Synthesis and Mechanistic Study of Steroidal Oxime Ethers

Reaction of 5α‐cholestan‐6‐one oxime ( 1 ), its 3β‐acetoxy and 3β‐chloro analogs, 2 and 3 , respectiveley, with ClCH₂CH₂NH₂?HCl in presence of MeONa afforded 6‐[(2‐aminoethoxy)imino]‐5α‐cholestane ( 4 ), 3β‐acetoxy‐6‐[(2‐aminoethoxy)imino]‐5α‐cholestane ( 5 ), and 6‐[(2‐aminoethoxy)imino]‐3β‐chloro‐5α‐cholestane ( 6 ), respectively. The structures of newly synthesized compounds have been established on the basis of physical, analytical, and spectral data. Theoretical calculations were assessed by using DFT at B3LYP/6‐31G* level to describe the mechanism of the reaction. The stability and feasibility of all the generated structures studied in this report were supported by their respective fundamental frequencies and energy minima.     

Two New Homo‐aro‐cholestane Glycosides and a New Cholestane Glycoside from the Roots and Rhizomes of Paris polyphylla var. pseudothibetica

Two new homo‐aro‐cholestane glycosides and a new cholestane glycoside, along with three known saponins, were isolated from the 95% EtOH extract of the roots and rhizomes of Paris polyphylla var. pseudothibetica. The structures of the new compounds were elucidated as 3β‐O‐{α‐L ‐rhamnopyranosyl‐(1→4)‐α‐L ‐rhamnopyranosyl‐(1→4)‐[α‐L ‐rhamnopyranosyl‐(1→2)]}‐β‐D ‐glucopyranosylhomo‐aro‐cholest‐5‐ene‐26‐O‐β‐D ‐glucopyranoside (parispseudoside A, 1 ), 3β‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐β‐D ‐glucopyranosylhomo‐aro‐cholest‐5‐ene‐26‐O‐β‐D ‐glucopyranoside (parispseudoside B, 2 ), and (25R)‐3β‐O‐{α‐L ‐rhamnopyranosyl‐(1→4)‐α‐L ‐rhamnopyranosyl‐(1→4)‐[α‐L ‐rhamnopyranosyl‐(1→2)]}‐β‐D ‐glucopyranosyl‐cholesta‐5,17(20)‐diene‐16,22‐dione‐26‐O‐β‐D ‐glucopyranoside (parispseudoside C, 3 ) by spectroscopic methods, including 1D‐ and 2D‐NMR, and MS experiments, as well as chemical evidences.     

Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

Two New Cholestane Bisdesmosides from Reineckia carnea

Three cholestane bisdesmosides, together with the corresponding aglycone, were isolated from the whole plant of Reineckia carnea. By detailed analysis of the 1D‐ and 2D‐NMR spectra, chemical methods, and comparison with spectral data of known compounds, the structures were determined to be (1β,3β,16β,22S)‐cholest‐5‐ene‐1,3,16,22‐tetrol ( 1 ), (1β,3β,16β,22S)‐cholest‐5‐ene‐1,3,16,22‐tetrol 1,16‐di(β‐D ‐glucopyranoside) ( 2 ), (1β,3β,16β,22S)‐cholest‐5‐ene‐1,3,16,22‐tetrol 1‐[O‐α‐L ‐rhamnopyranosyl‐(1→2)‐β‐D ‐glucopyranoside] 16‐(β‐D ‐glucopyranoside) ( 3 ), (1β,3β,16β,22S)‐cholest‐5‐ene‐1,3,16,22‐tetrol 1‐(β‐D ‐glucopyranoside) 16‐(3‐O‐acetyl‐β‐D ‐glucopyranoside) ( 4 ). Compounds 3 and 4 appeared to be new compounds, while compound 1 was isolated for the first from a natural source. Compound 2 was isolated from the genus Reineckia for the first time.     

Cholestane glycosides from the bulbs of Galtonia candicans and their cytotoxicity

Further search for cytotoxic compounds contained in the bulbs of Galtonia candicans (Liliaceae) led to the isolation of four potent cytotoxic cholestane glycosides (1-4) based upon 3beta,16beta,17alpha-trihydroxycholest-5-en-22-one, three of which (2-4) have not been reported previously. A new cholestane bisdesmoside (5) and a new rearranged cholestane glycoside (6) were also isolated. The structural assignment of the new constituents was carried out by spectroscopic analysis and a few chemical transformations.     

