Subsequent Methanolysis Research Articles

Total Synthesis of Suberitines A-D Featuring Tunable Biomimetic Late-Stage Oxidative Dearomatization and Acetalization.

Aaptaminoids are a unique family of marine alkaloids bearing a benzo[de][1,6]-naphthyridine core. This work describes the first total synthesis of suberitines A-D (1-4), four typical dimeric natural aaptaminoids, employing a step-saving bidirectional strategy. Key methods applied in the total synthesis include a cationic cascade to construct the bis-isoquinoline(s) with Hendrickson reagent-mediated Friedel-Crafts-type cyclization and eliminative aromatization, and a Bronsted acid-promoted Vilsmeier cyclization to generate the naphthyridine(s). The conditionally tunable PIDA-mediated oxidative dearomatization and subsequent methanolysis or hydrolysis successfully served as a powerful biomimetic tool to elaborate the essential oxygenated functionalities of suberitines A-D (1-4) in proper solvent-combinations at the final stage of total synthesis. The biomimetic proposal employed in the late-stage redox interchanges of related natural products was eventually supported by the isolation of synthetic intermediate 23 a as a natural product from the same natural source. Biological screening revealed that five of the synthetic samples including two natural suberitines and three full-skeleton natural product-like intermediates exhibited low micromolar inhibitory activities against the growth of cancer cell line K562.

Exploring Coumarins Reduction: NaBH4/MeOH versus Nickel Boride Generated In Situ.

AbstractThe role of reagents NaBH4/MeOH and nickel boride (Ni2B) generated in situ from NaBH4 and NiCl2, are compared in the reduction process of coumarin and a variety of 3,7‐substituted coumarins bearing electro‐donating (ED‐group) or electro‐withdrawing groups (EW‐group). Coumarins (chromen‐2‐ones) are only reduced by Ni2B to the cyclic chromanones. This provides a useful and very simple reduction method for electron‐rich coumarins, which are resistant to many other reducing methods. DFT calculations underlined the role of substituents electronic effects in the reactivity. Subsequent methanolysis may open the ring to methyl phenylpropanoate esters and alcohols resulting from their reductions can also be produced.

Fractionation of plant-cuticle-based bio-oils by microwave-assisted methanolysis combined with hydrothermal pretreatment and enzymatic hydrolysis

Microwave-assisted methanolysis was performed to fractionate a mixture of fatty acid methyl-esters from the cuticles of various wild plants and agricultural wastes. A combination of hydrothermal pretreatment and enzymatic hydrolysis effectively removed hemicellulose and cellulose to afford plant cuticles concentrated in residual materials. The subsequent methanolysis treatment afforded bio-oil from plant cuticles in ∼10% yield with a maximum higher heating value (HHV) of 32 MJ kg-1 from bagasse. The proposed cascading treatments allow the total use of herbaceous soft biomass by utilizing hemicellulose and cellulose fractions as well as plant cuticles to produce bio-oils with high HHVs.

Synthesis and Biological Activity of Alkane-1,1-diylbis(phosphonates) of Diterpenoid Isosteviol

Isosteviol reacted with α,ω-dibromoalkanes to give 19-(ω-bromoahkyl) esters which were treated with tetraethyl methylenebis(phosphonate) to obtain bis(phosphonates) conjugated to the deterpenoid skeleton through a polymethylene spacer. The bis(phosphonates) were converted to the corresponding bis(phosphonic acids) by transformation to trimethylsilyl esters and subsequent methanolysis. One of the synthesized compounds showed a high antimicrobial activity (MIC 3.9 µg/mL) against S. aureus and a high cytotoxicity (IC50 15–18 µM) toward M-HeLa and MCF-7 human cancer cell lines.

Biosynthetically Inspired Transformation of Iboga to Monomeric Post-iboga Alkaloids

Summary Organisms have evolved to produce various natural products from a common precursor as a means of maximizing the number of secondary metabolites, thus acquiring selectional advantages. By adopting nature's divergent biosynthetic strategy, we transformed (+)-catharanthine to various iboga and post-iboga alkaloids, including (−)-conodusine A, (+)-conodusines B and C, (−)-voatinggine, (−)-tabertinggine, and (+)-dippinine B. Well-orchestrated oxidations and reorganizations of catharanthine derivatives enabled chemical access to these natural products.

