucial to reproduce the stereoselective formation of the cis product observed experimentally.

The Zn(OTf)₂-catalyzed domino reaction of enamide-ynamides in the presence of trimethylsilyl cyanide as an external nucleophile to construct spirocyclic indolines was developed. This domino reaction involved cyclization of enamide to ynamide to generate 4', 5'-dihydrospiro[indoline-3, 3'-pyrrol]-1'-ium followed by cyanide addition to produce spiroindolopyrrolidines with good diastereoselectivity.

Visible light induced singlet nucleophilic carbenes undergo rapid [2 + 1]-cycloaddition with tethered olefins to afford unique bicyclo[3.1.0]hexane and bicyclo[4.1.0]heptane scaffolds.

Electrochemical glycosylation of a linear oligosaccharide with a protecting-group-free primary hydroxyl group afforded cyclic oligo-saccharides, up to hexasaccharides, in high yields. Precursors of the cyclic oligosaccharides were prepared by automated electro-chemical assembly-a method for the automated electrochemical solution-phase synthesis of oligosaccharides. We demonstrated that electrochemical glycosylation is useful not only for intermolecular glycosylation but also for intramolecular glycosylation to synthesize cyclic oligosaccharides.

Here we present the design of a highly enantioselective, catalytic (4 + 3) cycloaddition ofgem-dialkyl 2-indolylalcohols and dienolsilanes, enabled by strong and confined IDPi Lewis acids. The method furnishes novel bicyclo[3.2.2]cyclohepta-[b]indoles with up to three stereogenic centers, one of which is quaternary. A broad substrate scope is accompanied by versatiledownstream chemical modifications. Density functional theory-supported mechanistic studies shed light on the importance of the insitu generated silylium species in an overall concerted yet asynchronous cycloaddition.

The obligate intracellular bacterium Chlamydia trachomatis is the major causative agent of bacterial sexually transmitted diseases worldwide. In infected cells, the ceramide transport protein (CERT) is recruited to inclusions, where C. trachomatis replicates using host-synthesized ceramide. The ceramide is converted to sphingomyelin (SM) by a chlamydial infection-dependent SM synthesis (cidSM-synthesis) pathway, which occurs even in the absence of the SM synthases (SMS)-1 and -2 of host cells. The ceramide mimetic compound (1R,3S)-HPA-12 and the nonmimetic compound E16A, both of which are potent inhibitors of CERT, repressed the proliferation of C. trachomatis in HeLa cells. Unexpectedly, (1R,3R)-HPA-12, a ceramide mimetic compound that lacks CERT inhibitory activity, also exhibited potent anti-chlamydial activity. Using endogenous SMS-knockout mutant HeLa cells, we revealed that (1R,3R)-HPA-12 mildly inhibited cidSM-synthesis. In addition, LC-MS analysis revealed that (1R,3R)-HPA-12 is converted to a phosphocholine-conjugated metabolite in an infection-dependent manner. Imaging analysis with a fluorescent analog of ceramide suggested that cidSM-synthesis occurs in the bacterial bodies and/or inclusions. Collectively, these results suggested that (1R,3R)-HPA-12 exerts its anti-chlamydia activity not only as an inhibitor of cidSM-synthesis, but also via putative toxic effects of its phosphocholine adduct, which is most likely produced by the cidSM-synthesis route.

Free fatty acid receptor 1 (FFAR1) is a potential therapeutic target for the treatment of type 2 diabetes (T2D). It has been validated that agonists targeting FFAR1 can achieve the initial therapeutic endpoints of T2D, and the epimer agonists (R,S) AM-8596 can activate FFAR1 differently, with one acting as a partial agonist and the other as a full agonist. Up to now, the origin of the stereoselectivity of FFAR1 agonists remains elusive. In this work, we used molecular simulation methods to elucidate the mechanism of the stereoselectivity of the FFAR1 agonists (R)-AM-8596 and (S)-AM-8596. We found that the full agonist (R)-AM-8596 disrupts the residue interaction network around the receptor binding pocket and promotes the opening of the binding site for the G-protein, thereby resulting in the full activation of FFAR1. In contrast, the partial agonist (S)-AM-8596 forms stable electrostatic interactions with FFAR1, which stabilizes the residue network and hinders the conformational transition of the receptor. Our work thus clarifies the selectivity and underlying molecular activation mechanism of FFAR1 agonists., QC 20230510

