Clerodane diterpenoids from Microglossa angolensis

Two new diterpenoids, 6β-(2-methylbut-2(Z)-enoyl)-3α,4α,15,16-bis-epoxy-8β,10βH-ent-cleroda-13(16),14-dien-20,12-olide and 10β-hydroxy-6-oxo-3α,4α,15,16-bis-epoxy-8βH-cleroda-13(16),14-dien-20,12-olide, together with the known β-amyrin, spinasterol, 5,7-dihydroxy-3,8,3′,4′-tetramethoxyflavone and 5,7-dihydroxy-3,8,3′,4′,5′-pentamethoxyflavone have been isolated from the aerial parts of Microglossa angolensis Oliv. et Hiern (Compositae). The structures were elucidated on the basis of spectral studies and comparison with published data.     

(S)-(−)-α-Methylbenzylamine as an efficient chiral auxiliary in enantiodivergent synthesis of both enantiomers of N-acetylcalycotomine

(S)-(−)-α-Methylbenzylamine 2 was used as a chiral auxiliary in the enantiodivergent synthesis of simple isoquinoline alkaloids. The prochiral imine moiety in compound 4 was reduced with different reagents, giving diastereomeric amines 5a or 5b, which subsequently were transformed to either (S)-(−)-N-acetylcalycotomine 6 or (R)-(+)-N-acetylcalycotomine ent-6 in good enantiomeric excess. ¹⁹F NMR of its Mosher's acid ester was used to establish the purities of final compounds.     

Transformations of hispanolone. Novel Michael adducts with in planta activity against rice blast

Two novel Michael adducts 9α-cyano-15,16-epoxy-7β-hydroxylabda-13(16),14-dien-6-one (2) and 9α-cyano-15,16-epoxy-7-hydroxylabda-7,13(16),14-trien-6-one (3) and the reduction product of 2, 9α-cyano-15,16-epoxy-6β,7β-dihydroxylabda-13(16),14-diene (4), were synthesized from the naturally occurring labdane diterpene hispanolone (1). Compounds 2-4 exhibited in planta activity against the pathogenic rice blast fungus Magnaporthe grisea.     

Desoxaphomin,das erste [13]Cytochalasan,ein möglicher biogenetischer Vorläufer der 24-Oxa-[14]cytochalasane

From cultures of a Phoma species (strain S 298) the hitherto unknown metabolite deoxaphomine has been isolated. On the basis of the spectral data, structure 1 of the (7S, 16R, 20R)-7,20-dihydroxy-16-methyl-10-phenyl-[13]cytochalasa-6(12),13^t,21^t-triene-1,23-dione is assigned to deoxaphomine. This structure is confirmed by the chemical degradation of 1 , yielding the products 4 and 6 which are identical with derivatives of phomine ( 2 )((7S,16R,20R)-7,20-dihydroxy-16-methyl-10-phenyl-24-oxa-[14]cytochalasa-6(12), 13^t,21^t-triene-1,23-dione) and cytohalasin D ( 8 ) ((7S,16S,18R,21R)-21-acetoxy-7,18-dihydroxy-16,18-dimethyl-10-phenyl-[11]sytochalasa-6(12),13^t,19^t-triene-1,17-dione). Deoxaphomine ( 1 ) is a potential biogenetic precursor of the 24-oxa-[14]cytochalasans. Preliminary results of the biological activity of deoxaphomine are reported.     

Autoxidation of isotachysterol

Isotachysterol, the acid-catalyzed isomerization product of vitamin D₃, produces seven previously unknown oxygenation products in a self-initiated autoxidation reaction under atmospheric oxygen in the dark at ambient temperature. They are (5R)-5,10-epoxy-9,10-secocholesta-6,8(14)-dien-3β-ol (6a), (5S)-5,10-epoxy-9,10-secocholesta-6,8(14)-dien-3β-ol (6b), (10R)-9,10-secocholesta-5,7,14-trien-3β,10-diol (7a), (10S)-9,10-secocholesta-5,7,14-trien-3β,10-diol (7b), (7R,10R)-7,10-epoxy-9,10-secocholesta-5,8(14)-dien-3β-ol (8), 5,10-epidioxyisotachysterol (9) and 3,10-epoxy-5-oxo-5,10-seco-9,10-secocholesta-6,8(14)-dien-10-ol (10). The formation of these products is explained in terms of free radical peroxidation chemistry.     

Synthesis and absolute configuration of two diastereoisomeric (1R,2S,3R)-and (1S,2S,3R)-2-amino-1-(2-furyl)-1,3-butandiols

The synthesis of (1R, 2S, 3R) and (1S, 2S, 3R)-2-(N-benzoylamino)-1-(2-furyl)-1, 3-butandiols (15) and (16) from D-threonine is described. The assignment of absolute configuration of the newly formed asymmetric center at C-1 was based on the ¹H-NMR spectra of O-isopropylidene derivatives 17 and 18.     