A new approach to the synthesis of lactams of muramic, isomuramic and normuramic acids via intramolecular O-alkylation: Stereochemical features of the intramolecular nucleophilic substitution

The title compounds were synthesized from the selectively protected N-acylated d-glucosamine derivatives, containing α-halo carboxylic acid moieties, via intramolecular 3-O-alkylation. It was found that if the starting compound contains asymmetric electrophilic center, isomuramic acid derivatives were mainly formed, regardless of the configuration of the electrophilic carbon atom. An explanation for the observed stereochemical results was proposed on the basis of the analysis of steric interactions in the molecules of the starting compounds, as well as using the concept of anchimeric assistance. It was shown that N-acetylation of the obtained lactam derivatives and subsequent methanolysis under mild conditions led to the selective cleavage of δ-lactam ring resulting in the formation of the corresponding ester derivatives of N-acetylmuramic acid or its analogues in high yields.

A convenient method for the preparation of 20-[18O]-labeled ingenol

A short and efficient protecting group-free synthesis of isotopically labeled 20-[18O]-ingenol has been developed. Based on a highly selective (only one out of four hydroxy groups) Mitsunobu reaction of ingenol with 18O2-acetic acid and subsequent methanolysis, this route yielded the desired 20-[18O]-ingenol in high yield and chemical and isotopic purity.

New Selective Synthesis of Dithiaboroles as a Viable Pathway to Functionalized Benzenedithiolenes and Their Complexes.

A synthetic protocol to synthesize 2-bromobenzo-1,3,2-dithiaboroles in one step from easily accessible benzene bis(isopropyl thioether)s has been developed. The reaction is remarkably specific in converting substrates with two adjacent (i)PrS moieties while leaving isolated thioether functions and other functional groups intact. On the basis of the spectroscopic detection or isolation of reaction intermediates, a mechanistic explanation involving a neighbor-group-assisted dealkylation as a key step is proposed. The resulting products featuring one or two dithiaborole units were isolated in good yields and fully characterized. Subsequent methanolysis, which was carried out either as a separate reaction step or in the manner of a one-pot reaction, gave rise to functionally substituted benzenedithiols. The feasibility of a methylphosphoryl-substituted benzenedithiol to act as a dianionic S,S-chelating ligand was demonstrated with the formation of paramagnetic Ni(III) and Co(III) complexes. Selective reduction of the phosphoryl group afforded a rare example of a phosphino dithiol which was shown to act as a monoanionic P,S-bidentate ligand toward Pd(II). All complexes were characterized by spectral data and X-ray diffraction studies, and the paramagnetic ones also by superconducting quantum interference device magnetometry.

Transition-metal complexes containing parent phosphine or phosphinyl ligands and their use as precursors for phosphide nanoparticles.

P-H functional transition-metal complexes were synthesized without using hazardous PH3 gas in good yields by photolysis of the transition-metal carbonyl complexes M(CO)(6-x) (M = Cr, W, Fe; x = 0, 1) in tetrahydrofuran followed by reaction with P2(SiMe3)4 and subsequent methanolysis to give the bridging complexes [(CO)(x)M(μ-PH2)]2 (M = Fe, x = 3 (1), M = Cr, x = 4 (2a), M = W, x = 4 (2b)). The photolysis of [(CO)4M(μ-PH2)]2 (M = Cr (2a), M = W (2b)) with P(SiMe3)3 was applied followed by methanolysis to synthesize the PH2 bridging transition-metal binuclear complexes with terminal PH3 groups. The products [(CO)4M(μ-PH2)2M(CO)3(PH3)] (M = Cr (3a), M = W (3b)) and [(CO)4W(μ-PH2)2W(CO)2(PH3)2] (4b) were isolated in moderate yield. Another synthetic approach to this type of compounds is the direct photolysis of the complexes [(CO)3M(PH3)3] (M = Cr (5a), M = W (5b)). The products were comprehensively characterized by (31)P NMR and IR spectroscopy as well as by X-ray structural analysis. Additionally, the relevancy of 2a as single source precursor for the synthesis of stoichiometry-controlled CrP nanoparticles has been demonstrated.

Synthesis of Enantiomerically Pure anti-1,2-Diaryl and syn-1,2-Alkylaryl vic-Selenoamines

Phenylselenyl benzylcarbanion stabilized by an (S)-2-p-tolylsulfinyl group evolves in a highly stereoselective way in the reactions with (S)-N-(p-tolylsulfinyl)imines at -98 °C affording diastereomerically pure 1,2-selenoamino derivatives in good yields. The syn or anti relationship of the obtained compounds depends on the alkyl or aryl character of the imine. They are easily transformed into enantiomerically pure (1R,2S)-1-aryl[or (1S,2S)-1-alkyl]-2-(phenylseleno)-2-phenylethylamines by reaction with t-BuLi and subsequent methanolysis of the generated sulfinamide derivatives with TFA.