We report the first examples of the use of a new class of ligands (NOBINAc) for performing asymmetric C–H activations using palladium catalysts. These ligands combine the axial chirality of binaphthyl scaffolds with the bifunctional and bidentate coordination properties of mono-N-protected amino acids (MPAAs), which are well-known to favor Pd-promoted C–H activations via concerted metalation–deprotonation mechanisms. We demonstrate that our new ligands enable substantially higher enantioselectivities than MPAAs in the assembly of 2-benzazepines through formal (5 + 2) cycloadditions between homobenzyltriflamides or o-methylbenzyltriflamides and allenes

Multi-step cascade reactions have gained increasing attention in the biocatalysis field in recent years. In particular, multi-enzymatic cascades can achieve high molecular complexity without workup of reaction intermediates thanks to the enzymes’ intrinsic selectivity; and where enzymes fall short, organo-or metal catalysts can further expand the range of possible synthetic routes. Here, we present two enantiocomplementary (chemo)-enzymatic cascades composed of either a styrene monooxygenase (StyAB) or the Shi epoxidation catalyst for enantioselective alkene epoxidation in the first step, coupled with a halohydrin dehalogenase (HHDH)-catalysed regioselective epoxide ring opening in the second step for the synthesis of chiral aliphatic non-terminal azidoalcohols. Through the controlled formation of two new stereocenters, corresponding azidoalcohol products could be obtained with high regioselectivity and excellent enantioselectivity (99% ee) in the StyAB-HHDH cascade, while product enantiomeric excesses in the Shi-HHDH cascade ranged between 56 and 61%., BT/Biocatalysis

Protected aldols (i.e., true aldols derived from aldehydes) with either syn- or anti- stereochemistry are versatile intermediates in many oligopropionate syntheses. Traditional stereoselective approaches to such aldols typically require several nonstrategic operations. Here we report two highly enantioselective and diastereoselective catalytic Mukaiyama aldol reactions of the TBS- or TES- enolsilanes of propionaldehyde with aromatic aldehydes. Our reactions directly deliver valuable silyl protected propionaldehyde aldols in a catalyst controlled manner, either as syn- or anti- isomer. We have identified a privileged IDPi catalyst motif that is tailored for controlling these aldolizations with exceptional selectivities. We demonstrate how a single atom modification in the inner core of the IDPi catalyst, replacing a CF3-group with a CF2H-group, leads to a dramatic switch in enantiofacial differentiation of the aldehyde. The origin of this remarkable effect was attributed to tightening of the catalytic cavity via unconventional C-H hydrogen bonding of the CF2H group.

[Background and Purpose]: Local anaesthetics block sodium and a variety of potassium channels. Although previous studies identified a residue in the pore signature sequence together with three residues in the S6 segment as a putative binding site, the precise molecular basis of inhibition of Kv channels by local anaesthetics remained unknown. Crystal structures of Kv channels predict that some of these residues point away from the central cavity and face into a drug binding site called side pockets. Thus, the question arises whether the binding site of local anaesthetics is exclusively located in the central cavity or also involves the side pockets. [Experimental Approach]: A systematic functional alanine mutagenesis approach, scanning 58 mutants, together with in silico docking experiments and molecular dynamics simulations was utilized to elucidate the binding site of bupivacaine and ropivacaine. [Key Results]: Inhibition of Kv1.5 channels by local anaesthetics requires binding to the central cavity and the side pockets, and the latter requires interactions with residues of the S5 and the back of the S6 segments. Mutations in the side pockets remove stereoselectivity of inhibition of Kv1.5 channels by bupivacaine. Although binding to the side pockets is conserved for different local anaesthetics, the binding mode in the central cavity and the side pockets shows considerable variations. [Conclusion and Implications]: Local anaesthetics bind to the central cavity and the side pockets, which provide a crucial key to the molecular understanding of their Kv channel affinity and stereoselectivity, as well as their spectrum of side effects.

