How Can Academia Help Industry Reduce the Footprint of Chemicals Manufacture?

Industrial representatives from the Swiss chemistry ecosystem met to formulate unmet needs in the field of sustainability and share the content of the exchange. The aim is to spark inspiration and trigger ambitious and pre-competitive projects collectively at the interface of the academic and industrial worlds, with the hope to profoundly change the current practices and provide an answer to some of the most urgent environmental challenges.

Synthesis of trifold-labeled versatile reagent [3,5-13 C2 ,4-15 N]4-phenyl-1,2,4-triazoline-3,5-dione.

Triazolinediones are an important class of derivatization agents that have found application in various research disciplines. Their unique reactivity often allows precise and selective tagging of relevant molecular scaffolds to facilitate structural elucidation, tracking in biological systems, and stabilization of labile compounds. Recent research efforts mainly focused on the development of novel fluorescent and ionizable or isotopically labeled tags improving the quantification and identification of the parent molecule by suitable analytical methods. However, these concepts often lack the ability to improve properties facilitating the analysis by nuclear magnetic resonance (NMR) spectroscopy. We herein describe the first synthesis of 13 C and 15 N labeled [3,5-13 C2 ,4-15  N]4-phenyl-1,2,4-triazoline-3,5-dione utilizing the Cookson/Zinner-Deucker synthesis of urazoles. The introduced isotopic labels are ideally suited to support the structural elucidation of unknown and complex derivatization mixtures by NMR, thereby exploiting the increased sensitivity of detecting long-range JHC and additional JCC and JCN couplings within the derivatized compounds of interest.

A Decade of Successful Collaborations in Nutritional Compound Process Research and Development.

Collaborations between academia and industry are vital for modern industrial research and development projects, combining the best of both worlds to develop sustainable chemical processes. Herein we summarize a number of successful cooperations between DSM Nutritional Products and Swiss academic institutions that have been carried out over approximately the past decade. A wide variety of reactions and processes have been investigated with experts located in Switzerland. New synthetic routes, chemical transformations and reactor concepts have been developed to produce industrially relevant compounds. Additionally the scope of known catalytic systems has been probed and new catalysts showing improved selectivity have been designed, synthesized and tested. We describe how the research was supported by DSM, the parallel in-house investigations and also how the projects were continued and further developed.

Discrimination of stereoisomers by one-dimensional 13 C NMR: All 16 stereoisomers of 4-hydroxy-α-tocopherol resolved.

All 16 resolved! A vitamin E-derived compound containing four chiral centers is the first example where all stereoisomers, that is, eight diastereomeric pairs of enantiomers, could be discriminated in a single NMR run. Measurement at 176 MHz in the presence of Pirkle's alcohol as a chiral solvating agent is a relatively robust, simple, easy-to-set-up, and fast method.

Enzymatic Asymmetric Reduction of Unfunctionalized C=C Bonds with Archaeal Geranylgeranyl Reductases.

The asymmetric reduction of activated C=C bonds such as enones is well established for non-enzymatic methods as well as in biocatalysis. However, the asymmetric reduction of unfunctionalized C=C bonds is mainly performed with transition metal catalysts whereas biocatalytic approaches are lacking. We have tested two FAD-dependent archaeal geranylgeranyl reductases (GGR) for the asymmetric reduction of isolated C=C bonds. The reduction of up to four double bonds in terpene chains with different chain lengths and head groups was confirmed. Methyl-branched E-alkenes were chemoselectively reduced in the presence of cyclic, terminal or activated alkenes. Using a removable succinate "spacer", farnesol and geraniol could be quantitatively reduced (>99 %). The reduction is strictly (R)-selective (enantiomeric excess >99 %). Hence, GGRs are promising biocatalysts for the asymmetric reduction of unactivated isolated C=C bonds, opening new opportunities for the synthesis of enantiopure branched alkyl chains.

Validation and extension of the gas-phase superacidity scale.