(Methoxyborole)cobalt Complexes – Synthesis, Structures and Bonding

AbstractHeating (η‐C4H4BCy)Co(CO)2I (Cy = cyclohexyl) in benzene in the presence of AlCl3 and subsequent methanolysis affords the cationic benzene complex [(η‐C4H4BOMe)Co(η‐C6H6)]+ (1). Under visible‐light irradiation, 1 reacts with MeCN and tBuNC to give the tris(ligand) complexes [(η‐C4H4BOMe)Co(L)3]+ [L = MeCN (2), tBuNC (4)]. A similar reaction with P(OMe)3 in MeCN affords [(η‐C4H4BOMe)Co(MeCN){P(OMe)3}2]+ (5). Cation 2 reacts with BPh4– in CH2Cl2 to give the zwitterionic arene complex (η‐C4H4BOMe)Co(η‐C6H5BPh3) (3). Reactions of 2 with TlCp and Tl(η‐9‐SMe2‐7,8‐C2B9H10) afford the sandwich compounds (η‐C4H4BOMe)CoCp (6) and (η‐C4H4BOMe)Co(η‐9‐SMe2‐7,8‐C2B9H10) (7). The structures of 3 and 7 were determined by X‐ray diffraction. The bonding in the borole complexes [(C4H4BR)Co(C6H6)]+ and (C4H4BR)CoCp (R = H, OMe) was compared with that in the cyclobutadiene analogues [(C4R4)Co(C6H6)]+ and (C4R4)CoCp (R = H, Me) using energy decomposition analysis.

A Simple Enantioselective Route to Functionalized Indolizidines: Synthesis of (+)‐Ipalbidine and (+)‐Antofine

AbstractAn efficient route to functionalized indolizidines from an enantiomerically enriched γ‐nitro ketone is described. The nitro ketone is obtained by an organocatalytic, enantioselective ketone‐nitro alkene Michael addition. Oxidative ring expansion of the nitro ketone and subsequent methanolysis provides a 8‐nitro‐4‐oxooctanoate. This is stereoselectively transformed to the key, functionalized indolizidine intermediate which is readily converted to (+)‐ipalbidine and (+)‐antofine.

Application of Bis(trimethylsilyl) Phosphonite in the Efficient Preparation of New Heterocyclic α-Aminomethyl-H-phosphinic Acids

A simple, reproducible, and efficient preparation of new heterocyclic α-aminomethyl-H-phosphinic acids is reported. The synthetic protocol is based on the application of bis(trimethylsilyl) phosphonite, as an efficient phosphorous nucleophile, in the reaction with the corresponding heterocyclic imines. Subsequent methanolysis of the addition intermediates leads to the expected heterocyclic α-aminomethyl-H-phosphinic acids in fair to good yields. Additionally, acidic hydrolysis of benzhydrylamino derivatives allows the efficient preparation of free α-aminomethyl-H-phosphinic acids in good yields and high purity after simple crystallization.

Synthesis and solution studies of Cu(II) complexes with pyridine derivatives of iminobisphosphonic acids

New 2-pyridyl, 3-pyridyl and 4-pyridyl derivatives of iminobisphosphonic acid were prepared by addition of tris(trimethylsilyl)phosphite to the corresponding derivatives of pyridineimine-methylphosphonates 3 and subsequent methanolysis of the silylated products 4. Solution studies on the coordination abilities of the ligands have shown that these compounds bind copper(II) ion through the tridentate {N,O,O} mode, where Cu(II) is stabilized by two five-membered chelate rings. The complexes obtained are very stable, with the pCu(II) value above 12, and therefore the ligands can be used as powerful chelating agents for copper ion.

(CO)4W(PH3)2] as a Source of Semi-interstitial Phosphorus Ligands in Cobalt Carbonyl Clusters

The PH3-containing complex [(CO)4W(PH3)2] (1) is synthesized in good yields by the “one-pot” reaction of [(CO)4W(nbd)] (nbd = norbonadiene) with P(SiMe3)3 and subsequent methanolysis of the reaction mixture. The further reaction of [(CO)4W(PH3)2] with [Co2(CO)8] results in three novel cobalt clusters, [Co8(CO)18(μ6-P)2(μ-CO)] (2), [Co10(CO)18(μ7-P)2(μ-CO)6] (3), and [[Co3(CO)8{μ4-PW(CO)5}][(μ4-P)Co3(CO)9]] (4). All products have been comprehensively characterized including X-ray diffraction.

