The first reported twisted bis-lactam, a racemic Trö ger's base (TB) analogue (2), was resolved i... more The first reported twisted bis-lactam, a racemic Trö ger's base (TB) analogue (2), was resolved into its enantiomers on a chiral stationary phase HPLC column. The absolute configuration of (+)-2 was determined to be (R,R)-2 by comparing experimental and calculated vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectra. The absolute configuration of (−)-2 was determined by comparing experimental and calculated electronic circular dichroism (ECD) spectra. The corresponding theoretical spectra were calculated using the lowest energy conformation of (R,R)-2 and (S,S)-2 at the B3LYP/6-31G(d,p) level of theory. The absolute configuration of (+)-2 was also determined to (R,R)-2 by anomalous X-ray diffraction (AXRD) in a chiral space group P2 1 2 1 2 1 using Cu-irradiation resulting in a very low Flack parameter of −0.06(3), despite the heaviest element being an oxygen atom, thus unambiguously confirming the results from the spectroscopic studies. We conclude that, for the Trö ger's base (TB) analogue (2), we may rank the reliability of the individual methods for AC determination as AXRD ≫ VCD > ECD, while the synergy of all three methods provides very strong confidence in the assigned ACs of (+)-(R,R)-2 and (−)-(S,S)-2.
Chemical processes capable of reducing the high oxygen content of biomass-derived polyols are in ... more Chemical processes capable of reducing the high oxygen content of biomass-derived polyols are in demand in order to produce renewable substitutes for chemicals of fossil origin. Deoxydehydration (DODH) is an attractive reaction that in a single step transforms a vicinal diol into an alkene, but the reaction requires a homogeneous catalyst, a reductant, and a solvent, which are typically expensive, unsustainable, or inefficient. Herein, we present the use of molybdenum(VI)-based compounds, in particular the cheap and commercially available (NH 4) 6 Mo 7 O 24 ·4H 2 O, as catalysts for the DODH of vicinal diols in isopropyl alcohol (i PrOH), which serves as both the solvent and reductant. The reaction proceeds at 240−250 °C in a pressurized autoclave, and the alkene yield from simple aliphatic diols can be as high as 77%. The major byproducts are carbonyl compoundsformed by dehydration of the dioland the alcohols formed by transfer hydrogenation of the carbonyl compounds; the total yield of reduced species (i.e., alkene and alcohols) can be as high as 92%. The DODH of glycerol yields allyl alcohol, which undergoes subsequent Mo-catalyzed deoxygenation to propylene driven by the oxidation of i PrOH; a major byproduct is the homocoupled product 1,5-hexadiene. Further insight in this Mo-catalyzed deoxygenation is gained by an investigation of model compounds: The allylic alcohol 1-hexen-3-ol is deoxygenated to hexene isomers in a yield of 65%, while benzyl alcohol is deoxygenated to toluene in a yield of 93%. The DODH of erythritol yields 39% 2,5-dihydrofuran, while the DODH of the proposed intermediate 1,4-anhydroerythritol yields 75%. The mechanism of the DODH of 1,4-anhydroerythritol was investigated by means of density functional theory (DFT), and the rate-determining step (24.1 kcal/mol) was found to be reduction of a molybdenum(VI) diolate to a molybdenum(IV) diolate.
beta-Peptoids are peptidomimetics based on N-alkylated b-aminopropionic acid residues (or N-alkyl... more beta-Peptoids are peptidomimetics based on N-alkylated b-aminopropionic acid residues (or N-alkyl-b-alanines). This type of peptide mimic has previously been incorporated in biologically active ligands and has been hypothesized to be able to exhibit foldamer properties. Here we show, for the first time, that b-peptoids can be tuned to fold into stable helical structures. We provide high-resolution X-ray crystal structures of homomeric b-peptoid hexamers, which reveal right-handed helical conformations with exactly three residues per turn and a helical pitch of 9.6–9.8 Å between turns. The presence of folded conformations in solution is supported by circular dichroism spectroscopy showing length-and solvent dependency, and molecular dynamics simulations provide further support for a stabilized helical secondary structure in organic solvent. We thus outline a framework for future design of novel biomimetics that display functional groups with high accuracy in three dimensions, which has potential for development of new functional materials.