Eight related alcohol dehydrogenases that had been originally isolated by laboratory evolution of ADH-A from Rhodococcus ruber DSM44541 for modified substrate scopes, were together with their parent wild-type, subjected to biochemical characterization of possible activities with a panel of chiral alcohols and pro-chiral ketones. Determinations of rates of catalyzed alcohol oxidations and ketone reductions, and of cofactor release, pointed out to the role of a W295A substitution as being decisive in steering enantioselectivity in the oxidation of arylated 1-methyl substituted alcohols. Molecular dynamics simulations of enzyme-substrate interactions in the Michaelis complexes of wild-type and a Y294F/W295A double mutant could rationalize the experimentally observed shift in enantioselectivity and differences in catalytic activity with 4-phenyl-2-butanol. Finally, we present herein evidence for apparent inter-dependency between substrate/product and the cofactor in the ternary complex, that directly affects the NADH dissociation rates, and thus that this substrate-coenzyme crosstalk plays a direct role in determining the turnover rates.

In this invited Account, we highlight the enormous scientific breadth of our mentor Professor Manfred T. Reetz. It stretches from the development of organometallic reagents and transition metal catalysts to the adventurous idea of directed evolution of chemo-, stereo-, and regioselective enzymes, which he considered to be most important. We hope to show that Reetz did not consider these research areas to be totally unrelated realms, and attempt to reveal his transdisciplinary way of thinking about methodology development. Since biocatalysis has become crucial for chemical synthesis, we mainly focus on Reetz's contributions in this area. Some personal reflections from some of his former co-workers are also included, which reveal the stimulating atmosphere in the Reetz group in terms of science, career advice, and the importance of ethical considerations., BT/Biocatalysis

Stereoselectivity in the mutual kinetic resolution (KR) of racemic 3,4-dihydro-3-methyl-2H-[1,4]benzoxazines and racemic 2-aryloxy propionyl chlorides was studied. Based on the results obtained, preparative methods for single enantiomers of a series of 2-aryloxy propionic acids via acylative KR of their racemates with enantiopure (S)-3,4-dihydro-3-methyl-2H-[1,4]benzoxazines have been proposed. © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Roles of internal salicylate donors (SID) in enhancing activity and stereoselectivity of Ziegler-Natta catalyzed propylene (PP) polymerization were examined using DFT calculations. Five salicylate donors were studied. The chelate mode is the preferred adsorption mode. The linear relationship (R-2 = 0.96) between calculated adsorption energies (E-ads) of five SIDs and the experimental PP activities was observed. Thus, the SID with the strongest adsorption energy will provide the highest activity in agreement with our previous studies. Compared with diisobutyl phthalate (DIBP), which is the industrial electron donor, SID has stronger E-ads. The insertion step, which involves the pi-complex formation (E-pi) and the insertion activation or intrinsic activation energy (E-a) for PP polymerization was also examined. The relation between ln(activity) and apparent activation energy (E-a(app)), which is E-pi + E-a for the primary(1,2)-re insertion with R-2 = 0.99, was observed. The salicylate donor also has a lower E-a(app) than that of DIBP. This explains the better catalytic performance of SID. Our results also demonstrated that the size and the type of hydrocarbon substituents play a key role in controlling stereoselectivity and activity. In addition, we found a good relationship between E-ads and both intrinsic (E-a) and apparent (E-a(app)) activation energies of five salicylate donors with R-2 of 0.90 and 0.97, respectively.

An efficient Ugi-type three-component reaction (U-3CR) for the synthesis of pipecolic amides is reported. The U-3CR between electronically diverse isocyanides, carboxylic acids and 4-substituted Δ1-piperideines proceeds in a highly diastereoselective fashion. The Δ1-piperideines are obtained by NCS-mediated oxidation of the corresponding 4-substituted piperidines, which in turn are generated by an efficient two-step procedure involving the alkylation of 4-picoline and subsequent catalytic hydrogenation of the pyridine ring. We demonstrate the utility of this U-3CR, in combination with the convertible isocyanide 2-bromo-6-isocyanopyridine, in the synthesis of the anticoagulant argatroban.

