Absolute stereochemistry of methanopterin and 5,6,7,8-tetrahydromethanopterin

The configuration at the C-9 of methanopterin (MPT) has been determined by comparing the circular dichroism (CD) spectra of MPT and its hydrolytic fragment, 1-[4-[[1-(2-amino-7-methyl-4-hydroxy-6-pteridinyl)-ethyl]amino]phenyl]-1-deoxy-D -ribitol (HP-1), with the CD spectra of a series of model compounds of known stereochemistry. These compounds included (S)-6-[1-(4-carboxymethylanilino)ethyl]pterin, (S-6(1-hydroxyethyl)-7-methylpterin, (S-6-(1-hydroxyethyl)pterin, (R)-6-(1-phenoxyethyl)pterin, D (+)-neopterin, and L -biopterin. From this comparison it was concluded that MPT has the R configuration at C-9 and is thus configurationally related to D (+)-neopterin, which has the S configuration at C-1. From previous work establishing the relative stereochemistry at C-6, C-7, and C-9 of N⁵-N¹⁰-methenyl-5,6,7,8-tetrahydromethanopterin (N⁵-N¹⁰-methenyl-H₄MPT) as R, S, and R, respectively, it is clear that the remaining asymmetric carbons at C-6 and C-7 of H₄MPT have the S and S configuration, respectively. Comparison of these latter two positions to the equivalent carbons in 5,6,7,8-tetrahydrofolate (H₄folate) show that the steps involved in the biological reduction of MPT to H₄MPT occur with the same stereochemical outcome as those involved in the biological reduction of folate to H₄folate. © 1996 Wiley-Liss, Inc.     

DFT calculation–assisted stereo-structural assignment of arundifungin

Arundifungin ( 1 ) has been reported as a potent antifungal agent against Candida and Aspergillus spp; however, only its planar structure has been disclosed. This paper describes the assignment of the relative and absolute configuration of 1 , which includes (a) determination of the relative configuration of the ABCD polycyclic ring moiety on the basis of detailed nuclear magnetic resonance (NMR) analysis, followed by the confirmation with density functional theory (DFT)–based ¹³C NMR chemical shift calculations, (b) determination of the absolute configuration of the ABCD polycyclic ring moiety by observing a positive Cotton effect at 217 nm because of the C-8/C-9 tetrasubstituted double bond and its reproduction using DFT calculations, (c) determination of the configurational relationship between C-17 and C-20 by a combination of nuclear Overhauser effect (NOE) analysis and DFT-based conformational analysis, and (d) determination of the relative and absolute configuration of the C-24 and C-25 asymmetric centers on the acyclic side chain by a combination of chemical derivatization including modified Mosher's method and DFT-based conformational analysis, followed by electronic circular dichroism (ECD) spectral reproduction. Present study also discovered 26-deoxyarundifungin ( 2 ) of which relative structure was readily elucidated by ¹H and ¹³C spectral comparison with those of 1 . Since 2 exhibits slightly weaker antifungal activity against Cochliobolus miyabeanus than 1 , the hydroxy group at C-26 moderately contributes to the activity.     

Optical Rotatory Dispersion and Circular Dichroism of Amino Acid Hydantoins

Optical rotatory dispersion (ORD) and circular dichroism (CD) of 17 amino acid hydantoins were measured between 190 and 600 nm. Most of hydantoins exhibited the negative Cotton effect which showed the trough between 238 and 245 nm. The negative trough of CD was also observed between 212 and 236 nm. The Cotton effect of hydantoins was attributable to n→π^* transition of carbonyl group at C-4 of hydantoin ring.     

On the structure of NADH-X

By following both the 285 nm Cotton effect and the increase in absorbance (ΔA₂₈₅) during the enzymic (glyceral-dehyde-3-phosphate dehydrogenase) and the non-enzymic (pyrophosphate buffer) formation of NADH-X, it is inferred that (i) the configuration at C-1′ is not changed, and (ii) the 285 nm Cotton effect in 6-hydroxy-1,4,5,6-tetrahydronicotinamide coenzymes arises not only from interaction with the ribose moiety but also from interaction with the C₆ chiral center.     

Circular dichroism of axially chiral methaqualone, 3-Aryl-2-mercapto- and 3-aryl-2-alkylthio-4(3H)-quinazolinones: conformational dependence of CD and assignment of absolute configuration

Rotational strengths calculated on the basis of quantum-mechanically obtained minimum energy geometries were used to determine the absolute configurations of axially chiral 3-aryl-4(3H)-quinazolinones from the sign of the observed Cotton effects (CEs). For the spectral data, CNDO/S calculations were used; for the geometries, ab initio (RHF/6-31G) and semiempirical (AM1) theories were used. Oscillator and rotational strengths of all excited states down to 200 nm were compared to experimental absorption and circular dichroism (CD) data. It was found that the sign of the ¹L_b Cotton effects obtained for the enantiomers of methaqualone and derivatives of 3-aryl-2-alkylthio-4(3H)-quinazolinones can be correlated unambiguously with the absolute configuration. Furthermore, the sign of the Cotton effect of the π-π* transition of the thiocarbonyl chromophore of 3-aryl-2-mercapto-4(3H)-quinazolinones is suitable for a successful stereochemical correlation. Chirality 10:253–261, 1998. © 1998 Wiley-Liss, Inc.     