Determination of neuroprotective oxysterols in Calculus bovis,human gallstones,and traditional Chinese medicine preparations by liquid chromatography with mass spectrometry

So far, the components responsible for the neuroprotective effects of Calculus bovis are unclear. Cholesterol, one of the major components in Calculus bovis, is easily oxidized into oxysterols, which possess direct or indirect neuroprotective effects proved by our and others’ previous studies. Therefore, a liquid chromatography with mass spectrometry method coupled with ultrasonic extraction and solid‐phase extraction was developed for the determination of neuroprotective oxysterols in Calculus bovis, human gallstones, and traditional Chinese medicine preparations. Chromatographic separation was achieved on a C₁₈ column with isocratic elution at a flow rate of 1 mL/min. The established method showed good linearity (R² > 0.998), sensitivity with low limits of detection (0.06–0.39 μg/g), acceptable precisions (relative standard deviations ≤ 7.4%), stability (relative standard deviations ≤ 5.9%), and satisfactory accuracy (92.4–102.9%) for all analytes identified by different retention times, which could be applied for the determination of oxysterols. Five kinds of oxysterols proved to function as neuroprotectants were detected at different concentrations. Among them, 7β‐hydroxycholesterol and cholestane‐3β,5α,6β‐triol were rather abundant in the samples. It could be concluded that the potential neuroprotective components in Calculus bovis may be these oxysterols.     

Synthesis of <Emphasis Type="Italic">α</Emphasis>-chloropyridine-containing oximes of 3<Emphasis Type="Italic">β</Emphasis>,5-dihydroxy-6-ketosteroids

New derivatives of steroidal 6-ketoximes containing α-chloropyridine neonicotinoid groups characteristic of bioactive compounds were synthesized by formation of oximes of cholestane and stigmastane 3β,5-dihydroxy-6-ketosteroids with O-(2-chloropyridin-5-ylmethyl)hydroxylamine in the presence of zinc or tin(IV) chloride.     

Mass spectral studies on steroidal compounds—II: 7a-aza compounds in the cholestane series (ring Bε-lactams)

The mass spectra of four structurally related 7a-aza compounds in the cholestane series have been examined. These spectra are conspicuous by the presence of a fragment ion peak at m/e 222 (C₁₅H₂₈N). which can be of diagnostic value in characterisation of such ε-lactams. The fragmentation pathways are supported by accurate mass measurement of the salient fragment ions and in some cases by appropriate metastable peaks.     

Two New 7‐Dehydrobrefeldin A Acids from Cylindrocarpon obtusisporum,an Endophytic Fungus of Trewia nudiflora

Two new 7‐dehydrobrefeldin A acids, (2E,4R*)‐4‐hydroxy‐4‐{(1R*,2S*)‐4‐oxo‐2‐[(1E)‐6‐oxohept‐1‐en‐1‐yl]cyclopentyl}but‐2‐enoic acid ( 3 ) and (2E,4R*)‐4‐hydroxy‐4‐{(1R*,2S*)‐2‐[(1E,6S*)‐6‐hydroxyhept‐1‐en‐1‐yl]‐4‐oxocyclopentyl}but‐2‐enoic acid ( 4 ), were isolated from the endophytic fungal strain Cylindrocarpon obtusisporum (Cooke & Harkness ) Wollenw . of Trewia nudiflora, together with two known compounds, 7‐dehydrobrefeldin A ( 2 ) and brefeldin A ( 1 ). Their structures were determined on the basis of extensive 1D‐ and 2D‐NMR‐spectral analysis.     

Two New Cytotoxic Nonsulfated Pentasaccharide Holostane (=20‐Hydroxylanostan‐18‐oic Acid γ‐Lactone) Glycosides from the Sea Cucumber Holothuria grisea

