Absolute configuration of (−)-myrtenal by vibrational circular dichroism

The VCD spectrum of the monoterpene (−)-myrtenal (1) was compared with theoretical spectra using ab initio density functional theory (DFT) calculations at the B3LYP/6-31G(d,p), B3LYP/6-31G+(d,p), B3LYP/6-311G+(d,p), B3LYP/DGDZVP, and B3PW91/DGTZVP levels of theory. Conformational analysis of 1 indicated that the lowest energy conformer was s-trans-C2-C10, which contributes more than 98.5% to the total conformational population regardless of the employed level of theory. The use of a recently developed confidence level algorithm demonstrated that VCD spectra calculated for the main conformer, using the indicated hybrid functionals and basis set, gave no significant changes, from where it follows that B3LYP/DGDZVP calculations provide a superior balance between computer cost and VCD spectral accuracy. The DGDZVP basis set demanded around a quarter the time than the 6-311G+(d,p) basis set while providing similar results. The spectral comparison also provided evidence that the levorotatory enantiomer of myrtenal has the 1R absolute configuration.     

Synthesis and absolute configuration of the stereoisomers of [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate,a muscarinic antagonist

The compound [2-(1-diethylaminopropyl)] 1-hydroxy-1,1′-bicyclohexyl-2-carboxylate 1 is a muscarinic antagonist characterized by the presence of three chiral atoms and eight possible stereoisomers. The binding affinities to the five cloned m₁–m₅ muscarinic receptors of the stereoisomers of 1 were previously investigated and proved to be related to the chirality of the molecules. The eight isomers are prepared through the synthesis of their racemates followed by chemical resolution as (+) and (−) tartrate or (+) and (−) dibenzoyltartrate salts. The isomers with cis-configuration of OH and COOH substituents of the cyclohexane are also obtained by coupling optically active (1S, 2S) or (1R,2R)-1-hydroxy-[1,1′-bicyclohexyl]-2-carboxylic acid with (S)- or (R)-1-diethylamino-2-propanol. Chiral GC and HPLC methods are used to determine their optical purity. The absolute configurations of the four cis- and four trans-isomers are established by stereospecific synthesis and X-ray crystallographic data. Chirality 9:713–721, 1997. © 1997 Wiley-Liss, Inc.     

Resolution of 1‐n‐Butyl‐3‐Methyl‐3‐Phospholene 1‐Oxide With TADDOL Derivatives and Calcium Salts of O,O'‐Dibenzoyl‐(2R,3R)‐ or O,O'‐di‐p‐Toluoyl‐(2R,3R)‐tartaric Acid

The resolution methods applying (?)‐(4R,5R)‐4,5‐bis(diphenylhydroxymethyl)‐2,2‐dimethyldioxolane (“TADDOL”), (?)‐(2R,3R)‐α,α,α',α'‐tetraphenyl‐1,4‐dioxaspiro[4.5]decan‐2,3‐dimethanol (“spiro‐TADDOL”), as well as the acidic and neutral Ca²⁺ salts of (?)‐O,O'‐dibenzoyl‐ and (?)‐O,O'‐di‐p‐toluoyl‐(2R,3R)‐tartaric acid were extended for the preparation of 1‐n‐butyl‐3‐methyl‐3‐phospholene 1‐oxide in optically active form. In one case, the intermediate diastereomeric complex could be identified by single‐crystal X‐ray analysis. The absolute P‐configuration of the enantiomers of the phospholene oxide was also determined by comparing the experimentally obtained and calculated CD spectra. Chirality 26:174–182, 2014. © 2014 Wiley Periodicals, Inc.     

GABAB antagonists: Resolution,absolute stereochemistry,and pharmacology of (R)- and (S)-phaclofen

Phaclofen, which is the phosphonic acid analogue of the GABA_B agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABA_B antagonist. As part of our studies on the structural requirements for activation and blockade of GABA_B receptors, we have resolved phaclofen using chiral chromatographic techniques. The absolute stereochemistry of (?)-(R)-phaclofen was established by X-ray crystallographic analysis. (?)-(R)-Phaclofen was shown to inhibit the binding of [³H]-(R)-baclofen to GABA_B receptor sites on rat cerebellar membranes (IC₅₀ = 76 ± 13 μM), whereas (+)-(S)-phaclofen was inactive in this binding assay (IC₅₀ > 1000 μM). (?)-(R)-Phaclofen (200 μM) was equipotent with (RS)-phaclofen (400 μM) in antagonizing the action of baclofen in rat cerebral cortical slices, while (+)-(S)-phaclofen (200 μM) was inactive. The structural similarity of the agonist (R)-baclofen and the antagonist (?)-(R)-phaclofen suggests that these ligands interact with the GABA_B receptor sites in a similar manner. Thus, it may be concluded that the different pharmacological effects of these compounds essentially result from the different spatial and proteolytic properties of their acid groups. © 1994 Wiley-Liss, Inc.     