[EN] A highly regio- and stereoselective synthesis of 3-alkylidene-2-oxindoles has been described through a nucleophilic vinylic substitution (SNV) of (E)-3-(nitromethylene)indolin-2-one using pyrazol-3-ones as nucleophiles and Et3N as a base. The reaction affords selectively the Z-isomer when pyrazol-3-ones without substituents at the 4 position are used. While the reaction is E-selective with 4- substituted pyrazolones. The stereoselectivity (up to >20:1) and the yields (up to 98%) are very high under mild reaction conditions.

Enzymes are biomolecules built from amino acids and catalyze the chemical transformations in a cell. Enzymes are by nature stereoselective, biodegradable, environmentally friendly, and can perform catalysis in aqueous solutions and at ambient temperatures. Due to these advantages the use of enzymes as biocatalysts for chemical transformations has emerged as an attractive “greener” alternative to conventional chemical synthesis strategies. And, if naturally occurring enzymes cannot carry out the desired chemical transformations, the functional properties of enzymes can be modified by directed evolution or protein engineering techniques. Since enzymes are genetically encoded they can be optimized for desired traits such as substrate selectivity or improved catalytic efficiency. Considering these advantages and also keeping the synthetic and industrial application in mind, we have employed alcohol dehydrogenase-A (ADH-A) from Rhodococcus ruber DSM 44541 as a study object in engineering for new catalytic properties. ADH-A tolerates water miscible organic solvents, accepts a relatively wide range of aromatic sec-alcohols/ketones as substrates and is therefore a potentially useful biocatalyst for asymmetric synthesis of organic compounds. Presented research work in this thesis has been primarily focused on engineering of ADH-A and characterization of resulting enzyme variants. The engineering efforts have aimed for altered substrate scope, as well as stereo- and regioselectivities. Furthermore, possible substrate promiscuity in engineered enzyme variants has also been addressed. In short, i). Paper I: three sub sites, each consisting of two-three amino acid residues within the active-site cavity were exposed to saturation mutagenesis in step-wise manner, coupled to an in vitro selection for improved catalytic activity with the unfavored (R)-1-phenylethanol. The observed stereoselectivity could be explained partly by a shift in nonproductive substrate binding. ii). Paper

A highly efficient palladium-catalyzed functionalization of allenylsilanes to give regio- and stereodefined fully-substituted alkenylsilanes has been developed. This oxidative coupling reaction showed good functional group compatibility with exclusive regio- and stereoselectivity. The pending olefin on the silyl group was shown to be an indispensable element for the initial allenic C(sp(3))-H bond cleavage, and performs as the directing group to control the overall selectivity. The addition of substoichiometric amounts of Et3N was found to increase the reaction rate leading to a higher reaction yield. The reaction can be easily scaled up and applied for the late-stage functionalization of natural products and pharmaceutical compounds, including amino acids and steroid derivatives. The newly introduced functional groups include aryl, alkynyl, and boryl groups. The highly strained four-membered ring, silacyclobutene was obtained when B(2)pin(2) was employed as the coupling partner. Mechanistic studies, including kinetic isotope effects, showed that the allenic C(sp(3))-H bond cleavage is the rate-limiting step.

The white-rot fungus Ceriporiopsis subvermispora delignifies plant biomass extensively and selectively and, therefore, has great biotechnological potential. We previously demonstrated that after 7 weeks of fungal growth on wheat straw 70% w/w of lignin was removed and established the underlying degradation mechanisms via selectively extracted diagnostic substructures. In this work, we fractionated the residual (more intact) lignin and comprehensively characterized the obtained isolates to determine the susceptibility of wheat straw lignin's structural motifs to fungal degradation. Using 13C IS pyrolysis gas chromatography-mass spectrometry (py-GC-MS), heteronuclear single quantum coherence (HSQC) and 31P NMR spectroscopy, and size-exclusion chromatography (SEC) analyses, it was shown that β-O-4′ ethers and the more condensed phenylcoumarans and resinols were equally susceptible to fungal breakdown. Interestingly, for β-O-4′ ether substructures, marked cleavage preferences could be observed: β-O-4′-syringyl substructures were degraded more frequently than their β-O-4′-guaiacyl and β-O-4′-tricin analogues. Furthermore, diastereochemistry (threo > erythro) and γ-acylation (γ-OH > γ-acyl) influenced cleavage susceptibility. These results indicate that electron density of the 4′-O-coupled ring and local steric hindrance are important determinants of oxidative β-O-4′ ether degradation. Our findings provide novel insight into the delignification mechanisms of C. subvermispora and contribute to improving the valorization of lignocellulosic biomass.