Structural characterization of triorganotin(IV) complexes with sodium fusidate and DFT calculations

Three new complexes of the steroid sodium fusidate (sodium 2-[(1S,2S,5R,6S,7S,10S,11S,13S, 14Z,15R,17R)-13-(acetyloxy)-5,17-dihydroxy-2,6,10,11-tetramethyl tetracyclo[8.7.0.0^2,7.0^11,15] heptadecan-14-ylidene]-6-methylhept-5-enoate = (NaFusidate, NaFA)]), with triorganotin(IV) moieties have been prepared and investigated by conventional techniques as FTIR, Mössbauer, ESI-MS and NMR spectroscopy. The isolated compounds showed stoichiometries organotin(IV)/fusidate 1/1, R₃Sn(IV)FA (R = Me, FA1; Bu, FA2; Ph, FA3). The ligand coordination sites were determined by FTIR spectroscopic measurements. In the complexes, the carboxylate group of the fusidate ligand behaves as monodentate monoanionic donor, binding the Sn(IV) through one oxygen atom.On the basis of C-Sn-O_COO angles, calculated through the rationalization of the ¹¹⁹Sn Mössbauer parameter nuclear quadrupole splitting, it has been confirmed that, in all the solid state complexes, the Sn(IV) was tetracoordinated in a distorted tetrahedral structure.Further data from ¹¹⁹Sn CP-MAS spectra confirmed the distorted tetrahedral arrangement.In MeOH solution, ¹H, ¹³C and ¹¹⁹Sn NMR spectroscopy showed monomeric complexes, where the carboxylate group mainly acts as monodentate ester-type ligand, and the occurrence of a coordinated solvent molecule to the tin center, as validated by non-relativistic NMR DFT study.     

Highly Oxygenated Triterpenoids and Diterpenoids from Fructus Rubi (Rubus chingii Hu) and Their NF-kappa B Inhibitory Effects

During a phytochemical investigation of the unripe fruits of Rubus chingii Hu (i.e., Fructus Rubi, a traditional Chinese medicine named “Fu-Pen-Zi”), a number of highly oxygenated terpenoids were isolated and characterized. These included nine ursane-type (1, 2, and 4–10), five oleanane-type (3, 11–14), and six cucurbitane-type (15–20) triterpenoids, together with five ent-kaurane-type diterpenoids (21–25). Among them, (4R,5R,8R,9R,10R,14S,17S,18S,19R,20R)-2,19α,23-trihydroxy-3-oxo-urs-1,12-dien-28-oic acid (rubusacid A, 1), (2R*,4S*,5R*,8R*,9R*,10R*,14S*,17S*, 18S*,19R*,20R*)-2α,19α,24-trihydroxy-3-oxo-urs-12-en-28-oic acid (rubusacid B, 2), (5R,8R,9R,10R, 14S,17R,18S,19S)-2,19α-dihydroxy-olean-1,12-dien-28-oic acid (rubusacid C, 3), and (3S,5S,8S,9R, 10S,13R,16R)-3α,16α,17-trihydroxy-ent-kaur-2-one (rubusone, 21) were previously undescribed. Their chemical structures and absolute configurations were elucidated on the basis of spectroscopic data and electronic circular dichroism (ECD) analyses. Compounds 1 and 3 are rare naturally occurring pentacyclic triterpenoids featuring a special α,β-unsaturated keto-enol (diosphenol) unit in ring A. Cucurbitacin B (15), cucurbitacin D (16), and 3α,16α,20(R),25-tetrahydroxy-cucurbita-5,23- dien-2,11,22-trione (17) were found to have remarkable inhibitory effects against NF-κB, with IC₅₀ values of 0.08, 0.61, and 1.60 μM, respectively.     