Asymmetric transformation of a racemic α-(phthalimidooxy)arylacetic ester by a combination of preferential crystallization and simultaneous racemization

An asymmetric transformation of racemic t-butyl 2-(3,4-O-carbonyldioxy-phenyl)-2-(phthalimidooxy)acetate [(RS)- 2b ] into one of its optically active forms was carried out by a combination of preferential crystallization of a desired enantiomer and the simultaneous racemization of the antipode. (R)- 2b was easily racemized in diethylketone in the presence of a small amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Under the conditions for racemization, the asymmetric transformation was achieved successfully to give (S)- 2b with 84% optical purity in 80% yield. A potent antipseudomonal cephalosporin M-14659 ( 1 ) was prepared from the pure (S)- 2b which was obtained by the recrystallization of the crude (S)- 2b . © 1993 Wiley-Liss, Inc.     

Chiroptical properties and conformation of chiral enamines of 2-(2′-pyrido,or quinolino) acetophenone

CD study of the chiral enamines 4-9 revealed the presence of the azastil-bene-like chromophore, and exciton coupling between this chromophore (A) and aromatic chromophore B . Coupled excitons in 5 and 8 suggest M (−) absolute conformation between chromophores A and B . © 1996 Wiley-Liss, Inc.     

A new approach to determine the stereospecificity in lipase catalysed hydrolysis using circular dichroism (CD): lipases produce optically active diglycerides from achiral triglycerides

We describe a sensitive CD method for determining the stereospecificity in lipase (E.C.3.1.1.3) catalysed hydrolysis of triacyl glycerols into diacyl glycerols. The diglycerols were converted to chiral tert-butyldimethylsilylated 1,2- or 2,3-di-O-benzoyl-sn-glycerol (5 or 5'), and their CD was measured. This approach showed for the first time that lipases produce optically active diacyl glycerides from achiral tripalmitin and tribenzoyl glyceride with a variable extent of enantioselectivity depending on the acyl groups and the enzymes.     

GABAA agonists: Resolution and pharmacology of (+)- and (−)-isoguvacine oxide

(3SR,4RS)-3,4-Epoxypiperidine-4-carboxylic acid (isoguvacine oxide) is a potent and specific GABA_A receptor agonist. Isoguvacine oxide, originally designed as a potentially alkylating agonist, turned out to interact with the GABA_A receptor in a fully reversible manner. The protected form of isoguvacine oxide, benzyl (3SR,4RS)-1-(benzyloxycarbonyl)-3,4-epoxypiperidine-4-carboxylate ( 1 ) (Scheme 1), has now been resolved by chiral chromatography using cellulose triacetate as a chiral stationary phase. The enantiomers of 1 (ee ≥ 98.8%) were subsequently deprotected by hydrogenolysis. Whereas both enantiomers of isoguvacine oxide were inactive as inhibitors of the binding of [³H]GABA to GABA_B receptor sites (IC₅₀ > 100 μM), (+)-isoguvacine oxide (IC₅₀ = 0.20 ± 0.03 μM) and (?)-isoguvacine oxide (IC₅₀ = 0.32 ± 0.05 μM) showed comparable potencies as inhibitors of the binding of [³H]GABA to GABA_A receptor sites. Furthermore, (+)-isoguvacine oxide (EC₅₀ = 6 μM; 33% relative efficacy) and (?)-isoguvacine oxide (EC₅₀ = 5 μM; 38% efficacy relative to 10 μM muscimol) were approximately equipotent and equiefficacious as stimulators of the binding of [³H]diazepam to the GABA_A receptor-associated benzodiazepine site. This latter effect is an in vitro estimate of GABA_A agonist efficacy. These pharmacological data for isoguvacine oxide and its enantiomers do not seem to support our earlier conception of the topography of the GABA_A recognition site(s), derived from extensive structure—activity studies on GABA_A agonists. Thus, the model of the GABA_A recognition site(s) comprising a narrow cleft or pocket, in which the anionic moiety of the zwitterionic GABA_A agonists is assumed to be embedded during receptor activation, may have to be revised. © 1995 Wiley-Liss, Inc.     