Electrochemical glycosylation of a linear oligosaccharide with a protecting-group-free primary hydroxyl group afforded cyclic oligo-saccharides, up to hexasaccharides, in high yields. Precursors of the cyclic oligosaccharides were prepared by automated electro-chemical assembly-a method for the automated electrochemical solution-phase synthesis of oligosaccharides. We demonstrated that electrochemical glycosylation is useful not only for intermolecular glycosylation but also for intramolecular glycosylation to synthesize cyclic oligosaccharides., identifier:https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/open.201900185

An operationally simple in situ protection/deprotection strategy that significantly expands the scope of kinetically controlled catalytic Z- and E-selective olefin metathesis is introduced. Prior to the addition of a sensitive Mo- or Ru-based complex, treatment of a hydroxy- or a carboxylic-acid-containing olefin with commercially available HB(pin) or readily accessible HB(trip)2 (pin=pinacolato, trip=2,4,6-tri(isopropyl)phenyl) for 15 min is sufficient for efficient generation of a desired product. Routine workup leads to quantitative deprotection. A range of stereochemically defined Z- and E-alkenyl chlorides, bromides, fluorides, and boronates or Z-trifluoromethyl-substituted alkenes with a hydroxy or carboxylic acid group were thus prepared in 51-97 % yield with 93 to >98 % stereoselectivity. We also show that, regardless of whether a polar functional unit is present or not, a small amount of HB(pin) may be used to remove residual water, significantly enhancing efficiency.

ADH-A from Rhodococcus ruber DSM 44541 catalyzes the oxidation of (S)-1-phenylethanol 3000-fold more efficiently as compared with the 2-hydroxylated derivative (R)-phenylethane-1,2-diol. The enzyme is also highly selective for sec-alcohols with comparably low activities with the corresponding primary alcohols. When challenged with a substrate containing two secondary alcohols, such as 1-phenylpropane-(1R,2S)-diol, ADH-A favors the oxidation of the benzylic carbon of this alcohol. The catalytic efficiency, however, is modest in comparison to the activity with (S)-1-phenylethanol. To investigate the structural requirements for improved oxidation of vicinal diols, we conducted iterative saturation mutagenesis combined with activity screening. A first-generation variant, B1 (Y54G, L119Y) displays a 2-fold higher k(cat) value with 1-phenylpropane-(1R,25)-diol and a shift in the cooperative behavior in alcohol binding, from negative in the wild type, to positive in B1, suggesting a shift from a less active enzyme form (T) in the wild type to a more active form (R) in the B1 variant. Also, the regiopreference changed to favor oxidation of C-2. A second-generation variant, B1F4 (F43T, Y54G, L119Y, F282W), shows further improvement in the turnover and regioselectivity in oxidation of 1-phenylpropane-(1R,2S)-diol. The crystal structures of the B1 and B1F4 variants describe the structural alterations to the active site, the most significant of which is a repositioning of a Tyr side-chain located distal to the coenzyme and the catalytic zinc ion. The links between the changes in structures and stereoselectivities are rationalized by molecular dynamics simulations of substrate binding at the respective active sites., QC 20180917

The mechanism for the iridium-catalyzed asymmetric hydrogenation of prochiral imines has been investigated for an experimentally relevant ligand substrate combination using DFT calculations. The possible stereoisomers of the stereodetermining hydride transfer transition state were considered for four possible hydrogenation mechanisms starting from the recently disclosed active catalyst consisting of iridium phosphine-oxazoline with cyclometalated imine substrate. The hydrogenation was found to proceed via an outer sphere pathway. The transition state accurately describes the experimental observations of the active catalyst and provides a structural rationale for the high stereoinduction despite the lack of direct interaction points in the outer-sphere mechanism. The predicted enantioselectivity was consistent with experimental observations. Experimental studies support the hypothesis that the iridacycle forms spontaneously and functions as the active catalyst in the hydrogenation.

