Methoxide Promoted Anionic Cyclization of 2-Alkynylbenzonitrile:A New Synthesis of 3-Substituted Isoqunolin-1-one

The treatment of 2-(2-alkylethynyl)benzonitrile with sodium methoxide in methanol gave 3-alkyl-l(2H)-isoquinolinone in modest yield. Under the same reaction conditions methanolysis of 2-(2-arylethynyl)benzonitrile lead to the formation of 3-alkylidene isoindol-1-one. Partially hydrolysis of 2-(l-hexynyl)benzonitrile to the corresponding benzamide,followed by the treatment of the benzamide with sodium methoxide gave 3-pentylidene isoindol-1-one in 11% yield. This result suggests that benzamide is not the intermediate of the formation of isoquinolinone. The more plausible mechanism of this methanolysis process is involving the iminium anion cycloaromatization to form 2-methoxyisoquinoline and subsequent hydrolyze to isoquinolinone. In one case,2-methoxyisoquinoline product was isolated.     

A catalytic asymmetric synthesis of chiral glycidic acid derivatives through chiral dioxirane-mediated catalytic asymmetric epoxidation of cinnamic acid derivatives

A novel and practical asymmetric synthesis of chiral glycidic acid derivatives involving methyl (2R,3S)-3-(4-methoxyphenyl)glycidate ((2R,3S)-2a), a key intermediate for diltiazem hydrochloride (1), was developed. Treatment of methyl (E)-4-methoxycinnamate ((E)-3a) with chiral dioxirane, generated in situ from a catalytic amount (5 mol %) of an 11-membered C(2)-symmetric binaphthyl ketone (R)-7a, provided (2R,3S)-2a in 92% yield and 80% ee. Other cinnamic acid esters and amides were epoxidized by the use of the same procedure to give the corresponding chiral glycidic acid derivatives with up to 95% yield and 92% ee. Higher enantioselectivities in the asymmetric epoxidation of (E)-cinnamates than that of (E)-stilbene derivatives were observed and were proposed to be attributed to a dipole-dipole repulsion between oxygen atoms of an ester group in the cinnamates and those of the lactone moieties in the binaphthyl dioxirane.     

P(MeNCH2CH2)3N: an efficient catalyst for the desilylation of tert-butyldimethylsilyl ethers

tert-Butyldimethylsilyl (TBDMS) ethers of primary, secondary, and tertiary alcohols and phenolic TBDMS ethers are desilylated to their corresponding alcohols and phenols, respectively, in DMSO, at 80 degrees C, in 68-94% yield in the presence of 0.2-0.4 equiv of P(MeNCH2CH2)3N. Using P(i-PrNCH2-CH2)3N as the catalyst, 85-97% yields of desilylated alcohols were obtained from TBDMS ethers of 1-octanol, 2-phenoxyethanol, and racemic alpha-phenyl ethanol. These are the first examples of desilylations of silyl ethers catalyzed by nonionic bases. Both catalysts were much less effective for the desilylation of tert-butyldiphenylsilyl (TBDPS) ethers (22-45% yield) under the same conditions as used for TBDMS ethers. Possible pathways involving nucleophilic attack of the anion of the solvent molecule (generated by the catalyst) at the Si-O bond of silyl ether or a prior activation of the silyl ether by the catalyst via a P-Si interaction followed by nucleophilic attack of the solvent anion are proposed on the basis of 1H and 31P NMR experimental data.     

Synthesis of an L-proline modified mimetic of the A83586C antitumour cyclodepsipeptide

A mimetic of the A83586C cyclodepsipeptide has been synthesised via a three-segment coupling protocol involving dipeptides 9, 8 and 7; in contrast to our previous synthesis of A83586C, where the HATU-mediated macrolactamisation proceeded in 25% yield, the corresponding macro-lactamisation of seco-amino acid 18 occurred in ca. 78% yield.     

Reactions of hydro(pero)xy derivatives of polyunsaturated fatty acids/esters with nitrite ions under acidic conditions. Unusual nitrosative breakdown of methyl 13-hydro(pero)xyoctadeca-9,11-dienoate to a novel 4-nitro-2-oximinoalk-3-enal product