Two new lanostane‐type nonsulfated pentasaccharide triterpene glycosides, 17‐dehydroxyholothurinoside A ( 1 ) and griseaside A ( 2 ), were isolated from the sea cucumber Holothuria grisea. Their structures were elucidated by spectroscopic methods, including 2D‐NMR and MS experiments, as well as chemical evidence. Compounds 1 and 2 possess the same pentasaccharide moieties but differ slightly in their side chains of the holostane‐type triterpene aglycone. The structures of the two new glycosides were established as (3β,12α)‐22,25‐epoxy‐3‐{(O‐β‐D ‐glucopyranosyl‐(1→4)‐O‐[O‐3‐O‐methyl‐β‐D ‐glucopyranosyl‐(1→3)‐O‐β‐D ‐glucopyranosyl‐(1→4)‐6‐deoxy‐β‐D ‐glucopyranosyl‐(1→2)]‐β‐D ‐xylopyranosyl)oxy}‐12,20‐dihydroxylanost‐9(11)‐en‐18‐oic acid γ‐lactone ( 1 ) and (3β,12α)‐3‐{(O‐β‐D ‐glucopyranosyl‐(1→4)‐O‐[O‐3‐O‐methyl‐β‐D ‐glucopyranosyl‐(1→3)‐O‐β‐D ‐glucopyranosyl‐(1→4)‐6‐deoxy‐β‐D ‐glucopyranosyl‐(1→2)]‐β‐D ‐xylopyranosyl)oxy}‐12,20,22‐trihydroxylanost‐9(11)‐en‐18‐oic acid γ‐lactone ( 2 ). The 17‐dehydroxyholothurinoside A ( 1 ) and griseaside A ( 2 ) exhibited significant cytotoxicity against HL‐60, BEL‐7402, Molt‐4, and A‐549 cancer cell lines.     

A New Phenolic Diglycoside Produced in Response to Copper Toxicity and a New Flavan Dimer from the Leaves of Viburnum ichangense (Hemsl.) Rehd.

A new phenolic digycoside 1 was produced as stress metabolite in the fresh leaves of Viburnum ichangense (Hemsl.) Rehd ., in response to abiotic stress elicitation by CuCl₂. The stress metabolite was characterized as 1‐O‐[α‐L ‐arabinofuranosyl(1→6)‐β‐D ‐glucopyranosyl]‐erythro‐1,2‐bis(4‐hydroxy‐3‐methoxyphenyl)propane‐1,3‐diol ( 1 ). A new flavan dimer, 2,3‐epoxyflavan‐3′,4′,5,7‐tetraol‐(4→8″)‐flavan‐3″,3′′′,4′′′,5′′′,6″‐pentaol ( 2 ), and two known compounds, hovetrichoside A ( 3 ) and asperglaucide ( 4 ), were also isolated. Their structures were established by spectroscopic means.     

Structure of the O‐Glycosylated Conopeptide CcTx from Conus consors Venom

The glycopeptide CcTx, isolated from the venom of the piscivorous cone snail Conus consors, belongs to the κA‐family of conopeptides. These toxins elicit excitotoxic responses in the prey by acting on voltage‐gated sodium channels. The structure of CcTx, a first in the κA‐family, has been determined by high‐resolution NMR spectroscopy together with the analysis of its O‐glycan at Ser7. A new type of glycopeptide O‐glycan core structure, here registered as core type 9, containing two terminal L ‐galactose units {α‐L ‐Galp‐(1→4)‐α‐D ‐GlcpNAc‐(1→6)‐[α‐L ‐Galp‐(1→2)‐β‐D ‐Galp‐(1→3)‐]α‐D ‐GalpNAc‐(1→O)}, is highlighted. A sequence comparison to other putative members of the κA‐family suggests that O‐linked glycosylation might be more common than previously thought. This observation alone underlines the requirement for more careful and in‐depth investigations into this type of post‐translational modification in conotoxins.     

Three New Triterpenoid Saponins from Ardisia crenata

Three new triterpenoid saponins, ardisicrenoside I ( 1 ), ardisicrenoside J ( 2 ), and ardisicrenoside M ( 3 ), along with eight known compounds, were isolated from the roots of Ardisia crenata Sims . Their structures were elucidated as 16α‐hydroxy‐30,30‐dimethoxy‐3β‐O‐{β‐D ‐xylopyranosyl‐(1→2)‐β‐D ‐glucopyranosyl‐(1→4)‐[β‐D ‐glucopyranosyl‐(1→2)]‐α‐L ‐arabinopyranosyl}‐13β,28‐epoxyoleanane ( 1 ), 16α‐hydroxy‐30,30‐dimethoxy‐3β‐O‐{α‐L ‐rhamnopyranosyl‐(1→2)‐β‐D ‐glucopyranosyl‐(1→4)‐[β‐D ‐glucopyranosyl‐(1→2)]‐α‐L ‐arabinopyranosyl}‐13β,28‐epoxyoleanane ( 2 ), 30,30‐dimethoxy‐16‐oxo‐3β‐O‐{β‐D ‐xylopyranosyl‐(1→2)‐β‐D ‐glucopyranosyl‐(1→4)‐[β‐D ‐glucopyranosyl‐(1→2)]‐α‐L ‐arabinopyranosyl}‐13β,28‐epoxyoleanane ( 3 ), ardisiacrispin A ( 4 ), ardisiacrispin B ( 5 ), ardisicrenoside B ( 6 ), ardisicrenoside A ( 7 ), ardisicrenoside H ( 8 ), ardisicrenoside G ( 9 ), cyclamiretin A‐3β‐O‐β‐D ‐xylopyranosyl‐(1→2)‐β‐D ‐glucopyranosyl‐(1→4)‐α‐L ‐arabinopyranoside ( 10 ), and cyclamiretin A‐3β‐O‐α‐L ‐rhamnopyranosyl‐(1→2)‐β‐D ‐glucopyranosyl‐(1→4)‐α‐L ‐arabinopyranoside ( 11 ) by means of chemical and spectral analysis, and their cytotoxicities were evaluated in vitro.     

