Synthesis of racemic and enantiomerically pure 2′-thia-2′,3′-dideoxycytidine as potential anti-hepatitis B virus agents

A novel class of nucleosides with the C₁, atom bonded to three hetero atoms was synthesized. 2′-Thia-2′,3′-dideoxycytidine was the pilot compound of this series. (±)-β-2′-Thia-1′,3′-dideoxycytidine ( 6 ) and (±)-α-2′-thia-2′,3′-dideoxycytidine ( 7 ) were synthesized from (±)-3-mercapto-1,2-propanediol. The synthesis of the enantiomerically pure 2′-thia-2′,3′-dideoxycytidines (α-D-form, β-D-form, α-1-form and β-L-form) from optically pure (S)-(2,2-dimethyl-1,3-dioxalan-yl)methyl p-toluenesulfonate ( 8 ) and its (R)-isomer 18 was also described. The preliminary biological results showed that (+)-β-D-2′-thia-2′,3′-dideoxycytidine ( 26 ) was the most active against human hepatitis B virus with an ED₅₀ of 3 μM.     

Novel Trinor-eremophilanes (Dendryphiellin B,C, and D), Eremophilanes (Dendryphiellin E,F, and G), and Branched C9-Carboxylic Acids (Dendryphiellic Acid A and B) from the Marine Deuteromycete Dendryphiella salina (SUTHERLAND) PUGHet NICOT

Further investigation of global extracts from cultures of the marine deuteromycete Dendryphiella salina leads to the isolation of three novel trinor-eremophilanes esterified by branched C₉-carboxylic acids, dendryphiellin B (= (+)-(1R*,2S*,7R*,8aR*)-1,2,6,7,8,8a-hexahydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6R*, 2E, 4E)-6-hydroxy-6-methylocta-2,4-dienoate; (+)- 2 ), dendryphiellin C (=(+)-(1R*, 2S*, 7R*, 8aR*)-1,2,6,7,8,8a-hexa-hydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6S, 2E, 4E)-6-methylocta-2,4-dienoate; (+)- 3 )), and dendryphiellin D (=(+)-(1R*, 2S*, 7R*, 8aR*)-1,2,6,7(8,8a-hexahydro-7-hydroxy-1,8a-dimethyl-6-oxonaphthalen-2-yl (6R*,2E,4E)-6-(hydroxymethyl)octa-2,4-dienoate; (+)- 4 ). An intact eremophilane, dendryphiellin E ( 5 ), and its ethanolysis product dendryphiellin F whose absolute configuration is represented by structural formula (+)- 6 are also isolated from the above extracts. Dendryphiellin E exists as an open form 5a in equilibrium with a closed form 5b . A similar equilibrium exists between the open form 8a and the closed form 8b of a non-esterified eremophilane, dendryphiellin G ( 8 ), which is isolated too from the above extracts and proves structurally related to the cyclic portion of 5 . Finally, the free, branched C₉-carboxylic acids dendryphiellic acid A ((+)- 9 ) and B ((+)- 10 ) which correspond to side chains of the above esterified terpenes are also isolated from the above extracts.     

SYNTHESIS OF THE FOUR POSSIBLE STEREOISOMERS OF N-2′-METHYLBUTYL-2-METHYLBUTYLAMIDE,THE SEX PHEROMONE OF THE LONGHORN BEETLE MIGDOLUS FRYANUS WESTWOOD

The four stereoisomers of N-2′-methylbutyl-2-methylbutylamide, the sex pheromone of the longhorn beetle Migdolus fryanus, an economically important pest of sugarcane in South America, were synthesized. The key intermediate 2-methylbutan-1-ol is commercially available only in its (S)-(?)-form. The (R)-(+)-enantiomer was obtained optically pure from methyl (S)-(+)-3-hydroxy-2-methylpropionate in five steps.     