Determination of experimental kinetic isotope effects (KIE) is one of the most useful tools for t... more Determination of experimental kinetic isotope effects (KIE) is one of the most useful tools for the exploration of reaction mecha- nisms in organometallic chemistry. The approach has been further strengthened during the last decade with advances in modern compu- tational chemistry. This allows for the calculation of a theoretical KIE that can often be compared directly to the experimental value. This combined experimental/theoretical approach can be particularly useful in cases where the value of the experimental KIE is not directly associat- ed with one particular reaction step (e.g., in a catalytic reaction). The approach is highlighted by using recent examples from both stoichio- metric and catalytic reactions, homogeneous and heterogeneous catal- ysis, and enzyme catalysis to illustrate the expected accuracy and utility of this approach.
This study focuses on increasing the selectivity to methyl lac-tate from sugars using stannosilic... more This study focuses on increasing the selectivity to methyl lac-tate from sugars using stannosilicates as heterogeneous catalyst. All group I ions are found to have a promoting effect on the resulting methyl lactate yield. Besides, the alkali ions can be added both during the preparation of the catalyst or directly to the solvent mixture to achieve the highest reported yield of methyl lactate (ca. 75 %) from sucrose at 170 8C in methanol. The beneficial effect of adding alkali to the reaction media applies not only to highly defect-free Sn-Beta prepared through the fluoride route, but also to materials prepared by post-treatment of dealuminated commercial Beta zeolites, as well as ordered mesoporous stannosilicates, in this case Sn-MCM-41 and Sn-SBA-15. These findings open the door to the possibility of using other preparation methods or different Sn-containing sil-icates with equally high methyl lactate yields as Sn-Beta.
The mechanism of the molybdenum-catalyzed de- oxydehydration (DODH) of vicinal diols has been inv... more The mechanism of the molybdenum-catalyzed de- oxydehydration (DODH) of vicinal diols has been investigat- ed using density functional theory. The proposed catalytic cycle involves condensation of the diol with an MoVI oxo complex, oxidative cleavage of the diol resulting in an MoIV complex, and extrusion of the alkene.
The mechanism of the CH3ReO3-catalyzed deoxydehydration of a vicinal diol to an alkene driven by ... more The mechanism of the CH3ReO3-catalyzed deoxydehydration of a vicinal diol to an alkene driven by oxidation of a secondary alcohol was investigated by time-resolved, in situ IR spectros- copy and was found to occur in three steps: 1) reduction of the catalytically active methyltrioxorhenium(VII) to a rhenium(V) complex (the rate-limiting step), 2) condensation of the diol and the rhenium(V) complex to a rhenium(V) diolate, and 3) extrusion of the alkene accompanied by oxidation of the Re center and thus regeneration of CH3ReO3. The reaction follows zero-order kinetics initially but, unexpectedly, accelerates to- wards the end, which is explained in terms of a deactivating pre-equilibrium, in which the catalytically active CH3ReO3 con- denses reversibly with the diol to form an inactive rhenium(VII) diolate. This conclusion is supported by the direct observation of a catalytically inactive species as well as DFT calculations of the IR spectra of the relevant compounds.
We disclose a hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds wi... more We disclose a hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds with dialkylzinc as the alkyl source. The reaction is applicable to all common classes of ketones including 1,3-dicarbonyl compounds and regular ketones via their lithium enolates. The α-alkylated carbonyl products are formed in up to 93% yield. An ionic mechanism is inferred based on meticulous analysis, NMR studies, trapping and crossover experiments, and computational studies.
The crystallization of Sn-Beta in fluoride medium is greatly influenced by the amount and type of... more The crystallization of Sn-Beta in fluoride medium is greatly influenced by the amount and type of tin source present in the synthesis gel. By varying the amount of tin in the form of tin(IV) chloride pentahydrate, the time required for crystallization was studied. It was found that tin not only drastically affects the time required for crystallization, but also that the presence of tin changes the morphology of the formed Sn-Beta crystals. For low amounts of tin (Si/Sn ¼ 400) crystallization occurs within four days and the Sn-Beta crystals are capped bipyramidal in shape, whereas for high amounts of tin (Si/Sn ¼ 100) it takes about sixty days to reach full crystallinity and the resulting crystals are highly truncated, almost plate-like in shape. Using SEM-WDS to investigate the tin distribution along transverse sections of the Sn-Beta crystals, a gradient distribution of tin was found in all cases. It was observed that the tin density in the outer parts of the Sn-Beta crystals is roughly twice as high as in the tin depleted core of the crystals. Sn-Beta was found to obtain its maximum catalytic activity for the conversion of dihydroxyacetone to methyl lactate close to the minimum time required for obtaining full crystallinity. At excessive crystallization times, the catalytic activity decreased, presumably due to Ostwald ripening.
Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for... more Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides (J. Med. Chem. 2013, 56, 6512). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme−ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1−3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.
PERSPECTIVE P. Fristrup et al. Synergy between experimental and theoretical methods in the explor... more PERSPECTIVE P. Fristrup et al. Synergy between experimental and theoretical methods in the exploration of homogeneous transition metal catalysis Featuring the themed issue: Synergy between experiment and theory In this Perspective, we will focus on the use of both experimental and theoretical methods in the exploration of reaction mechanisms in homogeneous transition metal catalysis. We briefly introduce the use of Hammett studies and kinetic isotope effects (KIE). Both of these techniques can be complemented by computational chemistry – in particular in cases where interpretation of the experimental results is not straightforward. The good correspondence between experiment and theory is only possible due to recent advances within the applied theoretical framework. We therefore also highlight the innovations made in the last decades with emphasis on dispersion-corrected DFT and solvation models. The current state-of-the-art is highlighted using examples from the literature with particular focus on the synergy between experiment and theory.
The commercially available (NH 4) 6 Mo 7 O 24 and other molybde-num compounds are shown to be via... more The commercially available (NH 4) 6 Mo 7 O 24 and other molybde-num compounds are shown to be viable substitutes for the typically employed rhenium compounds in the catalytic deoxy-dehydration of aliphatic diols into the corresponding alkenes. The transformation, which represents a model system for the various hydroxyl groups found in biomass-derived carbohydrates , can be conducted in an inert solvent (dodecane), under solvent-free conditions, and in a solvent capable of dissolving biomass-derived polyols (1,5-pentanediol). The reaction is driven by the simultaneous oxidative deformylation of the diol resulting in an overall disproportionation of the substrate. The transformation of biomass-derived compounds into platform chemicals is one of the possible contributions to the realization of an economy completely independent of fossil reserves. In order for oxygen-rich biomass-derived compounds such as glycerol and sugar alcohols to substitute petroleum, reactions capable of reducing their oxygen content are in demand, [1] and in particular the deoxydehydration (DODH) of vicinal diols into alkenes in the presence of a reductant (" red ") and a catalyst (typically a rhenium complex) has been studied by a number of groups (Scheme 1). [2] This transformation represents a model system for the various hydroxyl groups present in biomass (e.g., in carbohydrates), but is also relevant in itself as a potentially useful transformation of glycerol. Considering the huge amounts of glycerol and sugar alcohols that would have to be processed for the utilization of biomass to make a substantial impact, the development of alternative catalysts, based on elements with higher terrestrial abundance than rhenium, is clearly desirable. We therefore set out to investigate the possibility of using the transition metal molybdenum because of the similarities between oxorhenium(VII) and oxomolybdenum(VI) complexes. [3, 4] Rhenium's ability to catalyze the reaction seems to be due to the ability of oxorhenium complexes to cycle between the two oxidation states + V and + VII [5] (or, alternatively, between the oxidation states + III and + V, as recently proposed [6]), and we expected that molybdenum's ability to cycle between the two oxidation states + IV and + VI could make it a viable substitute. The ability of oxomolybdenum(VI) complexes to catalyze the removal of oxygen from epoxides and diols is not completely unprecedented, but a recent study of the DODH of 1,2-cyclo-octanediol using PPh 3 as reductant resulted in a low yield (55 %). [7] It has recently been shown that oxovanadium(V) complexes can catalyze the DODH of various diols in the presence of the reducing PPh 3 ; [8] although the yields are high, the reaction requires high catalyst loading (10 mol %) and long reaction time (24–96 h). We report herein the viability of a number of different mo-lybdenum compounds for the DODH of glycerol and glycerol model compounds (aliphatic 1,2-diols). We show that the DODH can be conducted in an inert and potentially recyclable solvent (dodecane), under solvent-free conditions (i.e., in the neat substrate), and in a solvent that is not completely inert but is capable of dissolving biomass-derived polyols (1,5-pen-tanediol). The starting point for the investigation was the methyltrioxorhenium(VII)-catalyzed DODH of 1,2-tetradecane-diol to 1-tetradecene in the solvent dodecane using 3-octanol (2.5 equiv) as the reductant; we have recently [9] examined the mechanism of this reaction—which is a slightly modified version of the one published by Bergmann and Ellman [2d] —and obtained yields above 90 % at 175 8C. Replacing CH 3 ReO 3 by MoO 2 (CH 3) 2 (bipy) (bipy = 2,2'-bipyridine) produced only trace amounts of the alkene, but raising the temperature to 195 8C resulted in a yield of 37 %. Although attempts to replace 3-oc-tanol by other sacrificial reductants did not increase the yield significantly (see Supporting Information for details), the results were promising as none of the reductants were oxidized to any considerable extent. Since something has to be oxidized for the DODH to proceed, the only reasonable reductant is the diol itself, and, in line with this, omission of 3-octanol increased the alkene yield to 40–45 %. Throughout the paper, the alkene yield will be calculated as n(alkene)
