Thomas Netscher

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.

Anticancer activity of vitamin E-derived compounds in murine C6 glioma cells.

for reproduction in rats, VE has many more important biological roles, such as the scavenging of reactive oxygen and nitrogen species, thus protecting the organism against the attack of free radicals, and the modulation of cellular signaling, enzymatic activity and gene expression in antioxidant and non-antioxidant manners. In recent years, evidence has accumulated on the antitumor and anti-inflammatory activity of VE metabolites and synthetic derivatives. The succinic monoester of a-tocopherol (1), atocopheryl succinate (aTOS, 2), a representative VE analogue, has been reported as a potent cytostatic and cytotoxic agent in several cancer cell models, showing high selectivity for malignant cells and low toxicity to normal cells. 11] It was proposed that the chroman ring of 2 is responsible for the activation of specific signaling pathways, such as PP2A/PKC, leading to cell-cycle arrest or apoptosis, while the presence of the succinyl ester further increases these biological responses leading to cell and mitochondria membrane destabilization. Furthermore, methylation of the terminal free carboxylic group leads to loss of proapoptotic activity. The limiting factor for the clinical application of 2, in particular regarding oral administration, is that the ester bond is prone to cleavage by esterases, releasing a-tocopherol, which is not active as an anticancer agent. In that regard, a-tocopheryloxyacetic acid (3, aTEA) is a promising VE analogue, which, unlike 2, has an acetic acid moiety attached to the chroman hydroxy group via a non-hydrolyzable ether bond. Compound 3 was shown to be very effective in terms of selectivity and potency in suppressing the growth of various tumors, both in vitro and in vivo. 14] Recently, other VE analogues with non-hydrolyzable bonds were reported with enhanced proapoptotic activity against Jurkat, U937 and human Meso-2 malignant mesothelioma cells compared to compound 2. 16] While structurally related to 2, the ester bond is replaced by an amide bond, the precursors being aand d-tocopheramine. Apart from the expected increased stability, a substantial improvement in the apoptotic activity is observed when going from the ester to the amide analogues and introducing an olefinic bond in the acid moiety. Those results suggest that the amide modification can be used as a starting point for the design of new VE analogues with potent antitumor activity. The molecular mechanism that causes the induction of apoptosis by VE analogues is still unclear. Monosuccinate 2 leads to destabilization of lysosomes and mitochondria by sphingomyelinase activation, ultimately targeting mitochondria through the generation of reactive oxygen species (ROS), affording the release of cytochrome c and the activation of proapoptotic proteins, such as caspase 9 and the Bcl-2 protein family. Apoptosis induced by the ether analogue 3 seems to proceed through another mechanism involving death receptor Fas signaling, the activation of JNK and its substrate c-Jun, truncation of Bid, conformational change of Bax, and activation of caspases 9 and 3. Our research involves the systematic study of the application of VE and related compounds in the treatment of glioblastoma—one of the most frequently occurring brain tumors, accounting for ~12–15 % of all brain tumors. Glioblastomas are among the most aggressive malignant human tumors, characterized by a diffuse local invasion of the normal parenchyma that renders complete surgical resection of cancerous tissue [a] Dr. F. Mazzini Dipartimento di Chimica e Chimica Industriale, Universit di Pisa Via Risorgimento 35, 56126 Pisa (Italy) Fax: (+ 39) 0502219260 E-mail : lcap@ns.dcci.unipi.it [b] Dr. M. Betti, B. Canonico, F. Luchetti, S. Papa Dipartimento di Scienze dell’Uomo, dell’Ambiente e della Natura, Universit degli Studi di Urbino “Carlo Bo”, Via C le Suore 2, 61029 Urbino (Italy) Fax: (+ 39) 0722304226 E-mail : michele.betti@uniurb.it [c] Dr. T. Netscher Research and Development, DSM Nutritional Products P.O. Box 2676, 4002 Basel (Switzerland) [d] Dr. F. Galli Dipartimento di Medicina Interna, Sez. di Biochimica Applicata e Scienze Nutrizionali, Universit di Perugia, Via del Giochetto, 06126 Perugia (Italy) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.200900492.

Tert-butyl- and 2,2,2-trifluoro-1,1-diphenylethane-sulfonates -hindrance of SO-scission in SN2-substitution reactions

By application of the tert-butyl sulfonates (4a) and the 2,2,2-trifluoro-1,1-diphenylethane (TDE-) sulfonates (4b) SO-scission in SN2-substitution reactions can be drastically reduced.

New application of indium catalysts: A novel and green concept in the fine chemicals industry*

New industrially important catalytic processes for application in the fine chemicals industry (e.g., synthesis of vitamins and key-intermediates) are presented. Protocols with indium catalysts provide the advantages of high selectivity and low catalyst loading for Friedel-Crafts-type alkylation, Wagner-Meerwein rearrangement, and acylation reactions. The transformations discussed could be carried out in a continuous manner.

Circular dichroism of tocopherols versus tocotrienols.

Vitamin E is an essential nutrient of still increasing economic importance. Vitamin E derivatives include many nonracemic chiral compounds whose chirooptical characterization is scarcely described in the literature. We report the CD spectra of delta-tocopherol and its unsaturated analog delta-tocotrienol. TDDFT calculations demonstrate that the weak CD of delta-tocopherol is determined by the helicity of dihydropyrane ring. In addition, the moderate CD of delta-tocotrienol is due to the exciton interaction between the aromatic ring and the closest alkene group. Direct exciton-coupled CD calculations on structures generated by two different conformational sampling approaches reveal that, although such exciton coupling is expected to be weak, it is sufficient to explain the spectral differences between tocopherol and tocotrienol.

Thermal Isomerization of (+)‐cis‐ and (−)‐trans‐Pinane Leading to (−)‐β‐Citronellene and (+)‐Isocitronellene

Catalyzed and uncatalyzed rearrangement reactions of terpenoids play a major role in laboratory and industrial-scale synthesis of fine chemicals. Herein, we present our results on the thermally induced isomerization of pinane (1). Investigation of the thermal behavior of (+)-cis- (1 a) and (-)-trans-pinane (1 b) in a flow-type reactor reveals significant differences in both reactivity and selectivity concerning the formation of (-)-beta-citronellene (2) and (+)-isocitronellene (3) as main products. Possible explanations for these results are discussed on the basis of reaction mechanism and ground-state geometries for 1 a and 1 b. To identify side reactions caused from ene cyclizations of 2 and 3, additional pyrolysis experiments were conducted that enabled the identification of almost all compounds in the network of C(10)H(18)-hydrocarbon products formed from 1.

Hydrogenation in the Vitamins and Fine Chemicals Industry – An Overview

In the pharmaceutical and partly also in the fine chemicals industry many chemical conversions require stoichiometric amounts of reagents, and thus generate large amounts of waste [1, 2]. This is in contrast to the production of bulk chemicals which mostly relies on catalysis. This difference can be explained by the higher complexity of pharmaceuticals and fine chemicals which makes catalysis more demanding and process development more expensive.

Methyltrioxorhenium-catalysed oxidation of pseudocumene in the presence of amphiphiles for the synthesis of vitamin E

Vitamin E is an essential food component and antioxidant of major economic relevance. 2,3,5-Trimethyl-1,4-benzoquinone is a key intermediate in the production of vitamin E, which can now be selectively achieved through MTO-catalysed oxidation of simple and inexpensive pseudocumene (1,2,4-trimethylbenzene), in the presence of hydrogen peroxide and an appropriate amphiphile.

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.

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.