Synthesis and Complexation Properties of Pyrimidine-Derived Crown Ether Ligands

Five new proton-ionizable macrocyclic ligands containing a pyrimidone-subcyclic unit, 6–10 , were prepared from the previously prepared pyrimidinocrown ethers 1–5 (see Figure 1 and Scheme 1). One of the new proton-ionizable crown ethers is chiral. The proton-ionizable pyrimidonocrown ethers were prepared in high yields by treating the appropriate methoxy-substituted pyrimidinocrown with 5 M sodium hydroxide in a 50% alcohol-water mixture. Complexation properties of four of the pyrimidine-derived macrocycles were studied by various nmr techniques. Pyrimidono-18-crown-6 (9) forms a strong complex with benzylammonium perchlorate and also forms a complex with benzylamine. (S, S)-Dimethyl-substituted pyrimidino- and pyrimidono-18-crown-6 ligands 4 and 9 form stronger complexes with the (R)-form of α-(1-naphthyl)ethylammonium perchlorate than with the (S)-form. (S, S)-Dimethyl-substituted pyrimidono-18-crown-6 ( 9 ) also forms a stronger complex with (R)-α-(1-naphthyl)ethylamine than with the (S)-form. The crystal structure for compound 7 is reported.     

Muricatetrocins A and B and Gigantetrocin B: Three New Cytotoxic Monotetrahydrofuran-Ring Acetogenins from Annona muricata

Extracts from the seeds of Annona muricata yielded three new Annonaceous acetogenins: muricatetrocin A (= (5S)-3-{(2R)-2-hydroxy-9-{(2R,5S)-tetrahydro-5-[(1S,4S,5S)-1,4,5-trihydroxyheptadecyl]furan-2-yl}nonyl}-5-methylfuran-2(5H)-one; 1 ), muricatetrocin B (= (5S)-{(2R)-2-hydroxy-9-{(2S,5S)-tetrahydro-5-[(1S,4S,5S)-1,4,5-trihydroxyheptadecyl]furan-2-yl}nonyl}-5-methylfuran-2(5H)-one; 2 ), and gigantetrocin B (= (5S)-3-{(2R)-2-hydroxy-7-{(2S,5S)-tetrahydro-5-[(1S,4R,5R)-1,4,5-trihydroxynonadecyl]furan-2-yl}heptyl}-5-methyl-furan-2(5H)-one; 3 ). Their C-skeletons were deduced by mass spectrometry. Configurations were determined by ¹H-NMR of ketal derivatives and 2D-NMR experiments utilizing Mosher esters. A previously described compound, gigantetrocin A (= (5S)-3-{(2R)-2-hydroxy-7-{(2S,5S)-tetrahydro-5-[(1S,4S,5S)-1,4,5-trihydroxynonadecyl]furan-2-yl}heptyl}-5-methylfuran-2-(5H)one; 4 ), was also isolated and is new to this species. Compounds 1–4 were all selectively cytotoxic for the HT-29 human colon-tumor cell line with potencies at least 10 times that of adriamycin.     

Proof of the Absolute Configuration of (−)-(S)-2-Hydroxy-β-ionone by correlation with ursolic acid and with (−)-trans-verbenol

(?)-(S)-2-Hydroxy-β-ionone ( 33 ), (+)-(2 S, 6 S)-2-hydroxy-α-ionone ( 34 ), and their acetates 35 and 36 have been synthesized from (+)-(S)-6-methylbicyclo [4.3.0]-non-1-ene-3, 7-dione ( 3 ). The key intermediate (+)-(1 R, 3 S, 6 S)-2, 2, 6-trimethyl-7-oxobicyclo [4.3.0]non-3-yl acetate ( 7 ) was correlated with a degradation product of the pentacyclic triterpene ursolic acid ( 16 ). Compound 33 was also synthesized by an alternative route starting from (?)-trans-verbenol ( 42 ).     

Enantioselective Synthesis of Glutarimide Alkaloids Cordiarimides A,B, Crotonimides A,B, and Julocrotine

Five glutarimide alkaloids cordiarimide A ( 5 ), cordiarimide B ( 6 ), crotonimide A ( 3 ), crotonimide B ( 4 ), and julocrotine ( 2 ) have been synthesized starting from Boc‐L‐glutamine ( 7 ). The benzylic alcohol chiral centre of cordiarimides B ( 6 ) has been established in 6:1 diastereoselectivity by catalytic asymmetric hydrogenation using Zhou's catalytic system Pd(CF₃CO₂)₂/(R,R)‐Me‐DuPhos.     