RATIONALE: In recent years it has become increasingly evident that the previously reported experimental gas-phase acidity (GA) values of several strong acids differ markedly from the corresponding high-level computational values. In this work, the superacidic part of the current gas-phase acidity scale was validated and extended. METHODS: For that, the strongly acidic section of the gas-phase acidity scale was remeasured using the equilibrium Fourier transform ion cyclotron resonance (FTICR-MS) method, adding new compounds and introducing methodological changes. In particular, a novel approach for anchoring the scale was used - the results were anchored to the computational (W1BD) GA values of trifluoromethanesulfonic acid and bis(fluorosulfonyl)imide (291.3 and 286.2 kcal mol-1 , respectively). RESULTS: The newly measured section consists of 20 gas-phase superacids and its consistency standard deviation is 0.2 kcal mol-1 , indicating good consistency. In contrast to the previously reported experimental gas-phase acidities for a number of important superacids, the current results are consistent with high-level theoretical GA values. Structure-acidity relationships based on the current results as well as available MeCN and DCE acidity data were described and explained. CONCLUSIONS: The introduced methodological innovations were found to be adequate and strong evidence is presented in support of the current GA values of the strong acids.

Total Synthesis of α-Tocopherol through Enantioselective Iridium-Catalyzed Fragmentation of a Spiro-Cyclobutanol Intermediate.

A conceptionally new strategy for the asymmetric (2R-selective) synthesis of α-tocopherol (vitamin E) was developed. In the stereocontrolled key step, a prochiral spiro[chromane-2,3'-cyclobutanol] unit is effectively desymmetrized under C-C bond activation in an unprecedented iridium-catalyzed transformation using (S)-DTBM-SegPhos as a chiral ligand (e.r. 97:3). To complete the synthesis, the side chain was attached through Ru-catalyzed cross-metathesis employing an alkene derived from (R,R)-hexahydrofarnesol. To suppress epimerization during the final hydrogenation, PtO2 had to be used as a catalyst instead of Pd/C. In an alternative approach (employing a propargyl-substituted spiro-cyclobutanol), the side chain was constructed prior to the Ir-catalyzed ring fragmentation (>99:1 d.r.) through enyne cross-metathesis (using an alkene derived from (R)-dihydrocitronellal) followed by Cr-catalyzed 1,4-hydrogenation and (diastereoselective) Pfaltz hydrogenation of the resulting triple-substituted olefin. The work demonstrates the potential of iridium catalysis for enantioselective C-C bond activation.

Vitamins and Nutraceuticals from the Perspective of Process Research.

The development of efficient, sustainable low-cost processes is the basis for providing high-quality products for daily life applications in human and animal nutrition. In this account, the importance of chemical process research towards ecologically benign and competitively advantageous processes for the large-scale preparation of various vitamins, nutraceuticals and fine chemicals is highlighted. Selected and representative examples are given, including contributions from collaborations with external partners. General trends include the shift from stoichiometric to catalytic protocols and from batch to continuous processes. In addition, the use of renewable (bio-based) raw materials as an alternative to access key building blocks for the production of vitamins is addressed.

Self-assembled α-Tocopherol Transfer Protein Nanoparticles Promote Vitamin E Delivery Across an Endothelial Barrier.

Vitamin E is one of the most important natural antioxidants, protecting polyunsaturated fatty acids in the membranes of cells. Among different chemical isoforms assimilated from dietary regimes, RRR-α-tocopherol is the only one retained in higher animals. This is possible thanks to α-Tocopherol Transfer Protein (α-TTP), which extracts α-tocopherol from endosomal compartments in liver cells, facilitating its distribution into the body. Here we show that, upon binding to its substrate, α-TTP acquires tendency to aggregation into thermodynamically stable high molecular weight oligomers. Determination of the structure of such aggregates by X-ray crystallography revealed a spheroidal particle formed by 24 protein monomers. Oligomerization is triggered by refolding of the N-terminus. Experiments with cultured cell monolayers demonstrate that the same oligomers are efficiently transported through an endothelial barrier (HUVEC) and not through an epithelial one (Caco-2). Discovery of a human endogenous transport protein with intrinsic capability of crossing endothelial tissues opens to new ways of drug delivery into the brain or other tissues protected by endothelial barriers.

A Simple ¹³C NMR Method for the Discrimination of Complex Mixtures of Stereoisomers: All Eight Stereoisomers of α-Tocopherol Resolved.