In order to describe possible reaction mechanisms involving amino acids, and the evolution of the... more In order to describe possible reaction mechanisms involving amino acids, and the evolution of the protonation state of amino acid side chains in solution, a reactive force field (ReaxFF-based description) for peptide and protein simulations has been developed as an expansion of the previously reported glycine parameters. This expansion consists of adding to the training set more than five hundred molecular systems, including all the amino acids and some short peptide structures, which have been investigated by means of quantum mechanical calculations. The performance of this ReaxFF protein force field on a relatively short time scale (500 ps) is validated by comparison with classical non-reactive simulations and experimental data of well characterized test cases, comprising capped amino acids, peptides, and small proteins, and reaction mechanisms connected to the pharmaceutical sector. A good agreement of ReaxFF predicted conformations and kinetics with reference data is obtained.
The first reported twisted bis-lactam, a racemic Trö ger's base (TB) analogue (2), was resolved i... more The first reported twisted bis-lactam, a racemic Trö ger's base (TB) analogue (2), was resolved into its enantiomers on a chiral stationary phase HPLC column. The absolute configuration of (+)-2 was determined to be (R,R)-2 by comparing experimental and calculated vibrational circular dichroism (VCD) and electronic circular dichroism (ECD) spectra. The absolute configuration of (−)-2 was determined by comparing experimental and calculated electronic circular dichroism (ECD) spectra. The corresponding theoretical spectra were calculated using the lowest energy conformation of (R,R)-2 and (S,S)-2 at the B3LYP/6-31G(d,p) level of theory. The absolute configuration of (+)-2 was also determined to (R,R)-2 by anomalous X-ray diffraction (AXRD) in a chiral space group P2 1 2 1 2 1 using Cu-irradiation resulting in a very low Flack parameter of −0.06(3), despite the heaviest element being an oxygen atom, thus unambiguously confirming the results from the spectroscopic studies. We conclude that, for the Trö ger's base (TB) analogue (2), we may rank the reliability of the individual methods for AC determination as AXRD ≫ VCD > ECD, while the synergy of all three methods provides very strong confidence in the assigned ACs of (+)-(R,R)-2 and (−)-(S,S)-2.
Chemical processes capable of reducing the high oxygen content of biomass-derived polyols are in ... more Chemical processes capable of reducing the high oxygen content of biomass-derived polyols are in demand in order to produce renewable substitutes for chemicals of fossil origin. Deoxydehydration (DODH) is an attractive reaction that in a single step transforms a vicinal diol into an alkene, but the reaction requires a homogeneous catalyst, a reductant, and a solvent, which are typically expensive, unsustainable, or inefficient. Herein, we present the use of molybdenum(VI)-based compounds, in particular the cheap and commercially available (NH 4) 6 Mo 7 O 24 ·4H 2 O, as catalysts for the DODH of vicinal diols in isopropyl alcohol (i PrOH), which serves as both the solvent and reductant. The reaction proceeds at 240−250 °C in a pressurized autoclave, and the alkene yield from simple aliphatic diols can be as high as 77%. The major byproducts are carbonyl compoundsformed by dehydration of the dioland the alcohols formed by transfer hydrogenation of the carbonyl compounds; the total yield of reduced species (i.e., alkene and alcohols) can be as high as 92%. The DODH of glycerol yields allyl alcohol, which undergoes subsequent Mo-catalyzed deoxygenation to propylene driven by the oxidation of i PrOH; a major byproduct is the homocoupled product 1,5-hexadiene. Further insight in this Mo-catalyzed deoxygenation is gained by an investigation of model compounds: The allylic alcohol 1-hexen-3-ol is deoxygenated to hexene isomers in a yield of 65%, while benzyl alcohol is deoxygenated to toluene in a yield of 93%. The DODH of erythritol yields 39% 2,5-dihydrofuran, while the DODH of the proposed intermediate 1,4-anhydroerythritol yields 75%. The mechanism of the DODH of 1,4-anhydroerythritol was investigated by means of density functional theory (DFT), and the rate-determining step (24.1 kcal/mol) was found to be reduction of a molybdenum(VI) diolate to a molybdenum(IV) diolate.