Determination of absolute configuration in 4‐aryl‐3,4‐dihydro‐2(1H)‐pyrimidones by high performance liquid chromatography and CD spectroscopy

The absolute configuration of three 4‐aryl‐3,4‐dihydro‐2(1H)‐pyrimidones (Biginelli compounds, DHPMs) was established by comparison of the typical circular dichroism (CD) spectra of individual enantiomers with reference samples of known absolute configuration. The enantiomers were obtained by semipreparative separation of racemic mixtures on a Chiralcel OD‐H chiral stationary phase. The method was used to establish the enantiopreference of various lipases in biocatalytic kinetic resolution experiments employing activated DHPM esters. Chirality 11:659–662, 1999. © 1999 Wiley‐Liss, Inc.     

Induced circular dichroism and mode of binding of acridine orange adsorbed on β-form poly(S-carboxyethyl-L-cysteine) in aqueous solutions

The absorption spectra and circular dichroism (CD) have been measured for aqueous solutions of acridine orange of a constant concentration, [D] = 5 × 10^?5M, mixed with poly(S-carboxyethyl-L -cysteine) in various mixing ratios, [P]/[D], ranging from 330 to 11, at different pH. The absorption spectra of the dye–polymer solutions are hypochromic, and the main band is located at 470 nm, accompanying a shoulder at 500 nm. At alkaline pH, no CD is induced in the visible region. At neutral and acidic pH, where the polymer is in the β-conformation, CD is induced in the visible and near-uv regions. A pair of CD bands is located at the region around 450 nm, when the pH is around the neutrality, while it appears at the region around 500 nm at acidic pH. Thus, the optically active species of bound dye changes from dimer to monomer on lowering the pH. These species form dissymmetric arrays along a polypeptide chain. The fraction of bound dye forming dissymmetric sequences is not high, but most of bound dye is adsorbed randomly on the ionized carboxyl groups of polypeptide chain and gives rise to hypochromism only. A dissymmetric structure of dye–polymer complexes is presented, in which the polymer has the β-conformation and the dye cations, either dimeric or monomeric, bind to its side chains, in such a way that the longer axes of molecular planes of bound dye form a two-fold, right-handed helix along the extended polypeptide chain. A zeroth-order calculation of CD based on the coupled oscillator model leads to the result that each dissymmetric array of dye consists, on the average, of two dimeric or monomeric cations. This low number of bound cations in a dissymmetric array and the large fraction of randomly adsorbed dye suggest that the hydrophobic interaction of dye with the polymer is strong, so that dye cations are adsorbed sparsely on both sides of the extended polypeptide chain.     

CYP105—diverse structures,functions and roles in an intriguing family of enzymes in Streptomyces

The cytochromes P450 (CYP or P450) are a large superfamily of haem‐containing enzymes found in all domains of life. They catalyse a variety of complex reactions, predominantly mixed‐function oxidations, often displaying highly regio‐ and/or stereospecific chemistry. In streptomycetes, they are predominantly associated with secondary metabolite biosynthetic pathways or with xenobiotic catabolism. Homologues of one family, CYP105, have been found in all Streptomyces species thus far sequenced. This review looks at the diverse biological functions of CYP105s and the biosynthetic/catabolic pathways they are associated with. Examples are presented showing a range of biotransformative abilities and different contexts. As biocatalysts capable of some remarkable chemistry, CYP105s have great biotechnological potential and merit detailed study. Recent developments in biotechnological applications which utilize CYP105s are described, alongside a brief overview of the benefits and drawbacks of using P450s in commercial applications. The role of CYP105s in vivo is in many cases undefined and provides a rich source for further investigation into the functions these enzymes fulfil and the metabolic pathways they participate in, in the natural environment.     

Optical resolution of β-lactams by chiral HPLC on tris(phenylcarbamate)s of cellulose and amylose

Separation and optical resolution of 6 diastereomers and 25 racemates of β-lactams were examined by HPLC on chiral stationary phases composed of six cellulose and one amylose tris(phenylcarbamate) derivatives. Most β-lactams were optically resolved at least by one of the derivatives. The absolute configuration of β-lactams was estimated by CD spectroscopy.     