Synthesis and Chemical Properties of Diacetylenes with Pyridinium and 4,4′‐Bipyridinium Groups

Diacetylenes (DAs) having a dipolar D‐π‐A structure (D=donor: amino group; π=π‐conjugation core; A=acceptor: pyridinium (Py) and bipyridinium (BPy) groups), i.e., 4 (APBPyDA) and 5 (APPyPyDA), or an A‐π‐A structure, i.e., 7 (DBPyDA) and 8 (PyDA(Cl)), were obtained by 1 : 1 and 1 : 2 reactions of 4,4′‐(buta‐1,3‐diyne‐1,4‐diyl)bis[benzenamine] (APDA; 3 ) with 1‐(2,4‐dinitrophenyl)‐1′‐hexyl‐4,4′‐bipyridinium bromide chloride (1 : 1 : 1) ( 1 ), 1‐(2,4‐dinitrophenyl)‐4‐(pyridin‐4‐yl)pyridinium chloride ( 2 ), or 1‐(2,4‐dinitrophenyl)pyridinium chloride ( 6 ) (Schemes 1 and 2). The anion‐exchange reactions of 8 with NaI and Li(TCNQ) (TCNQ^?=2,2′‐(cyclohexa‐2,5‐diene‐1,4‐diylidene)bis[propanedinitrile] radical ion (1?)) yielded the corresponding I^? and TCNQ^? salts 9 (PyDA(I)) and 10 (PyDA(TCNQ)). Compounds 10 and 4 exhibited a UV/VIS absorption due to a charge transfer between the TCNQ^? and the pyridinium groups and a strong solute–solvent interaction of a dipolar solute molecule in the polar environment, respectively. Compounds 8 – 10 exhibited photoluminescence in solution, whereas 4 and 7 did not because of the presence of the 4,4′‐bipyridinium quenching groups. Differential‐scanning‐calorimetry (DSC) measurements suggested that the DAs obtained in this study can be converted into poly(diacetylenes) by thermal polymerization.     

Structure elucidation of new oleanane‐type glycosides from three species of Acanthophyllum

From the roots of three species of Acanthophyllum (Caryophyllaceae), two new gypsogenic acid glycosides, 1 and 2, were isolated, 1 from A. sordidum and A. lilacinum, 2 from A. elatius and A. lilacinum, together with three known saponins, glandulosides B and C, and SAPO50. The structures of 1 and 2 were established mainly by 2D NMR techniques as 23‐O‐β‐D ‐galactopyranosylgypsogenic acid‐28‐O‐β‐D ‐glucopyranosyl‐(1→3)‐[β‐D ‐glucopyranosyl‐(1→6)]‐β‐D ‐galactopyranoside (1) and gypsogenic acid‐28‐O‐β‐D ‐glucopyranosyl‐(1→3)‐[β‐D ‐glucopyranosyl‐(1→6)]‐β‐D ‐galactopyranoside (2). The cytotoxicity of several of these saponins was evaluated against two human colon cancer cell lines (HT‐29 and HCT 116). Copyright © 2010 John Wiley & Sons, Ltd.     

3β-methoxy-5α-cholestane-4β,5-diol and related compounds

The major product of acid-catalysed hydrolysis of 4α,5-epoxy-3β-methoxy-5α-cholestane (5) has been shown to be the allylic alcohol 9 (R = H) and not diol 10 as previously reported. A preparation of the latter compound, and of a number of cholestane derivatives with oxygen substituents in rings A and B, is described.     