A simple one-dimensional (13)C NMR method is presented to discriminate between stereoisomers of organic compounds with more than one chiral center. By means of this method it is possible to discriminate between all eight stereoisomers of α-tocopherol. To achieve this the chiral solvating agent (S)-(+)-1-(9-anthryl)-2,2,2-trifluoroethanol and the compound of interest were dissolved in high concentrations in chloroform-d, and the nuclear magnetic resonance (NMR) spectrum was recorded at a low temperature. The individual stereoisomers of α-tocopherol were assigned by spikes of the reference compounds. The method was also applied to six other representative examples.

Building up quarternary stereocenters of chromans by asymmetric redox organocatalysis: a new entry to vitamin E.

High-turnover catalysis offers a novel concept for the efficient chemo- and enantioselective preparation of chroman intermediates, which are useful for the synthesis of tocopherols (vitamin E components) and other biologically active compounds. A chiral ammonium iodide catalyst mediates the cycloetherification in combination with a cooxidant and an inorganic base in excellent yield and up to 93 % ee. OTs=para-toluenesulfonyl.

Total synthesis of (R,R,R)-α-tocopherol through asymmetric Cu-catalyzed 1,4-addition.

By introducing a disposable activating substituent at C-3, the asymmetric 1,4-addition to a notoriously unreactive 2-substituted chromenone was achieved with high levels of (2R)-stereoselectivity in the presence of a chiral Cu(I)-phosphoramidite complex as a catalyst. This paved the way for an efficient and conceptually novel synthesis of (R,R,R)-α-tocopherol from readily available starting materials.

Thermal behavior of pinan-2-ol and linalool.

Linalool is an important intermediate for syntheses of isoprenoid fragrance compounds and vitamins A and E. One process option for its production is the thermal gas-phase isomerization of cis- and trans-pinan-2-ol. Investigations of this reaction were performed in a flow-type apparatus in a temperature range from 350-600 °C and a residence time range of 0.6-0.8 s. Rearrangement of the bicyclic alcohol led to linalool, plinols arising from consecutive reactions of linalool and other side products. Effects of residence time, temperature, surface-to-volume-ratio, carrier gas, and the presence of additives on yield and selectivity were studied. Furthermore, the effects of such parameters on ene-cyclization of linalool affording plinols were investigated. Results indicate that manipulation of the reaction in order to affect selectivity is difficult due to the large free path length to other molecules in the gas phase. However, conditions have been identified allowing one to increase the selectivity and the yield of linalool throughout pyrolysis of pinan-2-ol.

Tocopheramines and tocotrienamines as antioxidants: ESR spectroscopy, rapid kinetics and DFT calculations.

Tocopheramines (TNH2) and tocotrienamines (T3NH2) are analogues of tocopherols (TOH) and tocotrienols in which phenolic OH is replaced by NH2. It was shown in previous studies that TNH2 and T3NH2 act as potent antioxidants. In this study we compared the one-electron oxidation of TNH2/T3NH2 by diphenyl picryl hydrazyl (DPPH) and galvinoxyl (GOX) radicals with the one of α-TOH as a reference compound using ESR spectroscopy, stopped flow spectrophotometry and density functional theory (DFT) calculations. ESR spectroscopy revealed the presence of tocopheramine radicals during electrochemical oxidation of α-TNH2. Kinetic measurements demonstrated that in apolar n-hexane TNH2/T3NH2 derivatives reacted two to three orders of magnitude slower than α-TOH with the model radicals. DFT calculations indicated that this correlates well with the higher bond dissociation energy (BDE) for N-H in TNH2 than for O-H in α-TOH in pure H-atom transfer (HAT). In the more polar medium ethanol TNH2/T3NH2 derivatives partially reacted faster than α-TOH depending on the reaction partner. DFT calculations suggest that this is due to reaction mechanisms alternative to HAT. According to thermochemistry data sequential proton loss and electron transfer (SPLET) is more favored for α-TOH in ethanol than for TNH2. Therefore, for TNH2 a contribution of the alternative mechanism of sequential electron transfer-proton transfer (SET-PT) could be a possible explanation. These data show that the antioxidant reactivity strongly depends on the structure, reaction partners and environment. According to these findings TNH2/T3NH2 should be superior as antioxidants over α-TOH in polar head group regions of membranes but not in the apolar core of lipid bilayers.