The development of polymeric materials with novel structures and unique properties and functionalities is of both academic and industrial significance. In this work, functional poly(dihalopentadiene)s were synthesized by boron trihalide-mediated multicomponent polymerization routes in a stereoselective manner. The polymerizations of tetraphenylethylene-containing diyne, BX3 (X = Cl, Br) and p-tolualdehyde proceed smoothly in dichloromethane under mild conditions to afford high molecular weight poly(dihalopentadiene)s with a predominant (Z, Z)-configuration in moderate to good yields. The reaction conditions and the boron trihalide used were found to have great effects on the stereochemistry of the resulting polymer structures. The obtained poly(1,5-dihalo-(Z, Z)-1,4-pentadiene)s possess high thermal stability and good film-forming ability. Their thin films show high refractive index of 1.9007-1.6462 in a wide wavelength region of 380-890 nm with low optical dispersion. The polymers are weakly emissive in dilute solutions but become highly emissive upon aggregated, demonstrating a unique phenomenon of aggregation-enhanced emission. Their nanoaggregates in aqueous media can serve as sensitive fluorescent chemosensors for the detection of explosives with a superamplification effect and a low detection limit. © 2018 by the authors.

Highly enantioenriched, chromatographically-stable secondary allyl boronates featuring a 1,1,2,2-tetraethyl-1,2-ethanediol fragment (Epin) were obtained by kinetic resolution of their racemic mixtures. The Epin group at boron considerably improved stability of allyl boronates allowing them to be readily isolated by chromatography on silica. The resolved reagents were applied in stereoselective synthesis of homoallylic amines with an internal double bond employing unprotected imines formed in situ from aldehydes and ammonia. The reactions proceeded with an excellent transfer of chirality

The trans isomer of the organogold(III) difluoride complex [PPh4 ][(CF3 )2 AuF2 ] has been obtained in a stereoselective way and in excellent yield by reaction of [PPh4 ][CF3 AuCF3 ] with XeF2 under mild conditions. The compound is both thermally stable and reactive. Thus, the fluoride ligands are stereospecifically replaced by any heavier halide or by cyanide, the cyanide affording [PPh4 ][trans-(CF3 )2 Au(CN)2 ]. The organogold fluoride complexes [CF3 AuFx ]- (x=1, 2, 3) have been experimentally detected to arise upon collision-induced dissociation of the [trans-(CF3 )2 AuF2 ]- anion in the gas phase. Their structures have been calculated by DFT methods. In the isomeric forms identified for the open-shell species [CF3 AuF2 ]- , the spin density residing on the metal center is found to strongly depend on the precise stereochemistry. Based on crystallographic evidence, it is concluded that Auiii and Agiii have similar covalent radii, at least in their most common square-planar geometry.

A structure‐guided engineering of fructose‐6‐phosphate aldolase was performed to expand its substrate promiscuity toward aliphatic nucleophiles, i.e., unsubstituted alkanones and alkanals. A "smart" combinatorial library was created targeting residues D6, T26 and N28 that form a binding pocket around the nucleophilic carbon atom. Double‐selectivity screening was executed by high‐performance TLC that allowed simultaneous determination of total activity as well as a preference for acetone versus propanal as competing nucleophiles. While any mutation of N28 resulted in inactivation of the enzyme, D6 turned out to be the key residue that enabled activity with non‐hydroxylated nucleophiles. Altogether 25 single‐ and double‐site variants (D6X and D6X/T26X) were discovered that show useful synthetic activity and a varying preference for ketone or aldehyde as the aldol nucleophiles. Remarkably, all of the novel variants had completely lost their native activity for cleavage of fructose 6‐phosphate.