Chemoenzymatic synthesis and HPLC analysis of the stereoisomers of miyakosyne A [(4E,24E)-14-methyloctacosa-4,24-diene-1,27-diyne-3,26-diol], a cytotoxic metabolite of a marine sponge Petrosia sp., to determine the absolute configuration of its major component as 3R,14R,26R

Six samples [(3R,14R,26R)-, (3R,14S,26R)-, (3S,14R,26S)-, and (3S,14S,26S)-1, a mixture of (3R,14R,26S)- and (3S,14R,26R)-1, and a mixture of (3R,14S,26S)- and (3S,14S,26R)-1] of miyakosyne A [1, (4E,24E)-14-methyloctacosa-4,24-diene-1,27-diyne-3,26-diol] were synthesized starting from the enantiomers of citronellal (2), employing olefin cross metathesis and R-selective asymmetric acetylation of a stereoisomeric mixture of acetylenic alcohols with vinyl acetate and lipase PS as key reactions. Separation of the eight stereoisomer of 1 by reversed phase HPLC at −56 °C was achieved after their esterification with (1R,2R)-2-(anthracene-2,3-dicarboximido)cyclohexanecarboxylic acid (16), and the natural miyakosyne A was found to be a mixture of 95.7% of (3R,14R,26R)-1 and 4.3% of (3R,14S,26R)-1. This is different from the (3R,14S,26R)-configuration of 1 as tentatively assigned by X-ray analysis.     

Stereocontrolled synthesis of enantiomerically pure unsaturated analogues of 2,6-DAP. Part 5

An efficient new stereocontrolled synthesis of (2R,6R)-(+)- and (2S,6S)-(−)-2,6-diamino-4-methylene-1,7-heptanedioic acid 8a and 9a, respectively, has been accomplished starting from the glycine-derived chiral synthon 1. The enantiomerically pure α-alkyl derivatives 8b–d and 9b–d have also been synthesized. The absolute configuration of the new stereocenters was assigned on the basis of ¹H NMR spectra.     

Total synthesis of the 5-epimers of naturally occurring (−)-hyacinthacine A5 and unnatural (+)-hyacinthacine A4

(1R,2S,3R,5S,7aR)-1,2-Dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 10 [(+)-5-epihyacinthacine A₅] and (1R,2S,3R,5S,7aS)-1,2-dihydroxy-3-hydroxymethyl-5-methylpyrrolizidine 17 [ent-5-epihyacinthacine A₄] have been synthesized by either Horner–Wadsworth–Emmons (HWE) or Wittig methodology using aldehydes 6 and 13, prepared from (2R,3S,4R,5R)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine 5 (partially protected DALDP) and (2R,3S,4R,5S)-3,4-dibenzyloxy-N-benzyloxycarbonyl-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine 12 (partially protected DGADP), respectively, and the appropriated ylide, followed by cyclization through an internal reductive amination process of the corresponding intermediate pyrrolidinic ketones 7 and 14 and subsequent deprotection.     

Strategy for synthesis of the isoleucine conjugate of epi-jasmonic acid

The TES ether of 2-((1R,2S,3R)-3-hydroxy-2-((Z)-pent-2-enyl)cyclopentyl)acetic acid (5, equal to the reduction product of epi-jasmonic acid) derived from (1R,4S)-4-hydroxycyclopent-2-enyl acetate (19) in 13 steps was activated by using isobutyl chloroformate and was subjected to condensation with isoleucine at room temperature for 48 h. The product was desilylated and oxidized to the isoleucine conjugate of epi-jasmonic acid in 68% yield over three steps. Similarly, allo-isoleucine conjugate of epi-jasmonic acid and three isoleucine conjugates of ent-epi-jasmonic acid, jasmonic acid, and ent-jasmonic acid were synthesized.     

An enantiomerically pure bilirubin. Absolute configuration of (αR,α′R)-dimethylmesobilirubin-XIIIα

Enantiomerically pure (+)-(αR,α′R)-dimethylmesobilirubin-XIIIα 1 and its (αS,α′S) enantiomer ent-1 were synthesized in ten steps from simple precursors. Resolution was achieved at an early stage in the synthesis, with a racemic monopyrrole precursor rac-6 being converted to its amides 8 with (1S)-camphor-2,10-sultam. Resolution of 8 to 99% d.e. was accomplished in three crystallizations, and the absolute configuration of the acid 6 was deduced by X-ray crystallography of the more crystalline, diastereomerically pure amide 7. Circular dichroism spectroscopy of 1 showed intense bisignate Cotton effects: Δε^max₄₃₅=+344, Δε^max₃₉₁=−193 (CHCl₃), as expected for a molecular exciton, and consistent with a P-helical intramolecularly hydrogen-bonded ridge-tile conformation. The Cotton effect magnitudes of 1 match almost exactly those found for (−)-(βS,β′S)-dimethylmesobilirubin-XIIIα 11 and (+)-(αR,β′R)-dimethylmesobilirubin-XIIIα. However, the Cotton effect of the pseudo-meso diastereomer (αR,β′S)-dimethylmesobilirubin-XIIIα 12 is not zero. Its large positive exciton couplet and ¹H NMR NOE analysis confirm that an α-CH₃ exerts a greater steric demand than a β-CH₃—by a factor of ∼3.     