A conformational analysis of mono and dialkyl ethers of 2,2′-dihydroxy-1,1′-binaphthalene by circular dichroism spectroscopy and cholesteric induction in nematic liquid crystals

The coupling of the analysis of the absorption and circular dichroism (CD) spectra with that of the cholesteric mesophases induced in nematic liquid crystals indicated some interesting conformational features of bridged and nonbridged mono- and dialkylethers of optically active 2,2′-dihydroxy-1,1′-binaphthalene. Bridged derivatives are characterized by relatively small dihedral angles. Simple monoalkyl ethers are characterized by larger dihedral angles but they all assume an s-cis conformation, owing to the existence of intramolecular hydrogen bonds. Nonbridged dialkylethers prefer even larger dihedral angles and, depending on the bulkiness of the alkyl groups, the s-trans conformation can be found. Interestingly, the conformation of dialkylethers is strongly dependent on the structure of the liquid crystal solvent, because the intramolecular hydrogen bond is not possible there. © 1995 Wiley-Liss, Inc.     

Vibrational circular dichroism of a 2,5‐diketopiperazine (DKP) peptide: Evidence for dimer formation in cyclo LL or LD diphenylalanine in the solid state

The diastereomer diketopiperazine (DKP) peptides built on phenylalanine, namely, cyclo diphenylalanine LPhe‐LPhe and LPhe‐DPhe, were studied in the solid phase by vibrational circular dichroism (VCD) coupled to quantum chemical calculations. The unit structure of cyclo LPhe‐LPhe in KBr pellets is a dimer bridged by two strong NH…O hydrogen bonds. The intense bisignate signature in the CO stretch region is interpreted in terms of two contributions arising from the free COs of the dimer and the antisymmetrical combination of the bound COs. In contrast, cyclo LPhe‐DPhe shows no VCD signal in relation to its symmetric nature.     

Nervous system development in Spinicaudata and Cyclestherida (Crustacea,Branchiopoda)—comparing two different modes of indirect development by using an event pairing approach

Cladocera are the ecologically most important group within the Branchiopoda. They are unquestionably branchiopods but their evolutionary origin remains unclear. One favored explanation of their origin is that they evolved from a reproductive larva of a clam shrimp‐like ancestor. To reveal a transformation and identify (potential) changes in chronology (heterochrony), we investigated and compared the development of representatives of two clam shrimp taxa, one of the Spinicaudata (Leptestheria dahalacensis) and one of the Cyclestherida (Cyclestheria hislopi), the sister group of Cladocera. Both taxa develop indirectly although the exact modes are quite different. The development of the nervous system, labeled and analyzed using immunohistochemical techniques and confocal microscopy, and that of the external morphology, scanned with an electron microscope, was investigated. L. dahalacensis hatch as a free‐swimming nauplius and the nervous system and external morphology develop gradually. In C. hislopi, on the other hand, several internal and external structures develop before the hatching of a nonswimming embryo‐like larva which is still carried in a dorsal brood pouch. The development in L. dahalacensis is directed from anterior to posterior, whereas in C. hislopi a more synchronous anterior and posterior differentiation is present. A comparison of both developmental sequences gives us the first indications of the evolutionary transformation which the Cladocera may have undergone from a clam shrimp‐like ancestor. J. Morphol., 2012. © 2012 Wiley Periodicals, Inc.     

A Phytoplankton Bloom in Shallow Divor Reservoir (Portugal)—The Importance of Internal Nutrient Loading

The development of a heavy phytoplankton bloom (chl. a = 360 mg/m³), which occurred in the summer 1983 in a shallow reservoir, Divor, is described. The study shows that remobilization of phosphate from the sediment was initiating the phytoplankton bloom. This was confirmed not only by calculations of the change in iron-phosphate pool, but also supported by sorption experiments carried out with the sediment. It is discussed that turbidity of the water due to suspended matter caused the reduction in standing stock of phytoplankton to approx. 50 mg chl. a/m³ in late summer.     

A new approach to graphical analysis of feeding strategy from stomach contents data—modification of the Costello (1990) method

A modification of the graphical Costello method is proposed for the analysis of stomach contents data. The new method allows prey importance, feeding strategy and the interand intra-individual components of niche width to be explored using graphical presentation. The analysis is based on a two-dimensional representation of prey-specific abundance and frequency of occurrence of the different prey types in the diet. The paper describes the new method and the parameters therein, and also present some examples of the utilization of the method. The method may be particularly well-suited for the examination of predictions made from optimal foraging, competition and niche theories.