beta-Peptoids are peptidomimetics based on N-alkylated b-aminopropionic acid residues (or N-alkyl... more beta-Peptoids are peptidomimetics based on N-alkylated b-aminopropionic acid residues (or N-alkyl-b-alanines). This type of peptide mimic has previously been incorporated in biologically active ligands and has been hypothesized to be able to exhibit foldamer properties. Here we show, for the first time, that b-peptoids can be tuned to fold into stable helical structures. We provide high-resolution X-ray crystal structures of homomeric b-peptoid hexamers, which reveal right-handed helical conformations with exactly three residues per turn and a helical pitch of 9.6–9.8 Å between turns. The presence of folded conformations in solution is supported by circular dichroism spectroscopy showing length-and solvent dependency, and molecular dynamics simulations provide further support for a stabilized helical secondary structure in organic solvent. We thus outline a framework for future design of novel biomimetics that display functional groups with high accuracy in three dimensions, which has potential for development of new functional materials.
Determination of experimental kinetic isotope effects (KIE) is one of the most useful tools for t... more Determination of experimental kinetic isotope effects (KIE) is one of the most useful tools for the exploration of reaction mecha- nisms in organometallic chemistry. The approach has been further strengthened during the last decade with advances in modern compu- tational chemistry. This allows for the calculation of a theoretical KIE that can often be compared directly to the experimental value. This combined experimental/theoretical approach can be particularly useful in cases where the value of the experimental KIE is not directly associat- ed with one particular reaction step (e.g., in a catalytic reaction). The approach is highlighted by using recent examples from both stoichio- metric and catalytic reactions, homogeneous and heterogeneous catal- ysis, and enzyme catalysis to illustrate the expected accuracy and utility of this approach.
This study focuses on increasing the selectivity to methyl lac-tate from sugars using stannosilic... more This study focuses on increasing the selectivity to methyl lac-tate from sugars using stannosilicates as heterogeneous catalyst. All group I ions are found to have a promoting effect on the resulting methyl lactate yield. Besides, the alkali ions can be added both during the preparation of the catalyst or directly to the solvent mixture to achieve the highest reported yield of methyl lactate (ca. 75 %) from sucrose at 170 8C in methanol. The beneficial effect of adding alkali to the reaction media applies not only to highly defect-free Sn-Beta prepared through the fluoride route, but also to materials prepared by post-treatment of dealuminated commercial Beta zeolites, as well as ordered mesoporous stannosilicates, in this case Sn-MCM-41 and Sn-SBA-15. These findings open the door to the possibility of using other preparation methods or different Sn-containing sil-icates with equally high methyl lactate yields as Sn-Beta.
The mechanism of the molybdenum-catalyzed de- oxydehydration (DODH) of vicinal diols has been inv... more The mechanism of the molybdenum-catalyzed de- oxydehydration (DODH) of vicinal diols has been investigat- ed using density functional theory. The proposed catalytic cycle involves condensation of the diol with an MoVI oxo complex, oxidative cleavage of the diol resulting in an MoIV complex, and extrusion of the alkene.
The mechanism of the CH3ReO3-catalyzed deoxydehydration of a vicinal diol to an alkene driven by ... more The mechanism of the CH3ReO3-catalyzed deoxydehydration of a vicinal diol to an alkene driven by oxidation of a secondary alcohol was investigated by time-resolved, in situ IR spectros- copy and was found to occur in three steps: 1) reduction of the catalytically active methyltrioxorhenium(VII) to a rhenium(V) complex (the rate-limiting step), 2) condensation of the diol and the rhenium(V) complex to a rhenium(V) diolate, and 3) extrusion of the alkene accompanied by oxidation of the Re center and thus regeneration of CH3ReO3. The reaction follows zero-order kinetics initially but, unexpectedly, accelerates to- wards the end, which is explained in terms of a deactivating pre-equilibrium, in which the catalytically active CH3ReO3 con- denses reversibly with the diol to form an inactive rhenium(VII) diolate. This conclusion is supported by the direct observation of a catalytically inactive species as well as DFT calculations of the IR spectra of the relevant compounds.