Synthesis and stereochemistry of ceramide B, (2S,3R,4E,6R)-N-(30-hydroxytriacontanoyl)-6-hydroxy-4-sphingenine, a new ceramide in human epidermis

(2S,3R,4E,6R)-N-(30-Hydroxytriacontanoyl)-6-hydroxy-4-sphingenine (1) and its (6S)-isomer (1′) were synthesized by starting from pentadecan-15-olide, the enantiomers of 1-pentadecyn-3-ol, and (S)-Garner's aldehyde. Comparison of the ¹H NMR spectra of the tetraacetyl derivatives of 1 and 1′ with that of ceramide B, a new protein-bound ceramide in human stratum corneum, revealed it to be (2S,3R,4E,6R)-1.     

Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.     

Asymmetric C–C bond forming reactions with chiral crown catalysts derived from d-glucose and d-galactose

New chiral monoaza-15-crown-5 derivatives anellated to methyl-4,6-O-benzylidene-α-d-glucopyranoside 2a, 2e, 2g–i and to methyl-4,6-O-benzylidene-α-d-galactopyranoside 3a, 3e, 3i have been synthesized. These crown ethers showed significant asymmetric induction as phase transfer catalysts in the Michael addition of 2-nitropropane to chalcone (87% ee), in the Darzens condensation of phenacyl chloride with benzaldehyde (71% ee) and in the self-condensation of phenacyl chloride (64% ee) to give 14. The absolute configurations of (−)-(2R,3S)-epoxy-3-(4-chlorophenyl)-1-phenyl-1-propanone 12 and (−)-4-chloro-(2R,3S)-epoxy-1,3-diphenyl-1-butanone 14 have also been determined by X-ray diffraction.     

Chiron approach for the synthesis of (1S,2R,5R,7S)-2-hydroxy-exo-brevicomin

(1S,2R,5R,7S)-2-Hydroxy-exo-brevicomin ent-1 was synthesized from 1,2;5,6-di-O-isopropylidene-d-glucose in seven steps. The key reaction in our synthesis is the formation of bicyclic ketal 7 under acid mediated acetal exchange of a 1,2-acetonide of d-glucose derivative 6.     

1,3-Heterazolidin-2-one as starting materials for optically active 1,3,2-oxazaborolines and 1,3,2-diazaboroline derived from ephedrines

(4R,5R)-3,4-Dimethyl-5-phenyl-1,3,2-oxazaboroline (1a) derived from pseudoephedrine and (4R,5S)-1,3,4-trimethyl-5-phenyl-1,3,2-diazaboroline (1d) derived from ephedrine have been prepared from the corresponding 1,3-heterazolin-2-one. Hydrolysis of 1d afforded the 1-methyl-3-(methylamine)-2-phenyl-propylamine 5. The structures were established from ¹H, ¹³C and ¹¹B NMR data. The X-ray diffraction analysis of (4R,5S)-(+)-3,4-dimethyl-5-phenyl-1-hydro-1,3-diazolidine-2-one (4e) was performed. Isomeric N-monoborane adducts of the 1,3,2-diazaboroline 1d were prepared, and their structures were deduced from the NMR data.     

Synthesis of mono- and dihydroxy-substituted 2-aminocyclooctanecarboxylic acid enantiomers

(1R,2S,6R)-2-Amino-6-hydroxycyclooctanecarboxylic acid (?)-10 was synthesized from (1R,2S)-2-aminocyclooct-5-enecarboxylic acid (+)-2 via an iodolactone intermediate, while (1R,2S,3R,4S)-2-amino-5,6-dihydroxycyclooctanecarboxylic acid (?)-12 was prepared by using the OsO₄-catalyzed oxidation of Boc-protected amino ester (?)-5. The stereochemistry and relative configurations of the synthesized compounds were determined by 1D and 2D NMR spectroscopy (based on 2D NOE cross-peaks and ³J(H,H) coupling constants) and X-ray crystallography.     

Enantioselective synthesis of some tetrahydroisoquinoline and tetrahydro-β-carboline alkaloids

Four alkaloids: (R)-(+)-cryspine A 5, (R)-(+)-octahydroindolo[2,3-a]quinolizidine 8, (R)-(+)-harmicine 19 and (R)-(+)-desbromoarborescidine 22 were prepared via the asymmetric transfer hydrogenation reaction of a prochiral enamine (iminium salt). The enantiomeric excesses of the isolated alkaloids were determined from their ¹H NMR spectra measured in the presence of (+)-(R)-tert-butylphenylphosphinothio(seleno)ic acids as chiral solvating agents. The absolute configurations at the newly created stereogenic carbon atoms were confirmed, in all cases, by X-ray crystallography.