13(S)-hydroperoxy- and 13(S)-hydroxyoctadeca-9,11-dienoic acids (1a/b), 15(S)-hydroperoxy- and 15(S)-hydroxyeicosa-5,8,11,13-tetraenoic acids (2a/b), and their methyl esters reacted smoothly with NO2- in phosphate buffer at pH 3-5.5 and at 37 degrees C to afford mixtures of products. 1b methyl ester gave mainly the 9-nitro derivative 3b methyl ester (11% yield) and a peculiar breakdown product identified as the novel 4-nitro-2-oximinoalk-3-enal derivative 4 methyl ester (15% yield). By GC-MS hexanal was also detected among the products. Structures 3b and 4 methyl esters were secured by 15N NMR analysis of the products prepared from 1b methyl ester upon reaction with Na15NO2. 4 methyl ester (14% yield) was also obtained from 1a methyl ester along with the nitrated hydroperoxy derivative 3a methyl ester (10% yield). Under the same conditions, 2a/b methyl esters gave mainly the corresponding nitrated derivatives 5a/b, with no detectable breakdown products, whereas the model compound (E,E)-2,4-hexadienol (6) afforded two main nitrated derivatives identified as 7 and 8. A reaction pathway for 1a/b methyl esters was proposed involving conversion of nitronitrosooxyhydro(pero)xy intermediates which would partition between two competing routes, viz., loss of HNO2, to give 3a/b methyl esters, and a remarkably facile fission leading to 4 methyl ester and hexanal.     

Synthesis of dihydroxylated prolines and iminocyclitols from five-membered endocyclic enecarbamates. Total synthesis of the potent glycosidase inhibitor (2R,3R,4R,5R)-2,5-dihydroxymethyl-3,4-dihydroxypyrrolidine (DMDP)

cis- and trans-3,4-Dihydroxylated prolines and the iminocyclitol 1,4-dideoxy-1,4-imino ribitol were synthesized employing a strategy involving the Heck arylation of five-membered endocyclic enecarbamates with aryldiazonium salts followed by oxidative cleavage of the electron-rich aromatic ring. The total synthesis of the potent α- and β-glucosidase inhibitor (2R,3R,4R,5R)-2,5-hydroxymethyl-3,4-dihydroxypyrrolidine (DMDP) was also achieved by the same strategy in ten steps from a chiral five-membered enecarbamate in 12% overall yield.     

A short approach to the bicyclo[4.3.0]nonane fragment of stawamycin

The bicyclo[4.3.0]nonane (C₁₁-C₂₁) fragment of stawamycin has been prepared by a sequence involving 11 steps (10% overall yield) from methyl (R)-(−)-3-hydroxy-2-methylpropionate. Key steps are a Pd-catalysed Stille coupling reaction between a vinyl iodide and a vinyl stannane followed by an intramolecular Diels-Alder cycloaddition reaction to give the desired adduct as the major isomer in 21% overall yield.     

Step-economic synthesis of (±)-debromoflustramine A using indole C3 activation strategy

A concise and practical strategy to obtain C3 reverse-prenylated pyrrolidinoindoline scaffold has been executed in 28.8% overall yield. The key conjugative step involved a Booker-Milburn-Feudoloff reaction involving an NCS-mediated activation of indole, followed by coupling to C₅ dimethylallylalcohol. This linchpin step proceeded in 74% yield. The overall sequence proceeded in five steps from commercially available N-methyltryptamine with a single protection-deprotection operation and a single redox manipulation. Mechanistic insights of NCS activation, and an ensuing rearrangement of the isoprene unit were gained by rationally varying the C3 substituent.     

Robust and straightforward chemo-enzymatic enantiopure dipeptide syntheses and diketopiperazines thereof

We have explored the scope of the synthetic route towards d-phenylglycyl diketopiperazines, involving a penicillin acylase catalysed formation of d-phenylglycyl dipeptides of l-amino acids with functional groups in the side chain. The synthesis of dipeptides from serine, threonine, glutamic acid, glutamine and methionine was successful. In contrast, aspartic acid, asparagine and cysteine only afforded trace amounts of dipeptides while no dipeptide was detected with arginine, lysine and tyrosine. Isolated dipeptide yields varied from 10% to 76%. The dipeptides were successfully converted into their corresponding enantiopure diketopiperazines by chemical esterification and cyclization under alkaline conditions, in 35–43% yield. In the case of glutamic acid, the procedure yielded the diketopiperazine with an esterified side chain. Remarkably with glutamine, the amide function in the side chain was transformed into an ester moiety, resulting in the same diketopiperazine as with glutamic acid.     

Total synthesis of (±)-aplysin-20

The first total synthesis of (±)-aplysin-20 involving 16 steps from nerolidol in a 10% overall yield is described.     

基于火花放电等离子体部分氧化重整二甲醚制氢研究

应用自制的多级式等离子体富氢气体制备装置，进行了二甲醚部分氧化重整制氢实验。实验结果表明，常温常压下二甲醚的转化率和氢产率随占空比的增大先增大后减小，当占空比为80%时最大值分别为87.6%和39.4%。随着电源电压的增加，放电能量和持续时间逐渐增加，转化率和氢产率逐渐增加。当反应器采用保温措施或对反应物进行加湿时，转化率和氢产率均有明显提高，同时制氢能耗下降，热效率有一定提高。实验过程中附着在电极上的积炭主要是由于氧气不足造成，随空醚比的增大，积炭明显减少。     

Direct conversion of hydroxy aromatic compounds to heteroarylamines via a one-pot smiles rearrangement procedure

8-Hydroxyquinoline ( 9 ) was converted to 8 -aminequinoline ( 10 ) in a one-pot procedure involving alleviation with 2-bromo-2-methylpropionamide ( 2 ) followed by Smiles rearrangement and hydrolysis, in 41% yield. The scope and limitations of this new procedure were explored with additional hydroxyquinolines.     