We disclose a hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds wi... more We disclose a hypervalent iodine mediated α-alkylative umpolung reaction of carbonyl compounds with dialkylzinc as the alkyl source. The reaction is applicable to all common classes of ketones including 1,3-dicarbonyl compounds and regular ketones via their lithium enolates. The α-alkylated carbonyl products are formed in up to 93% yield. An ionic mechanism is inferred based on meticulous analysis, NMR studies, trapping and crossover experiments, and computational studies.
The crystallization of Sn-Beta in fluoride medium is greatly influenced by the amount and type of... more The crystallization of Sn-Beta in fluoride medium is greatly influenced by the amount and type of tin source present in the synthesis gel. By varying the amount of tin in the form of tin(IV) chloride pentahydrate, the time required for crystallization was studied. It was found that tin not only drastically affects the time required for crystallization, but also that the presence of tin changes the morphology of the formed Sn-Beta crystals. For low amounts of tin (Si/Sn ¼ 400) crystallization occurs within four days and the Sn-Beta crystals are capped bipyramidal in shape, whereas for high amounts of tin (Si/Sn ¼ 100) it takes about sixty days to reach full crystallinity and the resulting crystals are highly truncated, almost plate-like in shape. Using SEM-WDS to investigate the tin distribution along transverse sections of the Sn-Beta crystals, a gradient distribution of tin was found in all cases. It was observed that the tin density in the outer parts of the Sn-Beta crystals is roughly twice as high as in the tin depleted core of the crystals. Sn-Beta was found to obtain its maximum catalytic activity for the conversion of dihydroxyacetone to methyl lactate close to the minimum time required for obtaining full crystallinity. At excessive crystallization times, the catalytic activity decreased, presumably due to Ostwald ripening.
Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for... more Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides (J. Med. Chem. 2013, 56, 6512). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme−ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1−3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.
PERSPECTIVE P. Fristrup et al. Synergy between experimental and theoretical methods in the explor... more PERSPECTIVE P. Fristrup et al. Synergy between experimental and theoretical methods in the exploration of homogeneous transition metal catalysis Featuring the themed issue: Synergy between experiment and theory In this Perspective, we will focus on the use of both experimental and theoretical methods in the exploration of reaction mechanisms in homogeneous transition metal catalysis. We briefly introduce the use of Hammett studies and kinetic isotope effects (KIE). Both of these techniques can be complemented by computational chemistry – in particular in cases where interpretation of the experimental results is not straightforward. The good correspondence between experiment and theory is only possible due to recent advances within the applied theoretical framework. We therefore also highlight the innovations made in the last decades with emphasis on dispersion-corrected DFT and solvation models. The current state-of-the-art is highlighted using examples from the literature with particular focus on the synergy between experiment and theory.
