The stereochemistry of intermediates involved in the synthesis of tricyclovetivane sesquiterpenes

The stereospecificity of addition to the double bond of 2-substituted bicyclo[6.2.1.0^1·6]undec - 5 - enes has been studied and shown to be influenced mainly by the bicycloheptyl moiety in the case of epoxidation and hydroboration. These reactions proceed to give predominantly products of endo attack on the double bond. However for osmylation the important effect is the stereochemistry of the C₂-substituent due to steric interactions involved in the cyclic osmate ester intermediate. This results in attack by OsO₄ on the double bond trans to the C₂-substituent.     

Asymmetric synthesis of 4-ethoxy-1-p-tolylsulfonyl-3,6-dioxabicyclo[3.1.0]hexan-2-ones

Optically pure sulfinylfuranones undergo oxidation at sulfur followed by a totally stereoselective epoxidation at the electron deficient double bond by treatment with MCPBA at room temperature to afford, in good yields, enantiomerically pure 4-ethoxy-5-alkyl-1-p-tolylsulfonyl-3,6-dioxabicyclo[3.1.0]hexan-2-ones. These epoxyfuranones are obtained along with cyclopropanefuranones by reaction of 4-ethoxy-6-p-tolylsulfinylfuro[3,4-c]pyrazolin-6-ones with MPCBA. In both cases, the formation of the sulfonyl epoxylactones takes place by oxidation of the sulfonylfuran-2(5H)-one resulting from the starting materials. This reaction is completely stereoselective (controlled by the configuration of C-5 of furanone) and results from the nucleophilic attack of the peroxycarboxylate generated by interaction of the reagent with weak basic centres at the substrates.     

Rhodium catalyzed hydroacylation of ethylene with 4-pentenals. reactions of 4-hexenal-1-d

A catalyst derived from 2,4-pentanedionatobis(ethylene)rhodium(I), I, promoted the addition of 4-pentenal to ethylene. The reaction was accompanied by the formation of double bond migration products derived from the 4-pentenal reactant and from the 6-hepten-3-one primary product. Compound I accomplished the addition of 4-hexenal to ethylene to afford high yields of 6-octen-3-one. The fate of the aldehyde hydrogen in this transformation has been determined in experiments employing 4-hexenal-1-d as reactant. Treatment of 4-hexenal-1-d with I in CHCl₃ and CDCl₃ afforded 6-octen-3-one possessing >50% d_o molecules while the isotopic composition of recovered unexpended 4-hexenal remained >96% d₁. 6-Octen-3-one products with isotopic compositions of >66% d_o were afforded when ethylene was introduced to reaction mixtures. The location of deuterium in 6-octen-3-one, derived from treatment of 4-hexenal-1-d with I in the absence of added C₂H₄, was determined to be distributed at C-1 and C-2 and at the CC bond by analysis of the ¹H and ²H NMR spectra. Unexpended ethylene was recovered and was found to contain a substantial amount of deuterium. Mechanistic implications of these results are discussed.     

Rate constants for the reaction of the chloromethyne radical with alkynes

Absolute rate constants were measured for the gas phase reactions of the CCl(X?²Π) radical produced in the flash photolysis of CHBr₂Cl with a representative series of alkynes. The rate of addition to the triple bond follows the trend established for the addition CCl(X?²Π) to olefinic double bonds and the acetylenic triple bond by the latter reagent. A linear correlation between log k and ionization potentials of the alkynes reflects the electrophilic nature of the reaction.     

Improved thermal stability of crosslinked PTFE using fluorine gas treatment

Crosslinked PTFE (XF) samples were fluorinated at 293-593 K under 0.7-101 kPa F₂ and for 1 h to 7 days to improve its thermal stability. Because the weight uptake which may be caused by the fluorine addition was detected at room temperature, CC bonds in XF can be fluorinated and the fluorine content was saturated after 72 h. Weights of all samples increased more than that of original XF through additional fluorination of CC bonds, whereas it decreased by the chain-scission to form gaseous fluorocarbons such as CF₄. The intensity ratio in IR spectra of the peaks correspond to the double bond (CFCF₂) at 1785 cm⁻¹ and the characteristic peaks of PTFE at 1794 cm⁻¹, I_PTFE/I_PTFE was smaller for the fluorinated XF rather than that for XF. Average values of heat of crystallization (ΔH_c) for all fluorinated XF samples were about 2 J/g higher than that of the original XF. The decomposition temperature calculated from the TG curves increased with increasing reaction temperature and reaction time up to 72 h. Thermal stability of XF was improved through fluorine gas treatment.     

Structure, configuration, conformation and quantification of the push-pull effect of 2-alkylidene-4-thiazolidinones and 2-alkylidene-4,5-fused bicyclic thiazolidine derivatives

Structures of a series of push-pull 2-alkylidene-4-thiazolidinones and 2-alkylidene-4,5-fused bicyclic thiazolidine derivatives were optimized at the B3LYP/6-31G(d) level of theory in the gas phase and discussed with respect to configurational and conformational stability. Employing the GIAO method, ¹³C NMR chemical shifts of the C-2, C-2′, C-4 and C-5 atoms were calculated at the same level of theory in the gas phase and with inclusion of solvent, and compared with experimental data. Push-pull effect of all compounds was quantified by means of the quotient π^∗/π, length of the partial double bond, ¹³C NMR chemical shift difference (Δδ_CC) and ¹H NMR chemical shifts of olefinic protons. The effect of bromine on donating and accepting ability of other substituents of the push-pull CC double bond is discussed, too.     