A novel pseudo four component reaction involving homoenolate for the synthesis of γ-aminobutyric acid (GABA) derivatives

Homoenolate generated from alpha,beta-unsaturated aldehydes by NHC catalysis underwent facile addition to conjugated sulfonimines, generated in situ, and subsequent methanolysis to afford protected GABA derivatives stereoselectively and in high yields, thus constituting a novel pseudo four component reaction.

Cycloartane glycosides from Euphorbia glareosa

We have previously reported the isolation from various species of Euphorbia growing in Georgia of flavonoids [1] and polyphenols [2]. We also found that all studied species contained in addition to the aforementioned classes of compounds triterpene glycosides of the cycloartane series. Herein we communicate results from a study of the structure of cycloartane glycosides isolated from E. glareosa (Euphorbiaceae). Triterpene glycosides were obtained by exhaustive extraction (2 × 5 L) of ground air-dried roots (0.8 kg) at room temperature. The MeOH extract was evaporated and worked up by the literature method [3] to afford triterpenoids (20.5 g total) that were separated over a column of silica gel (L 40/100, Czech Rep.) using CHCl3:CH3OH (1, 15:1), CHCl3:CH3OH:H2O (2, 70:23:4), C6H6:EtOAc (3, 2:1 and 1:1), and CHCl3:C6H14:EtOAc (4, 1:1:1) [3]. We isolated eight compounds designated in order of increasing polarity as 1–8. Compounds 1 and 2 were the genins cyclosiversigenin and asgenin; the others, their glycosides. Compound 1, cyclosiversigenin, C30H50O5 (cycloastragenol, astramembrangenin [4]), yield 0.036% (here and henceforth of the weight of air-dried raw material), mp 238–240°C, [ ] α D 20 +50.4° (c 2.0, MeOH). IR spectrum (KBr, νmax, cm −1): 3500–3350 (OH), 3040, 1760, 1750, 1260–1250. PMR spectrum (Py-d5, δ, ppm, J/Hz, 0 = HMDS): 4.90 (1H, q, J = 7.0, H-16), 3.78 (1H, br.q, H-24), 3.57 (2H, m, H-3, H-6), 0.51 (d, J = 4.0) and 0.23 (br.s, 2H-19); CH3 groups 1.76, 1.46, 1.35, 1.25, 1.21, 1.18, 0.92 [3]. Compound 2, cycloasgenin, C30H48O6, yield 0.011%, mp 234–235°C, [ ] α D 20 +130.4° (c 0.8, MeHO). IR spectrum (KBr, νmax, cm −1): 3450–3350 (OH), 3060 (cyclopropane CH2), 1706–1695 (C=O). PMR spectrum (Py-d5, δ, ppm, J/Hz, 0 = HMDS): 4.92 (1H, q, J = 7.3, H-16), 4.20 (1H, dd, J = 9.8, 2.5, H-11), 3.72 (1H, m, H-6), 1.64 (d, J = 4.0) and 0.46 (br.s, 2H-19), 3.75 (1H, dd, J = 8.8, 5.6, H-24), CH3 groups 1.70, 1.44, 1.41, 1.39. 1.21, 1.16, 0.84 [3]. A study of the acid hydrolysis products of the glycosides [5] showed that they all contained cyclosiversigenin as the genin. The structures of the carbohydrate parts of the glycosides were established using chemical transformations (Hakomori methylation [6] with subsequent methanolysis and GC of the sugars) and IR and PMR spectral data. Compound 3, cyclosiversigenin 3,6-O-β-D-dixylopyranoside, C40H66O13, 0.008%, mp 218–221°C (MeOH), [ ] α D 20 +29.0° (c 0.71, MeOH). IR spectrum (KBr, νmax, cm −1): 3200-3600 (OH), 3040–3060 (cyclopropane CH2). PMR spectrum (Py-d5, δ, ppm, J/Hz): 4.56 and 4.42 (d, J = 7.2, H′ and H′′), 1.70, 1.44, 1.25, 0.95 (eath 3H, s, CH3), 1.16 (9H, s, CH3 × 3), 0.46 (1H, br.s, Ha-19) [7, 8]. Compound 4, cyclosiversigenin 3-O-[β-D-xylopyranoside-(2′-O-acetyl)]-6-O-β-D-xylopyranoside, C42H68O14, 0.03%, mp 253–254°C (MeOH), [ ] α D 20 +31° (c 0.90, MeOH). IR spectrum (KBr, νmax, cm −1): 3360–3500 (OH), 1750, 1260 (ester). PMR spectrum (Py-d5, δ, ppm, J/Hz): 5.32 (1H, br.t, H-2′), 4.68 (1H, d, J = 6.2) and 4.55 (1H, d, J = 7.5); anomeric protons of two xyloses: 1.90 (3H, s, CH3CO), 1.52, 1.41, 1.26, 1.18, 1.15, 1.07, 0.95, (each 3H, s, CH3), 0.45 (1H, d, J = 4.0, Ha-19) [8, 9]. Compound 5, cyclosiversigenin 3-O-β-D-xylopyranoside-6-O-β-D-glucopyranoside, C41H68O14, 0.009%, mp 247– 249°C (MeOH), [ ] α D 20 +37.0° (c 0.5, MeOH). IR spectrum (KBr, νmax, cm −1): 3300–3500 (OH), 3040 (cyclopropane CH2). PMR spectrum (Py-d5, δ, ppm, J/Hz): 4.78 (1H, d, J = 7.8, H-1′′), 4.52 (1H, d, J = 7.4, H-1′), 1.82, 1.40, 1.26, 0.80, (each 3H, s, CH3), 1.16 (9H, s, CH3), 0.44 (1H, d, J = 3.9, Ha-19) [10].