Electrophilic addition of alcohols to 1-vinyl-2-phenylazopyrroles and unexpected formation of 2-methylquinoline

1-Vinyl-2-phenylazopyrroles react with alcohols in the presence of acids or PdCl₂ to give 1-(1-alkoxyethyl)-2-phenylazopyrroles in up to 49% yield. In the presence of trifluoroacetic acid 2-methylquinoline unexpectedly formed (yield up to 26%) involving into the reaction the phenylazo and 1-vinyl groups.     

Synthesis of nitrooxazoles

A reaction sequence involving halogenation and replacement of the halo substituent by a nitro group using dinitrogen tetraoxide has led to a general, convenient route to 5-nitrooxazoles. Reaction schemes employing both bromine and iodine as the halo substituent have been investigated; however, the method using iodine preceded by a mercuration step affords a better overall yield in the range of 20–50%. Both 2- and 4-nitro-oxazoles can be prepared by this latter sequence, though in lower overall yields (4–12%).     

An expeditious route to the antipode of harzialactone A

The antipode of the antitumor marine metabolite harzialactone A was synthesized from l-malic acid via a very efficient route in 40% overall yield involving only two chromatographic separations.     

Enantioselective total synthesis of the potent anti-HIV nucleoside EFdA

A concise enantioselective total synthesis of 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), an extremely potent anti-HIV agent, has been accomplished from (R)-glyceraldehyde acetonide in 18% overall yield by a 12-step sequence involving a highly diastereoselective ethynylation of an α-alkoxy ketone intermediate.     

Microbial synthesis of the energetic material precursor 1,2,4-butanetriol

The lack of a route to precursor 1,2,4-butanetriol that is amenable to large-scale synthesis has impeded substitution of 1,2,4-butanetriol trinitrate for nitroglycerin. To identify an alternative to the current commercial synthesis of racemic d,l-1,2,4-butanetriol involving NaBH4 reduction of esterified d,l-malic acid, microbial syntheses of d- and l-1,2,4-butanetriol have been established. These microbial syntheses rely on the creation of biosynthetic pathways that do not exist in nature. Oxidation of d-xylose by Pseudomonas fragi provides d-xylonic acid in 70% yield. Escherichia coli DH5alpha/pWN6.186A then catalyzes the conversion of d-xylonic acid into d-1,2,4-butanetriol in 25% yield. P. fragi is also used to oxidize l-arabinose to a mixture of l-arabino-1,4-lactone and l-arabinonic acid in 54% overall yield. After hydrolysis of the lactone, l-arabinonic acid is converted to l-1,2,4-butanetriol in 35% yield using E. coli BL21(DE3)/pWN6.222A. As a catalytic route to 1,2,4-butanetriol, microbial synthesis avoids the high H2 pressures and elevated temperatures required by catalytic hydrogenation of malic acid.     

A novel one-pot synthesis of secondary alcohols from esters

Alkylation or vinylation by using organometallic reagents after partial reduction of carboxylic esters with LDBBA gave secondary alcohols, also involving allyl alcohols, without any isolation of intermediates in good yield (54-78%).     

Photophysical properties of a new DyLight 594 dye

We describe spectral properties of novel fluorescence probe DyLight? 594. Absorption and fluorescence spectra of this dye are in the region of Alexa 594 fluor spectra. The quantum yield of DyLight 594 in conjugated form to IgG is higher than corresponding quantum yield of Alexa 594 by about 50%. The new DyLight dye also shows slightly longer lifetime and photostability. These favorable properties and high anisotropy value, as well as a high cross-section for two-photon excitation, make this fluorophore attractive as a fluorescence probe in biochemical/biological studies involving fluorescence methods.     

Organocatalytic synthesis of chiral benzopyrans

Benzopyrans, or chromenes, are widespread in nature and are considered to be a privileged scaffold in medicinal chemistry. Herein, we report the first organocatalyzed asymmetric synthesis of chiral benzopyrans. The benzopyran unit is constructed through a domino reaction involving an oxa-Michael attack of salicylic aldehyde derivatives onto α,β-unsaturated aldehydes, activated through iminium-ion formation with the organocatalyst, followed by an intramolecular aldol reaction and subsequent elimination of water. This overall reaction sequence provides benzopyrans with aromatic C-2 substituents in up to 60% yield and 60% enantioselectivity, while C-2 aliphatic analogues can be obtained in 90% enantiomeric excess, but with only 20% yield. The role of additives, as well as the possible racemization of the benzopyran, was also investigated.