One hundred years of vitamins-a success story of the natural sciences.

The discovery of vitamins as essential factors in the diet was a scientific breakthrough that changed the world. Diseases such as scurvy, rickets, beriberi, and pellagra were recognized to be curable with an adequate diet. These diseases had been prevalent for thousands of years and had a dramatic impact on societies as well as on economic development. This Review highlights the key achievements in the development of industrial processes for the manufacture of eight of the 13 vitamins.

Tocotrienamines and tocopheramines: reactions with radicals and metal ions.

The antioxidant activity of vitamin E (VE) homologs α, γ and δ-tocotrienamines (4b-6b), never studied before, and α, γ and δ-tocopheramines (4a-7a) was investigated by means of different total antioxidant capacity (TAC) tests. In all the test model systems, compounds 4a-7a and 4b-6b showed similar or higher TAC values than the parental vitamin E forms and their physiological metabolites. α-Homologs of VE amines showed markedly higher activity than the VE congeners in the TEAC test, which is tailored for liposoluble antioxidants, while γ-homologs of the amine analogs showed higher activity in the FRAP tests. Kinetics analysis of the reaction with DPPH(·) showed higher second order rate k for 4a than for α-tocopherol (1a). α-Tocopherolquinone 1f was the common main oxidation product for both 1a and α-tocopheramine (4a) exposed to ferric ions or DPPH(·), and the implied oxidative deamination of 4a was accompanied by a nitration reaction of phenolic substrates that were added to the reaction medium. Possible mechanisms of these reactions were studied.

Large-scale production of bioactive ingredients as supplements for healthy human and animal nutrition.

In this review, synthetic strategies and the development of environmentally benign methods for the production of economically important vitamins, carotenoids, and nutraceuticals used as food and feed supplements are illustrated by selected examples. The application of efficient catalytic transformations in multi-step chemical syntheses of such natural products enables technically feasible and cost-effective processes. For the preparation of fat-soluble (isoprenoid) vitamins A and E and the water-soluble vitamin (+)-biotin, homogeneous metal catalysis, including enantioselective transformations, heterogeneous and enzymatic catalysis serve as key methodologies. In the area of carotenoids, general building concepts and coupling methods for the total synthesis of beta-carotene and astaxanthin are discussed. Biotechnological methods and isolation from natural sources are also employed successfully, as exemplified for the xanthophyll lutein and the antioxidant (-)-epigallocatechin gallate. Lastly, key steps of the chemical synthesis of the polyphenol resveratrol are highlighted.

Modulation of the mitochondrial cytochrome bc1 complex activity by chromanols and related compounds.

Tocopherols (alpha-, beta-, gamma-, and delta-Toc) and tocopheryl quinones (alpha-, beta-, gamma-, and delta-TQ) were recently suggested to modulate mitochondrial electron transfer in mammals. Intriguingly, Tocs and stigmatellin, a potent inhibitor of the mitochondrial cytochrome (cyt) bc(1) complex, possess a common structural feature: the chroman core. Therefore, we studied the interference of Tocs as well as synthetic model compounds (low molecular weight TQ analogues and tetramethyl chromanones) at the mitochondrial cyt bc(1) complex. Enzymatic experiments revealed that besides the inhibitor stigmatellin, among natural vitamin E-related derivatives, gamma-TQ/delta-TQ and, among synthetic compounds, TMC2O (6-hydroxy-4,4,7,8-tetramethyl-chroman-2-one) were most effective in decreasing the cyt bc(1) activities. Stopped-flow photometric and low-temperature electron paramagnetic resonance spectroscopic experiments showed for TMC2O an inhibition of electron transfer to cyt c(1) and a modulation of the environment of the Rieske iron-sulfur protein (ISP). Docking experiments suggest a binding interaction of the 6-OH group and 1-O atom/2-C( horizontal lineO) group of TMC2O with Glu-271 (cyt b) and His-161 (ISP) in the cyt bc(1) complex, respectively. This binding pose is similar but not identical to the potent inhibitor stigmatellin. The data suggest that chroman-2-ones are possible templates for modulatory molecules for the cyt bc(1) target.