Synthesis and structures of 1,1"-dialkyl-3,3"-bidiaziridines

First representatives of 3,3"-bidiaziridines, viz., 1,1"-dialkyl-3,3"-bidiaziridines, were synthesized and isolated as mixtures of two diastereomers. In the case of Alk = Me, the diastereomers were separated. It was demonstrated by nuclear Overhauser effect experiments and X-ray diffraction analysis that the diastereomers are the racemate (rac-1R*,2R*,3S*,1"R*,2"R*,3"S*) and the meso-form (1S*,2S*,3R*,1"R*,2"R*,3"S*).     

Isolierung von (2S, 4S)-(+)-γ-Hydroxynorvalin und (2S, 4R)-(−)-γ-Hydroxynorvalin aus Boletus satanas Lenz

We have isolated from the carpophores of Boletus satanas Lenz (Basidiomycetae) (2S,4S)-(+)-γ-hydroxynorvaline ( 1 ) and (2S,4R)-(?)-γ-hydroxynorvaline ( 2 ). The chirality of each diastereomer has been determined by chemical synthesis starting from optically active precursors and by application of different chiroptical methods. Gaschromatographic separation of the derived diastereomeric N-[(S)-α-methoxypropionyl]-lactones reveals that the optical purity of natural 2 is 88% whereas 1 exists as a partial racemate: (2S,4S): (2R,4R) = 3:2. Muscarine could not be detected in the carpophores of B. satanas, contrary to some literature data but basic substances of unknown structure are present in low concentration.     

Stoffwechselprodukte von Mikroorganismen. 190. Mitteilung. Über das 4-Oxo-homotyrosin,ein Abbauprodukt des Echinocandins B

D , L -4-Oxo-homotyrosine was synthesized by the acetylaminomalonic ester pathway. The optical resolution was carried out by means of the enzyme acylase I. The L -configuration of the enzymatically produced amino acid was confirmed by degradation to L -aspartic acid. 4-Oxo-homotyrosine obtained by degradation of the polypeptide antibiotic echinocandine B has D -configuration, but his optical purity is low. A hypothetical explanation for its formation from the (2 S, 3 S, 4 S)-3,4-dihydroxyhomotyrosine residue of echinocandine B is proposed.     

Synthese von (±)-Diplodialid B und A

Synthesis of (±)-Diplodialide B and A Two steroid hydroxylase inhibitors, diplodialide B (1) and A (2) have been synthesized in the following way: The lithium enolate 5 of S-t-butyl thioacetate (4) was added to (E)-7-(2′-tetrahydropyranoxy)-2-octen-1-al (8) and the newly formed 3-hydroxy group in the product 9 was protected as t-butyl-diphenyl silyl ether followed by selective hydrolysis of the tetrahydropyranyl ether to give 10. Treatment with AgNO₃/H₂O cleaved the S-t-butyl ester group in 10 to give the corresponding hydroxy carboxylic acid which was converted into the S-2-pyridyl thioester by treatment with di(2-pyridyl)disulfide and triphenyl phosphine and cyclized with AgClO₄ to give the (4E,3,9-trans)- and (4E,3,9-cis)-lactone 11 and 12 (R?t-Bu(C₆H₅)₂Si) in 67% yield. Chromatographic separation of 11 and 12 and cleavage of the t-butyl-diphenyl silyl ether with tetrabutyl ammonium fluoride yielded (±)-diplodialide B (1) with (4E,3,9-trans)-configuration and the (4E,3,9-cis)-isomer 12 (R?H). Both isomers could be oxidized to diplodialide A (2) with manganese dioxide. The synthesis described above has also been carried out via the intermediates 10 , 11 and 12 with R?COOCH₂CH₂Si(CH₃)₃.     