Isoindolones from Lasiosphaera fenzlii Reich. and Their Bioactivities

Two new, 1 and 2 , along with one known isoindolone, 3 , were isolated from the AcOEt extract of Lasiosphaera fenzlii Reich . The structures of these compounds were determined as 4,6‐dihydroxy‐1H‐isoindole‐1,3(2H)‐dione ( 1 ), 4,6‐dihydroxy‐2,3‐dihydro‐1H‐isoindol‐1‐one ( 2 ), and clitocybin A ( 3 ) on the basis of chemical and spectroscopic evidences. The bioactivity assays revealed that all of them were devoid of significant cytotoxicities against tumor cells, whereas 1 exhibited potent antiangiogenic activity by inhibiting the secretion of vascular endothelial growth factor (VEGF) in A549 cells.     

The Total Synthesis and Biological Assessment of trans‐Epothilone A

The total synthesis of (12S,13S)‐trans‐epothilone A ( 1a ) was achieved based on two different convergent strategies. In a first‐generation approach, construction of the C(11) C(12) bond by Pd⁰‐catalyzed Negishi‐type coupling between the C(12)‐to‐C(15) trans‐vinyl iodide 5 and the C(7)‐to‐C(11) alkyl iodide 4 preceded the (nonselective) formation of the C(6) C(7) bond by aldol reaction between the C(7)‐to‐C(15) aldehyde 25 and the dianion derived from the C(1)‐to‐C(6) acid 3 . The lack of selectivity in the aldol step was addressed in a second‐generation approach, which involved construction of the C(6) C(7) bond in a highly diastereoselective fashion through reaction between the acetonide‐protected C(1)‐to‐C(6) diol 31 (‘Schinzer's ketone') and the C(7)‐to‐C(11) aldehyde 30 . As part of this strategy, the C(11) C(12) bond was established subsequent to the critical aldol step and was based on B‐alkyl Suzuki coupling between the C(1)‐to‐C(11) fragment 40 and C(12)‐to‐C(15) trans‐vinyl iodide 5 . Both approaches converged at the stage of the 3‐O, 7‐O‐bis‐TBS‐protected seco acid 27 , which was converted to trans‐deoxyepothilone A ( 2 ) via Yamaguchi macrolactonization and subsequent deprotection. Stereoselective epoxidation of the trans C(12) C(13) bond could be achieved by epoxidation with Oxone ^® in the presence of the catalyst 1,2 : 4,5‐di‐O‐isopropylidene‐L ‐erythro‐2,3‐hexodiuro‐2,6‐pyranose ( 42a ), which provided a 8 : 1 mixture of 1a and its (12R,13R)‐epoxide isomer 1b in 27% yield (54% based on recovered starting material). The absolute configuration of 1a was established by X‐ray crystallography. Compound 1a is at least equipotent with natural epothilone A in its ability to induce tubulin polymerization and to inhibit the growth of human cancer cell lines in vitro. In contrast, the biological activity of 1b is at least two orders of magnitude lower than that of epothilone A or 1a .     

Process‐Scale Total Synthesis of Nature‐Identical (−)‐(S,S)‐7‐Hydroxycalamenal in High Enantiomeric Purity through Catalytic Enantioselective Hydrogenation

A process‐scale stereoselective synthesis of nature‐identical (−)‐(S,S)‐7‐hydroxycalamenal (=(−)‐(5S,8S)‐5,6,7,8‐tetrahydro‐3‐hydroxy‐5‐methyl‐8‐(1‐methylethyl)naphthalene‐2‐carbaldehyde; (−)‐ 1a ) in 96% enantiomeric excess (ee) with the aid of chiral Ru complexes has been developed. The key step was the enantioselective hydrogenation of easily accessible 2‐(4‐methoxyphenyl)‐3‐methylbut‐2‐enoic acid ( 10 ) to (+)‐ 11 in a 86% ee (Scheme 5 and Table 1). A substantial increase in optical purity (96% ee) was achieved by induced crystallization of the intermediate (+)‐3,4‐dihydro‐4‐(1‐methylethyl)‐7‐methoxy‐2H‐naphthalen‐1‐one ((+)‐ 3 ). Computational conformation analysis carried out on the analog (−)‐ 9 rationalized the high diastereoselectivity achieved in the catalytic hydrogenation of the CC bond.