Aminophosphinic Acids in a Pyridine Series, Part 2: Synthesis of 2-, 3-, and 4-Pyridyl Derivatives of 1-(Benzylamino)-methyl-H-phosphinic Acids

New 2-pyridyl, 3-pyridyl, and 4-pyridyl derivatives of 1-[N-(benzyl)amino]-methyl-H-phosphinic acid were prepared by the addition of bis(trimethylsilyl)phosphonite to the corresponding imines and subsequent methanolysis of the addition products. Treatment of the 2-pyridyl- and 1-(4-pyridyl)-1-(benzylamino)-methyl-H-phosphinic acids with aqueous mineral acids leads to cleavage and formation of the corresponding secondary amines and phosphorous acid (H 3 PO 3 ).

Synthesis of novel carbocyclic nucleoside analogues derived from 7-oxabicyclo[2.2.1]heptane-2-methanol

Hydroboration of [(1R*,2R*,4R*)-7-oxabicyclo[2.2.1]hept-5-en-2-yl]methyl benzoate (5), which was prepared by Diels–Alder reaction of furan with acrolein and subsequent reduction and benzoylation of the Diels–Alder product, afforded [(1R*,2S*,4S*,6S*)-6-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (6) and [(1R*,2R*,4R*,5S*)-5-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (7). The key intermediates, [(1R*,2S*,4S*,6R*)-6-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (10) and [(1R*,2R*,4R*,5R*)-5-hydroxy-7-oxabicyclo[2.2.1]heptan-2-yl]methyl benzoate (11), were prepared from6and7, respectively, by oxidation with pyridinium dichromate and subsequent reduction of the thus obtained ketones. The Mitsunobu reaction of10and11with 6-chloropurine and subsequent reductive deprotection with diisobutylaluminium hydride afforded 6-chloropurine derivatives, which were converted to other purine analogues. Thymine analogues were prepared by Mitsunobu reaction of10and11with 3-benzoyl-5-methylpyrimidine-2,4(1H,3H)-dione and subsequent methanolysis. The target compounds were tested for the activity againstCoxsackievirus.

SN2′ Alkylation of Chiral Allylic Cyanohydrin O‐Phosphates with Organocuprates

AbstractEnantiomerically enriched cyanohydrin O‐phosphates, prepared by enantioselective cyanophosphorylation of α,β‐unsaturated aldehydes, react regioselectively at the γ‐position with organocuprates derived from alkyl Grignard reagents and CuCN to afford chiral γ‐alkyl‐substituted α,β‐unsaturated nitriles. The configuration of the new C–C double bond is mainly (E) when the reaction is performed at –78 °C and (Z) when it is carried out at higher temperatures (0 °C). A high level of transfer of the chirality in the new stereocentre, corresponding to a stereospecific anti attack onto the cyanophosphate, is observed. Enantiomerically enriched (E)‐γ‐alkylated α,β‐unsaturated esters are prepared after subsequent methanolysis in a three‐step sequence from the corresponding α,β‐unsaturated aldehydes. In addition, the synthesis of (R)‐4‐methylnonan‐1‐ol, also known as the sex pheromone of the yellow mealworm Tenebrio molitor L, and its (S) enantiomer have been carried out in a four‐step route from (E)‐oct‐2‐enal. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)