Precursor‐Directed Biosynthesis: Stereospecificity for Branched‐Chain Diketides of the β‐Ketoacyl‐ACP Synthase Domain 2 of 6‐Deoxyerythronolide B Synthase

Modular polyketide synthases such as 6‐deoxyerythronolide B synthase (DEBS) catalyze the biosynthesis of structurally complex natural products. Streptomyces coelicolor CH999/pJRJ2 harbors a plasmid encoding DEBS(KS1⁰), a mutant form of 6‐deoxyerythronolide B synthase that is blocked in the formation of 6‐deoxyerythronolide B ( 1 , 6‐dEB) due to a mutation in the active site of the ketosynthase (KS1) domain that normally catalyzes the first polyketide chain‐elongation step of 6‐dEB biosynthesis. Administration of (2S,3R,4S)‐ and (2S,3R,4R)‐3‐hydroxy‐2,4‐dimethylhexanoic acid N‐acetylcysteamine (SNAC) thioesters (= S‐[2‐(acetylamino)ethyl] (2S,3R,4S)‐ and (2S,3R,4R)‐3‐hydroxy‐2,4‐dimethylhexanethioates) 3 and 4 in separate experiments to cultures of Streptomyces coelicolor CH999/pJRJ2 led to production of the corresponding (14S)‐ and (14R)‐14‐methyl analogues of 6‐dEB, 10 and 11 , respectively. Unexpectedly, when a 3 : 2 mixture of 4 and 3 was fed under the same conditions, exclusively branched‐chain macrolactone 11 was isolated. In similar experiments, feeding of 3 and 4 to S. coelicolor CH999/pCK16, an engineered strain harboring DEBS1+TE(KS1⁰), resulted in formation of the branched‐chain triketide lactones 13 and 14 , while feeding of the 3 : 2 mixture of 4 and 3 gave exclusively 14 . The biochemical basis for this stereochemical discrimination was established by using purified DEBS module 2+TE to determine the steady‐state kinetic parameters for 3 and 4 , with the k_cat/K_M for 4 shown to be sevenfold greater than that of 3 .     

Total Synthesis of Plakortone B

Plakortone B is a naturally occurring bicyclic[3.3.0]furanolactone compound with attractive bioactivities. Although the relative configuration of plakortone B’s central core had been established by NMR spectroscopic methods, the absolute configuration of its four stereocenters remained unknown. In the present paper, all four possible isomers of plakortone B were synthesized and one of these molecules was found to be identical with the natural plakortone B on the basis of ¹H, ¹³C NMR spectra and specific rotation comparisons. Thus, the absolute configuration of the natural plakortone B was determined to be (3S,4S,6R,10R).     

Red yeast catalyzed amination of olefinic bonds and synthesis of optically pure S-amino acids

By using red yeast (Rhodotorula rubra AS 2.166) resting cells which possess the phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) activity as biocatalyst, enantiomerically pure S-3-(2-chloro-phenyl) alanine (2a) and S-3-(3-hydroxyphenyl) alanine (2d) have been synthesized from the corresponding 3-aryl substituted acrylic acid (1a and 1d) and ammonia.     

Paecilomycines A and B,Novel Diterpenoids,Isolated from Insect‐Pathogenic Fungi Paecilomyces sp. ACCC 37762

Two new diterpenoids, named paecilomycine A ( 1 ) and paecilomycine B ( 2 ), including a novel skeleton with a five‐membered lactone ring, together with three known labdane diterpenoids, rel‐(1R,3S,4aS,5R,8aS)‐5‐[(3E)‐4‐carboxy‐3‐methylbut‐3‐en‐1‐yl]decahydro‐3‐hydroxy‐1,4a‐dimethyl‐6‐methylidenenaphthalene‐1‐carboxylic acid ( 3 ), botryosphaerin E ( 4 ), and agathic acid ( 5 ), were isolated from solid culture of the insect pathogenic fungi strain Paecilomyces sp. The structures of all compounds were established on the basis of comprehensive spectroscopic studies. The relative configurations of 1 and 2 were determined by single‐crystal X‐ray diffraction analyses.     

Epoxidierung von Cucurbitaxanthin A: Herstellung von Cucurbitaxanthin B und seines 5′,6′-Epimeren

Epoxidation of Cucurbitaxanthin A: Preparation of Cucurbitaxanthin B and of Its 5′,6′-Epimer Cucurbitaxanthin A (= (3S,5R,6R,3′S)-3,6-epoxy-5,6-dihydro-β,β-carotene-5,3′-diol; 1 ) isolated from red pepper (Capsicum annuum var. longum nigrum) was trimethylsiylated and then epoxidized with monoperphthalic acid. After deprotection and chromatographic separation, cucurbitaxanthin B (= (3S,5R,6R, 3′S,5′R,6′S)-3,6:5′,6′-diepoxy-5,6,5′,6′-tetrahydro-β,β-carotene-5,3′-diol; 2 ) and 5′,6′-diepicucurbitaxanthin B (= (3S,5R,6R, 3′S,5′S,6′R)-3,6:5′,6′-diepoxy-5,6,5′,6′-tetrahydro-β,β-carotene-5,3′-diol; 5 ) were obtained and carefully characterized. They show mirror-like CD spectra and, therefore, emphasize the importance of the torsion angle of C(6)–C(7) on the electronic interaction between the polyene chain and the chiral end group.     