The commercially available (NH 4) 6 Mo 7 O 24 and other molybde-num compounds are shown to be via... more The commercially available (NH 4) 6 Mo 7 O 24 and other molybde-num compounds are shown to be viable substitutes for the typically employed rhenium compounds in the catalytic deoxy-dehydration of aliphatic diols into the corresponding alkenes. The transformation, which represents a model system for the various hydroxyl groups found in biomass-derived carbohydrates , can be conducted in an inert solvent (dodecane), under solvent-free conditions, and in a solvent capable of dissolving biomass-derived polyols (1,5-pentanediol). The reaction is driven by the simultaneous oxidative deformylation of the diol resulting in an overall disproportionation of the substrate. The transformation of biomass-derived compounds into platform chemicals is one of the possible contributions to the realization of an economy completely independent of fossil reserves. In order for oxygen-rich biomass-derived compounds such as glycerol and sugar alcohols to substitute petroleum, reactions capable of reducing their oxygen content are in demand, [1] and in particular the deoxydehydration (DODH) of vicinal diols into alkenes in the presence of a reductant (" red ") and a catalyst (typically a rhenium complex) has been studied by a number of groups (Scheme 1). [2] This transformation represents a model system for the various hydroxyl groups present in biomass (e.g., in carbohydrates), but is also relevant in itself as a potentially useful transformation of glycerol. Considering the huge amounts of glycerol and sugar alcohols that would have to be processed for the utilization of biomass to make a substantial impact, the development of alternative catalysts, based on elements with higher terrestrial abundance than rhenium, is clearly desirable. We therefore set out to investigate the possibility of using the transition metal molybdenum because of the similarities between oxorhenium(VII) and oxomolybdenum(VI) complexes. [3, 4] Rhenium's ability to catalyze the reaction seems to be due to the ability of oxorhenium complexes to cycle between the two oxidation states + V and + VII [5] (or, alternatively, between the oxidation states + III and + V, as recently proposed [6]), and we expected that molybdenum's ability to cycle between the two oxidation states + IV and + VI could make it a viable substitute. The ability of oxomolybdenum(VI) complexes to catalyze the removal of oxygen from epoxides and diols is not completely unprecedented, but a recent study of the DODH of 1,2-cyclo-octanediol using PPh 3 as reductant resulted in a low yield (55 %). [7] It has recently been shown that oxovanadium(V) complexes can catalyze the DODH of various diols in the presence of the reducing PPh 3 ; [8] although the yields are high, the reaction requires high catalyst loading (10 mol %) and long reaction time (24–96 h). We report herein the viability of a number of different mo-lybdenum compounds for the DODH of glycerol and glycerol model compounds (aliphatic 1,2-diols). We show that the DODH can be conducted in an inert and potentially recyclable solvent (dodecane), under solvent-free conditions (i.e., in the neat substrate), and in a solvent that is not completely inert but is capable of dissolving biomass-derived polyols (1,5-pen-tanediol). The starting point for the investigation was the methyltrioxorhenium(VII)-catalyzed DODH of 1,2-tetradecane-diol to 1-tetradecene in the solvent dodecane using 3-octanol (2.5 equiv) as the reductant; we have recently [9] examined the mechanism of this reaction—which is a slightly modified version of the one published by Bergmann and Ellman [2d] —and obtained yields above 90 % at 175 8C. Replacing CH 3 ReO 3 by MoO 2 (CH 3) 2 (bipy) (bipy = 2,2'-bipyridine) produced only trace amounts of the alkene, but raising the temperature to 195 8C resulted in a yield of 37 %. Although attempts to replace 3-oc-tanol by other sacrificial reductants did not increase the yield significantly (see Supporting Information for details), the results were promising as none of the reductants were oxidized to any considerable extent. Since something has to be oxidized for the DODH to proceed, the only reasonable reductant is the diol itself, and, in line with this, omission of 3-octanol increased the alkene yield to 40–45 %. Throughout the paper, the alkene yield will be calculated as n(alkene)
In order to describe possible reaction mechanisms involving amino acids, and the evolution of the... more In order to describe possible reaction mechanisms involving amino acids, and the evolution of the protonation state of amino acid side chains in solution, a reactive force field (ReaxFF-based description) for peptide and protein simulations has been developed as an expansion of the previously reported glycine parameters. This expansion consists of adding to the training set more than five hundred molecular systems, including all the amino acids and some short peptide structures, which have been investigated by means of quantum mechanical calculations. The performance of this ReaxFF protein force field on a relatively short time scale (500 ps) is validated by comparison with classical non-reactive simulations and experimental data of well characterized test cases, comprising capped amino acids, peptides, and small proteins, and reaction mechanisms connected to the pharmaceutical sector. A good agreement of ReaxFF predicted conformations and kinetics with reference data is obtained.
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center and thus regeneration of CH3ReO3. The reaction follows zero-order kinetics initially but, unexpectedly, accelerates to- wards the end, which is explained in terms of a deactivating pre-equilibrium, in which the catalytically active CH3ReO3 con- denses reversibly with the diol to form an inactive rhenium(VII) diolate. This conclusion is supported by the direct observation of a catalytically inactive species as well as DFT calculations of the IR spectra of the relevant compounds.
center and thus regeneration of CH3ReO3. The reaction follows zero-order kinetics initially but, unexpectedly, accelerates to- wards the end, which is explained in terms of a deactivating pre-equilibrium, in which the catalytically active CH3ReO3 con- denses reversibly with the diol to form an inactive rhenium(VII) diolate. This conclusion is supported by the direct observation of a catalytically inactive species as well as DFT calculations of the IR spectra of the relevant compounds.