Novel Syntheses of Gabapentin via Addition of Hydrocyanic Acid to Cyclohexylidenemalonate or Cyano(cyclohexylidene)acetate

Several synthetic pathways to the anticonvulsivum gabapentin (1-(aminomethyl)cyclohexaneacetic acid) have been investigated. Advantages and drawbacks of the different routes are discussed, and the most economical and technically most feasible synthesis is pointed out.     

Direct calculation of the energy gradient with cartesian Gaussian basis sets

A computer program POLYGRAD based on the POLYATOM/1 system is presented which evaluates analytically the energy gradient using thes-type and Cartesianp-type Gaussian basis functions. Model calculations on hydrogen peroxide were made to compare the accuracy and the computer time involved in the analytical and numerical determinations of the energy gradient.     

C45- und C50-Carotinoide. 5. Mitteilung

C₄₅- and C₅₀-Carotenoids. Synthesis of an Optically Active Cyclic C₂₀-Building Block and of (2R,2′S)-3′,4′-Didehydro-1′,2′-dihydro-2-(4-hydroxy-3-methylbut-2-enyl)-2′-(3-methylbut-2-enyl)-β,ψ-caroten-1′-ol (= C. p. 473) The synthesis of the optically active C₂₀-building block (R)- 16 and of the optically active C₅₀-carotenoid C.p. 473 ( 1 ) starting from (?)-β-pinene is reported.     

1,2-Epoxycarotinoide. 6. Mitteilung. Isolierung von 1′,2′-Epoxy-1′,2′-dihydro-ε,ψ-carotin aus der ‘Delta-Mutanten’-Tomate

1,2-Epoxycarotenoids Isolation of 1′,2′-Epoxy-1′,2′-dihydro-ε,ψ-carotene from a ‘Delta Mutant’ Tomato From ‘Delta Mutant’ tomatoes, optically active 1′,2′-epoxy-1′,2′-dihydro-ε,ψ-carotene ( 7 ) was isolated. According to the CD data, the configuration is 6R and presumably 2′S.     

DNA quality control by conformational readout on the undamaged strand of the double helix

Synthetic DNA probes were incubated in human cell extracts to dissect the early step of bulky lesion recognition in the nucleotide excision repair pathway. Excision was induced upon combination of the target adduct with either a two-sided bulge, involving both the damaged sequence and its undamaged partner strand, or a one-sided bulge, affecting exclusively the undamaged complementary sequence. Surprisingly, the same adduct became refractory to repair when only the modified strand was bulged out of the double helix. Adduct removal was further dependent on an intact opposing strand and, at carcinogen-DNA adducts, the assembly of excision complexes was triggered by a single flipped-out deoxyribonucleotide in the complementary sequence. These findings describe a mechanism of molecular readout in DNA repair that, unexpectedly, is entirely confined to the undamaged side of the double helix.     

Preparation and (E/Z)‐Isomerization of the Diastereoisomers of Violaxanthin

Violaxanthin A (=(all‐E,3S,5S,6R,3′S,5′S,6′R)‐5,6 : 5′,6′‐diepoxy‐5,6,5′,6′‐tetrahydro‐β,β‐carotene‐3,3′‐diol =syn,syn‐violaxanthin; 5 ) and violaxanthin B (=(all‐E,3S,5S,6R,3′S,5′R,6′S)‐5,6 : 5′,6′‐diepoxy‐5,6,5′,6′‐tetrahydro‐β,β‐carotene‐3,3′‐diol=syn,anti‐violaxanthin; 6 ) were prepared by epoxidation of zeaxanthin diacetate ( 1 ) with monoperphthalic acid. Violaxanthins 5 and 6 were submitted to thermal isomerization and I₂‐catalyzed photoisomerization. The structure of the main products, i.e., (9Z)‐ 5 , (13Z)‐ 5 , (9Z)‐ 6 , (9′Z)‐ 6 , (13Z)‐ 6 , and (13′Z)‐ 6 , was determined by their UV/VIS, CD, ¹H‐NMR, ¹³C‐NMR, and mass spectra.     