Chirality induction in cyclocopolymerization of bis(p-vinylbenzoate)s of carbohydrates with styrene: Chiroptical study of resulting polymer by exciton chirality method

Three bis(p-vinylbenzoate) monomers, 2,3-O-isopropylidene-1,4-bis-O-(p-vinylbenzoyl)-L-threitol (BIT), methyl 4,6-O-isopropylidene-2,3-bis-O-(p-vinylbenzoyl)-α,D -glucopyranoside (BIG), and 1,2:5,6-di-O-isopropylidene-3,4-bis-O(p-vinylbenzoyl)-D-mannitol (BIM), were prepared and cyclocopolymerized with styrene. The resulting copolymers were hydrolyzed with KOH to remove the chiral template, and treated with diazomethane to give poly[(methyl p-vinylbenzoate)-co-styrene] [poly(MVB-co-St)]. All the poly(MVB-co-St) had a specific rotation and their CD spectra exhibit a split Cotton effect. Poly(MVB-co-St) derived from poly(BIT-co-St) showed a positive Cotton effect at 255 nm and a negative one at 235 nm. According to the exciton chirality method, poly(MVB-co-St) possessed negative chirality, and the stereochemistry of the carbon atom attached to the 4-benzoyl group had the S configuration. The absolute configuration of poly(MVB-co-St) was determined as R for the BIG/St system and S for the BIM/St system. © 1995 Wiley-Liss, Inc.     

1′, 2′-Seco-2′,3′-Dideoxynucleoside Analogues: Synthesis and Antiviral Evaluation of Racemic Trans-[1′, 5′-Dihydroxy 3′, 4′-methylenylpent-2′-oxy)methyl] Nucleosides

Abstract

Reaction of (±)but-3-en-1,2-diol (3) with ethyl diazoacetate afforded two cyclopropyl compounds (5) and (6). Their relative trans stereochemistry at C-2 and C-3 has been determined by high-field and computational NMR spectroscopy. (±)Trans-1-(1′,5′-dihydroxy-3′,4′-methylenyl-pent-2′-oxy)methyl]thymine (1d) or -cytosine (1b) and (±)trans-9-(1′,5′-dihydroxy-3′,4′-methylenylpent-2′-oxy)-methyl]adenine (la) or -guanine (1c) have been obtained through a regiospecific alkylation procedure and their antiviral evaluation is reported.     

Attempt of Microbial Mutagen Screening with Rec-assay; Isolation of Chartreusin

A strong Cotton effect, which practically govern the sign of the optical rotation at 589 nm ([M]_d), was studied in phenyl 1-thio-α (and β)-d-glycopyranosides with our new chiroptical technique. The proposal optical rotatory dispersion (ORD) method, with calculations based on a one term Drude equation, showed the presence of a strong Cotton effect at 200–210 nm. Circular dichroism (CD), with accumulation technique, also gave the same Cotton effect. Agreement in these two methods suggests the usefulness of the proposed ORD calculation method. The rotational strengths and the signs were shown to reflect the anomeric configurations and conformations (α-anomer gave positive and β-anomer gave negative signs; axial gave strong and equatorial gave weak bands). This result is an extension of the ring oxygen helicity rule of alkyl and alkyl thioglycosides to phenyl 1-thioglycopyranosides, and probably to other aromatic glycosides.     

Configuration at C-25 in 5 beta-cholestane-3 alpha,7 alpha,12 alpha,25,26-pentol excreted by patients with cerebrotendinous xanthomatosis: circular dichroism and 13C-NMR studies

The configuration at C-25 in 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,25,26-pentol isolated from the bile and feces of patients with cerebrotendinous xanthomtosis (CTX) was determined from the lanthanide-induced circular dichroism (CD) Cotton effects and 13C-NMR measurements. Under anhydrous conditions, CD spectra of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha,25,26-pentol in the presence of Eu(fod)3 exhibited a large induced negative Cotton effect at 320 nm. On the basis of the empirical rule (primary-tertiary-alpha-diols) in which R compounds have positive Cotton effects and S compounds have negative Cotton effects at 320 nm, it was concluded that 25,26-pentol has the 1,2,glycol structure with C-25 having the S-configuration. This assignment was based upon comparison with model compounds, 25(R and S),26-dihydroxy cholesterols and 25(R and S),26-dihydroxy cholecalciferols whose single-crystal X-ray structure and 13C-NMR studies have been performed. It is suggested that these data may be helpful to clarify the stereospecificity of the hydroxylation of the terminal methyl group of the cholesterol side chain in CTX.     