Conomicidines A and B,Unusual Alkaloid–Hydroxycinnamyl Alcohol Conjugates from Tabernaemontana corymbosa

Conomicidines A and B ( 1a and 2a , resp.) together with the diastereomeric isoconomicidines A and B ( 1b and 2b , resp.) were isolated from Tabernaemontana corymbosa as unresolvable mixtures of the (1′S,2′S)‐ and (1′R,2′R)‐diastereoisomers (i.e., 1a and 1b ; 2a and 2b ). These novel natural products are constituted from the union of an iboga alkaloid, ibogaine, and hydroxycinnamyl alcohol moieties, and represent the first examples of such alkaloid–hydroxycinnamyl alcohol conjugates. The structures were determined by spectroscopic methods, including the extensive use of NOE experiments for the assignment of the configuration.     

Rubriflorin A and B,Two Novel Partially Saturated Dibenzocyclooctene Lignans from Schisandra rubriflora

From the stems of Schisandra rubriflora, two novel partially saturated dibenzocyclooctene lignans, named rubriflorin A ( 1 ) and B ( 6 ), as well as the seven known partially saturated dibenzocyclooctene lignans kadsumarin A ( 2 ), kadsurin ( 3 ), heteroclitin B ( 4 ), heteroclitin C ( 5 ), heteroclitin D ( 7 ), interiorin ( 8 ), and interiorin B ( 9 ) were isolated. The structures of the new compounds 1 and 6 were established on the basis of spectral analysis as (5R,6S,7R,8R,13aS)‐8‐(acetyloxy)‐5,6,7,8‐tetrahydro‐1,2,3,13‐tetramethoxy‐6,7‐dimethylbenz([3,4]cycloocta[1,2‐f][1,3]benzodioxol‐5‐yl (2Z)‐2‐methylbut‐2‐enoate and (6R,7R,12aS)‐7,8‐dihydro‐12‐hydroxy‐1,2,3,10,11‐pentamethoxy‐6,7‐dimethyl‐6H‐dibenzo[a,c]cycloocten‐5‐one, respectively.     

Structure Elucidation of Two New Diterpenoids from Isodon phyllostachys: Phyllostacins A and B

Two new ent‐kaurane‐derived diterpene derivatives, phyllostacins A ( 1 ) and B ( 2 ), were isolated from the aerial parts of Isodon phyllostachys, together with two known compounds, irroratin A ( 3 ) and serrin B ( 4 ). Both 1 and 2 were found to be present as diastereoisomers. In the case of 1 , the corresponding diastereoisomeric diacetates 5 and 6 were prepared and separated. The structures of the new compounds were elucidated by extensive 1D‐ and 2D‐NMR spectroscopic methods, in combination with MS experiments. In (D₅)pyridine solution, the two epimers of 1 are present in equal amounts, but in CDCl₃ or CD₃OD, the (S)‐epimer predominates in the mixture of hemiacetals.     

Determination of the Configuration of Wine Lactone

The intense sweet and coconut-like smelling odorant 1 , named ‘wine lactone’, was isolated from different wine varieties. The chemical structure of this compound, which has not yet been detected in wine or a food, was identified by high-resolution mass spectrometry (HR-MS) as 3a,4,5,7a-tetrahydro-3,6-dimethylbenzofuran-2(3H)-one. For the evaluation of the configuration of wine lactone, stereochemically controlled syntheses were developed. All eight isomers were characterized by NMR, MS, IR, and CD measurements. The configuration of ‘wine lactone’ was in agreement with synthesized (3S,3aS,7aR)-enantiomer ( 1a ) on the basis of enantioselective GC. For this isomer, the lowest odor threshold (0.02 pg/1 air) was detected.