Synthese von (R)-β, β-Carotin-2-ol und (2R, 2′R)-β, β-Carotin-2,2′-diol

Synthesis of (R)-β, β-Caroten-2-ol and (2R, 2′R)-β, β-Carotene-2,2′-diol Starting from geraniol, the two carotenoids (R)-β, β-caroten-2-ol ( 1 ) and (2R, 2′R)-β, β-carotene-2,2′-diol ( 3 ) were synthesized. The optically active cyclic building block was obtained by an acid-catalysed cyclisation of the epoxide (R)- 4 . The enantiomeric excess of the product was > 95 %.     

Untersuchungen zur Carotinoidzusammensetzung in Blüten der Gartenhybride Narcissus cvv ‘Golden Harvest’

Investigation of the Carotenoid Composition in the Petals of a Garden Hybrid Narcissus cvv ‘Golden Harvest’ The carotenoid composition of the petals of a yellow garden hybrid Daffodil is reported. As major compound (all-E)-lutein was isolated. As minor compounds phytoene, phytofluene, (all-E)-β-carotene, (9Z)-lutein, (9′Z)-lutein, (13Z)-lutein, violaxanthin, and luteoxanthin were identified. The position of the (Z)-double bond of the different isomers of lutein could be proved by ¹H-NMR spectroscopy.     

Development of a dual luciferase reporter screening assay for the detection of synthetic glucocorticoids in animal tissues

Synthetic glucocorticoids belong to the most frequently administered drugs in livestock production. These synthetic hormones are employed for therapeutic purposes against inflammatory reactions, disorders of the musculoskeletal system, bovine ketosis and many other diseases of farm animals. A widespread illegal use of synthetic glucocorticoids to improve feed intake and weight gain has also been observed. To enforce the residue limits imposed on glucocorticoid drugs and preclude their illicit administration as growth promoters, it is necessary to establish high throughput analytical methods that can be applied to the screening of animal tissues. Here, we developed a dual luciferase reporter assay that detects residues or contaminants with glucocorticoid activity. This screening assay is performed by transfection of human cell lines with two reporter constructs followed by the measurement of two distinct luminescence signals, one of which serves as internal control to correct for assay variabilities and unspecific matrix effects. The limit of detection (1.25 microg for dexamethasone in liver) depends on the biological potency of each synthetic glucocorticoid but, with all drugs tested, the maximal response reaches a 20 to 30 fold induction of luciferase activity. In combination with an appropriate sample clean-up method (recovery of 82%), this luciferase assay has been applied to the analysis of liver samples from calves treated with a single therapeutic injection of either dexamethasone or flumethasone. Thus, the dual luciferase reporter assay provides a new screening tool to detect unwanted glucocorticoid activities in animal tissues or other crude biological samples without knowledge of the precise chemical entity of the parent compounds or their metabolites.     

An Efficient Total Synthesis of Carbocyclic 2′-Deoxyribonucleosides

The present work describes a new and efficient method for the preparation of either racemic or enantiomerically pure carbocyclic 2′-deoxyribonucleosides 1 . Key steps are the efficient assembly of the racemic carbocyclic 2′-deoxyribose core (±)- 12 , its enzymatic resolution, and a new approach to covalently link the purine and pyrimidine bases with the cyclopentane moiety via the cyclic sulfate (+)- 19 . This total synthesis of enantiomerically pure and racemic carbocyclic 2′-deoxyribonucleosides 1 represents one of the most efficient approaches reported to date. Starting from cyclopentadiene, the four carbocycles corresponding to the naturally occurring 2′-deoxyribonucleosides could be prepared in 12 steps and 9–12% overall yield. For the corresponding racemic compounds, 10 steps were used with overall yields between 22 and 30%.