Novel Taxa-4(20),12-diene and 2(3→20)Abeotaxane from Needles of Taxus canadensis

A novel 6/8/6-membered taxane with a rare C-12(13)-double bond and rare 2(3→20)abeotaxane were isolated from the needles of Taxus canadensis. Their structures were characterized as 7β,9α,10β-triacetoxytaxa-4(20),12-diene-2α,5α,11β-triol (1) and 2α,7β,10β-triacetoxy-5α-hydroxy-2(3→20)abeotaxa-4(20),11-diene-9,13-dione (2) on the basis of 1D and 2D spectroscopic data. 1 is the first example of a natural taxane without substitution at both C-13 and C-14.     

Optical Rotatory Dispersion and Circular Dichroism of the Carboxyl Chromophore in Gibbane-10-carboxylic Acids with an Aromatic A Ring,and Their Application to the Stereochemistry of the B Ring of Gibberellins and Their Derivatives

CD and ORD of twelve gibbane-10-carboxylic acid compounds with an aromatic A ring together with two related compounds were measured. The sign of the Cotton effect was found to be positive (negative) when the configuration of the C–10 carboxyl is β (α). The ORD also provided information to determine the configuration at C–4b. The C–10 carboxyl gave a stronger magnitude and redshift of the peak in a cis relation with 4b–H compared with that in a trans relation.     

Hydroxylation of (+)-menthol by Macrophomina phaseolina

Abstract

Biotransformation of (+)-menthol with Macrophomina phaseolina led to hydroxylations at C-1, C-2, C-6, C-7, C-8 and C-9, with the C-8 position being preferentially oxidized. The resulting metabolites were identified as 8-hydroxymenthol (2), 6R-hydroxymenthol (3), 1R-hydroxymenthol (4), 9-hydroxymenthol (5), 2R,8-dihydroxymenthol (6), 8S,9-dihydroxymenthol (7), 6R,8-dihydroxymenthol (8), 1R,8-dihydroxymenthol (9) and 7,8-dihydroxymenthol (10). Metabolites 6–10 are described here for the first time. Their structures were characterized by spectroscopic analysis.     

Screening of terrestrial <Emphasis Type="Italic">Streptomyces</Emphasis> leading to identification of new stereoisomeric anthracyclines

Thirty different Streptomyces strains were isolated from soil samples collected from different places in Egypt. The strains were isolated using Oatmeal agar and ISP medium 2 agar at pH 7.5. The isolate Streptomyces sp. Eg23 was selected for further working up to yield three new streoisomers of anthracycline metabolites. The structures were elucidated as (7R, 9R, 10S)-e-Rhodomycinone (1), (7R, 9R, 10S) Aklavinone (2), and (9R, 10S) 7-Desoxy-z-Rhodomycinone (3) by interpretation of their 1D and 2D NMR spectra. The absolute stereochemistry of 1 was confirmed by modified Mosher’s method. The (7R, 9R, 10S)-e-Rhodomycinone (1) showed activity against human lung cancer cell H460, murine Lewis lung cancer cell LL/2 and human breast cancer cell MCF-7. Compounds 1–3 were known synthetically, but until now have not been isolated as natural products from a microorganism. The results showed that the Streptomyces sp. Eg23 seems to be an interesting target for studying the regio-and stereochemistry of the cyclization step catalysed by polyketide cyclases to produce new anthracyclines through combinatorial biosynthesis. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Synthesis of (S)-13-Hydroxy (2E,4E,8E)- and (2E,4E,8Z)-Tetradecatrienoic Acids

The syntheses of (S)-13-hydroxy-(2E,4E,8E)-tetradecatrienoic acid (1) and (2E,4E,8Z)-tetradecatrienoic acid (2) were carried out by using the Wittig reaction as the key step. The asymmetric center at C-13 and the double bond between C-8 and C-9 for natural compound 1 were reconfirmed as being of (S) configuration and E, respectively.

The relationship between the structure of the unsaturated hydroxy fatty acids and their inhibitory effect on the growth of lettuce was investigated.     

Synthesis of Both the Enantiomers of 3-Octanol,the Pheromone of Various Species of Ants

(2S,3R,1′S,2′S)-Serricorole (1) and (2S,3R,1′R)-serricorone (2), sex pheromone components of the cigarette beetle (Lasioderma serricorne F.), were synthesized, starting from the enantiomers of methyl 3-hydroxypentanoate. The stereochemistry of the naturally occurring 1 was determined to be 2S,3R,1′S,2′S, and that of 2 to be 2S,3R,1′RS by comparing between the CD spectra of the natural and synthetic samples.     