Complete stereocontrol on the transition‐metal‐free hydroboration of the distal double bond of allenamides could be achieved when allenamides contained acetyl substituents, which provided exclusively the Z‐isomer. The consecutive Pd‐catalyzed cross‐coupling reaction allowed the straightforward formation of trisubstituted enamides, with total control of the stereoselectivity.

Gem-diborylalkenes have emerged as efficient reagents for selective cross-coupling reactions, reduction approaches and Michael additions. The synthesis of the 1,1-diborylalkenes involves condensation of polyborated compounds with aldehydes or ketones followed by B-O elimination, geminal diboration of 1,1-dihaloalkenes, 1-haloalkenes as well as terminal alkynes, dehydrogenative borylation of alkenes, borylation of alkynylboronates and hydroboration of alkynylboronates. These new set of reactions become general for a wide range of substrates and they can be understood by complementary mechanisms.

Alcohol dehydrogenase A (ADH-A) from Rhodococcus ruber DSM 44541 is a promising biocatalyst for redox transformations of arylsubstituted sec-alcohols and ketones. The enzyme is stereoselective in the oxidation of 1-phenylethanol with a 300-fold preference for the (S)-enantiomer. The low catalytic efficiency with (R)-1-phenylethanol has been attributed to nonproductive binding of this substrate at the active site. Aiming to modify the enantioselectivity, to rather favor the (R)-alcohol, and also test the possible involvement of nonproductive substrate binding as a mechanism in substrate discrimination, we performed directed laboratory evolution of ADH-A. Three targeted sites that contribute to the active-site cavity were exposed to saturation mutagenesis in a stepwise manner and the generated variants were selected for improved catalytic activity with (R)-1-phenylethanol. After three subsequent rounds of mutagenesis, selection and structure-function analysis of isolated ADH-A variants, we conclude: (1) W295 has a key role as a structural determinant in the discrimination between (R)- and (S)-1-phenylethanol and a W295A substitution fundamentally changes the stereoselectivity of the protein. One observable effect is a faster rate of NADH release, which changes the rate-limiting step of the catalytic cycle from coenzyme release to hydride transfer. (2) The obtained change in enantiopreference, from the (S)- to the (R)-alcohol, can be partly explained by a shift in the nonproductive substrate binding modes.

An eco-friendly dual catalyst system for stereoselective aldol reactions in the presence of water is described. It is based on the cooperative action of acyclic amino acids and H-bond donating hydroxy oxime catalysts. The synthetic utility of this dual catalyst system was further demonstrated by applying it as the key step in the expeditious and highly stereoselective total synthesis of D-lyxo-phytosphingosine (29% overall yield). Here the amino acid/hydroxy oxime system significantly accelerated the direct aldol reactions in the presence of water as compared to organic solvents. The stereo-and chemoselectivity were also significantly increased., Financial support was provided by Mid Sweden University and the Swedish National Research Council (VR).

Alkenylboranes have been vital reagents in modern synthetic organic chemistry, whose carbon–boron bond is transformable into a carbon–carbon bond stereoretentively to give such invaluable mutisubstituted alkenes as natural products, biologically active molecules and functional materials. Introduction of a boryl moiety across a carbon–carbon triple bond of alkynes (borylation of alkynes) is one of the most direct and potent methods for synthesizing alkenylboranes, and this field has thus far experienced remarkable progress mainly with group 10 transition metal catalysts (Ni, Pd, Pt), which enables highly functionalized alkenylboranes to be constructed stereoselectively. On the other hand, much attention has recently been focused on appealing catalysis of base (Fe, Co) and coinage (Cu, Ag, Au) metals toward the borylation of alkynes, which is summarized in this perspective.

The catalytic asymmetric allylboration of cyclic imines with gamma,gamma-disubstituted allylboronic acids provides products with adjacent stereocenters in high yield and stereoselectivity. Various electrophiles, including 3,4-dihydroisoquinolines and indoles, were prenylated in a fully stereodivergent fashion by switching the E/Z geometry of the allylboronate and/or the enantiomer of the BINOL catalyst. 3-Methylindole provided products with three adjacent stereocenters with high stereoselectivity in one synthetic operation.

Directed evolution of stereo- and regioselective enzymes constitutes a prolific source of catalysts for asymmetric transformations in organic chemistry. In this endeavor (iterative) saturation mutagenesis at sites lining the binding pocket of enzymes has emerged as the method of choice, but uncertainties regarding the question of how to group many residues into randomization sites and how to choose optimal upward pathways persist. Two new approaches promise to beat the numbers problem effectively. One utilizes a single amino acid as building block for the randomization of a 10-residue site, the other also employs only one but possibly different amino acid at each position of a 9-residue site. The small but smart libraries provide highly enantioselective epoxide hydrolase or lipase mutants, respectively.

An efficient, one-pot procedure for the Hofmann rearrangement of aromatic and aliphatic amides has been developed. Methyl and benzyl carbamates are produced with N-bromoacetamide in the presence of lithium hydroxide or lithium methoxide, in high yields. -Phenylamino amides gave five-membered cyclic ureas stereospecifically. Side products of aryl or benzyl bromination were minimized. This procedure offers an easy access to various protected amines or diamines, which represent important synthetic precursors.

The large consumption of freshwater in fermentations and bio-transformations is a matter of concern for the sustainability of many bio-processes. The use of seawater to perform bio-processes is a sustainable alternative. In this work, we used marine yeasts from deep-sub-seafloor sediments grown in seawater as bio-catalysts to perform the stereoselective reduction of different ketones, and the bio-transformations were accomplished in seawater as well. Strains of Meyerozyma guilliermondii and Rhodotorula mucilaginosa were able to reduce different aromatic ketones with high molar conversions and moderate-to-high enantioselectivity with no significant differences between bio-catalysis performed in seawater and freshwater. Finally, the selected marine yeasts were used for the reduction of key intermediates in seawater for the synthesis of molecules of pharmaceutical interest (desogestrel, norgestrel, gestodene, pramipexole).

A detailed study on the diastereoselective oxidation of 1-thio-β-D-glucopyranosides is reported. It has been shown that the sense and the degree of stereochemical outcome of the oxidation are highly depen- dent on the substituent of the sulfur and on the protective group of the C2–OH. In the case of thioglyco-sides with a bulky aglycone, the mesylation of C2–OH has a significant effect on the stereochemical outcome of the oxidation, affording the usually less favoured RS sulfoxide as a single diastereoisomer. The absolute configuration of the final sulfinyl glycosides was ascertained by NMR analysis and corroborated by X-ray crystallography.

Pericyclic reactions are important class of chemical reaction because they occur stereospecifically often with a high degree of regio-, stereoselectivity, and atom economy. This dissertation summarizes our efforts – using chemical computations – to better understand how these reactions occur in both biological and abiological settings.This dissertation is divided into two portions; the first of which describes quantum mechanical studies of biosynthetic and enzyme-catalyzed cycloadditions. Chapter 1, 2, and 3 detail studies of these enzymatic processes. Using state-of-the-art density functional theory, we have determined whether these reactions are feasible biosynthetic transformations, elucidated the mechanistic subtleties of these reactions, and proposed how enzymes may catalyze such transformations. Chapter 1 describes a computational study of a strained biosynthetic transannular 1,3-dipolar cycloaddition. Computations reveal that substrate preorganization overrides distortion in the transitions, resulting in a reaction is feasible. Efforts to account for the influence of water – through solvent-solute hydrogen-bonding interactions – were modeled using “mircosolvated” reactant and transition states: We conclude that the reaction remains feasible in aqueous media. Strategic hydrogen bonding, according to theory, can accelerate the reaction by 2000-fold. Chapter 2 summarizes a computational investigation of the Diels-Alder reaction involved in the biosynthesis of spinosyn A. We find that the mechanism of this transannular cycloaddition is “ambimodal”, proceeding through a “bis-pericyclic” transition structure that leads directly two products, the observed Diels-Alder adduct and an unstable [6+4] adduct. This [6+4] adduct can readily and irreversibly rearrange into the Diels-Alder adduct via a Cope rearrangement. Simulations of the reaction mechanism determine that the nonenzymatic cycloaddition occurs predominantly via a mechanism that involves the intermediacy of t