Stereochemistry of biopterin cofactor and facile methods for the determination of the stereochemistry of a biologically active 5,6,7,8-tetrahydropterin

The structure of (-)-tetrahydrobiopterin, the cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases, was determined as (6R, 1'R, 2'S)-6-(1',2'-dihydroxypropyl)-5,6,7,8-tetrahydropterin by X-ray crystallographic analysis. The CD spectra of (-)-tetrahydrobiopterin exhibits a negative Cotton effect at 290-240 nm in pH 3.2 solution. The relationship of the negative Cotton effect and the 6R configuration was supported by the application of CD analysis with 2-methyltetrahydronaphthalene as a model compound. The stereochemistries at the C(6) position of various biologically active 6-substituted tetrahydropterins were determined from the CD spectra. The relative configuration of two asymmetric centers, C(6), and C(1'), was determined by HPLC analysis on a strong cation exchange column.     

C-26 vs. C-27 Hydroxylation of insect steroid hormones: Regioselectivity of a microsomal cytochrome P450 from a hormone-resistant cell line

Hydroxylation of steroids at one of the side chain terminal methyl groups, commonly linked to C-26, represents an important regulatory step established in many phyla. Discrimination between the two sites, C-26 and C-27, requires knowing the stereochemistry of the products. 26-Hydroxylation of the insect steroid hormone 20-hydroxyecdysone by a microsomal cytochrome P450 was previously found to be responsible for hormonal resistance in a Chironomus cell line mainly producing the (25S)-epimer of 20,26-dihydroxyecdysone. Here, we studied the 25-desoxy analog of 20-hydroxyecdysone, ponasterone A, to elucidate the stereochemistry of the expected 26-hydroxy product, inokosterone, which occurs as C-25 epimers in nature. We identified the predominant metabolite as the C-25 R epimer of inokosterone on comparison by RP-HPLC with the (25R)- and (25S)-epimers the stereochemistry of which was confirmed by X-ray crystallography. (25R)-inokosterone was further oxidized to the 26-aldehyde identified by mass spectroscopy, borohydride reduction and metabolic transformation to 26-carboxylic acid. The (25S)-epimers of inokosterone and its aldehyde were minor products. With 20-hydroxyecdysone as substrate, we newly identified the (25R)-epimer of 20,26-dihydroxyecdysone as a minor product. In conclusion, the present stereochemical studies revealed high regioselectivity of the Chironomus enzyme to hydroxylate both steroids at the same methyl group, denoted C-27.     

Synthesis of polyhydroxy 7- and N-alkyl-azepanes as potent glycosidase inhibitors

An effective synthetic method for polyhydroxylated azepanes that contain an alkyl group (Me or Bu) at either the 7- or N-positions is developed. The synthetic routes are accomplished in eight to ten steps from d-(−)-quinic acid. Among the compounds synthesized, the polyhydroxy 7-butyl azepane (compound 3), which possessed the R-configuration at C-7 position, is shown to give potent inhibition against β-galactosidase (IC₅₀ = 3 μM). Preliminary biological data indicate that the length of alkyl groups along with the proper stereochemistry at the C-7 position is essential for acquiring extra binding affinity. Using similar synthetic routes, the polyhydroxy N-methyl and N-butyl azepanes are synthesized for the comparison of their biological activities.     

Biotransformation of mestanolone and 17-methyl-1-testosterone by Rhizopus stolonifer

Abstract

Microbial transformation of mestanolone (1) using the plant pathogenic fungus, Rhizopus stolonifer, resulted in the production of two known metabolites, identified as 11α-hydroxymestanolone (3) and 6α-hydroxymestanolone (4). Transformation of 17-methyl-1-testosterone (2) by R. stolonifer yielded two known metabolites, methandrostenolone (5) and 11α,17β- dihydroxy-androsta-1,4-diene-3-one (6). These transformations included α-hydroxylations at C-11 and C-6, dehydrogenation at C-4, androsta and a demethylation at C-17 positions. Structures of transformed products were determined using spectroscopic techniques.     

Synthesis of (2RS,8R,10R)-YM-193221 and an Improved Approach to Tyroscherin,Bioactive Natural Compounds from Pseudallescheria sp.

Short-step syntheses of (2RS,8R,10R)-YM-193221 (1) and tyroscherin (2), which are biologically active compounds isolated from Pseudallescheria sp., were accomplished in six and eight steps from L-tyrosine. The relative stereochemistry of natural YM-193221 was determined to be 8R ^*,10R ^*.