Reactivity of fluorinated sulfur-containing heterocycles towards nucleophilic and oxidizing reagents

The reaction of 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.1]hept-2-ene, 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.2]oct-2-ene and 2,2-bis(trifluoromethyl)-3,6-dihydro-4,5-dimethyl-2H-thiopyran with i-C₃H₇MgCl leads to the formation of ring opening products as the result of nucleophilic attack of the Grignard reagent on the sulfur atom. According to DFT calculations the reactivity of the sulphur-containing substrate correlates with the strain energy of the heterocycle. The oxidation of 3-thia-4,4-bis(trifluoromethyl)tricyclo[5.2.1.0^2,5]non-7-ene by hydrogen peroxide in hexafluoro-iso-propanol solvent resulted in formation of the corresponding sulfoxide however, the reaction with m-chloroperoxybenzoic acid produced the product of exhaustive oxidation of sulfur and the double bond. In sharp contrast, the oxidation of 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.1]hept-2-ene and 5,5-bis(trifluoromethyl)-6-thia-bicyclo[2.2.2]oct-2-ene by MCPBA (2d, 25 °C) proceeds with the preservation of the double bond, leading to the selective formation of the corresponding sulfones.     

Enantioselective total synthesis and correction of the absolute configuration of megislactone

The title compound, one of the constituents from Iryanthera megistophylla, has been synthesized in enantiopure forms. The stereogenic centers at C-2 and C-3 were constructed by using a chiral auxiliary induced asymmetric aldolization and the C-4 was derived from the corresponding optically active lactates. The carbon-carbon double bond in the side chain was derived from a pure cis vinyl iodide using a Suzuki coupling with an alkyl borane formed in situ from the corresponding terminal alkene. A previously unknown (partial) cis to trans transformation of an isolated C-C double bond in a long alkyl chain was observed during the deprotection of TBS group with CAN. Somewhat unexpectedly, the otherwise undetectable co-presence of the trans isomer of the remote double bond in a long alkyl chain was clearly revealed in ¹H and ¹³C NMR in the presence of a lactone ring. The present work unambiguously shows that the absolute configuration of the natural compound is the antipode of the one originally reported. Some errors in the previous ¹H and ¹³C NMR signal assignments are also corrected.     

Epoxidation of α,β-unsaturated acids catalyzed by tungstate (VI) or molybdate (VI) in aqueous solvents: a specific direct oxygen transfer mechanism

The epoxidation mechanism of α,β-unsaturated acids catalyzed by Na₂WO₄ or Na₂MoO₄ in aqueous solvents has been studied by means of kinetic experiments, MS, ³¹P NMR and ¹³C NMR. The results show Na₂WO₄ or Na₂MoO₄ and H₂O₂ can rapidly form the diperoxocomplex irreversibly in aqueous solvent. ³¹P NMR and kinetics study reveal that -PO in cis-1-propenylphosphonic acid (CPPA) can fast coordinate to the metal center (Mo or W) of the diperoxocomplex irreversibly to form a stable complex. The subsequent direct oxygen transfer from peroxo bond to double bond is a monomolecular process, thus the epoxidation is zero-order on CPPA. However, ¹³C NMR shows the -CO in α,β-unsaturated carboxylic acids cannot coordinate to metal center of the diperoxocomplex. Therefore, the oxygen transfer is a bimolecular process and the epoxidation is a first-order reaction on the acids. In the mechanism, the nucleophilic attack of double bond towards the peroxo bond is regarded as through a spiro-transition structure.     

Zur lokalisierung funktioneller gruppen mit hilfe der massenspektrometrie—VIII : 6-hydroxy-androstan-3,17-dione und 6,17β-dihydroxy-androstan-3-one

5β-androstan-3-ones carrying a 6α-OH group show in their mass spectra a key-ion indicating the loss of water and C-1 to C-4 as C₄H₅O? particle. 6β-OH isomers lose instead C-1 to C-4 in form of C₄H₇O?.In 6α-hydroxy-androstan-3-ones differentiation between the connection of the A/B-ring system is possible, because in 5α-isomers the loss of C-3 to C-7 occurs as a C₅H₆O₂ particle, while the 5β-isomers lose the same C atoms as a C₅H₇O? unit.Compounds with a 6β-OH group in an A/B trans connected ring system show a tendency for thermal water elimination. After rearrangement of the double bond in 4,5 position the typical fragments for 3-keto-Δ⁴-steroids are obtained.Occasionally a strong influence of a 6-OH group on fragmentation reactions in the D-ring system is observed: The presence of a 6α-OH group in an androstan-3,17-dione enhances the loss of C-16 and C-17 in the form of acetaldehydenol. Also the connection of the A/B-ring system may have a considerable influence on this type of reaction: In 6,17β-dihydroxy-androstan-3-ones only by trans connection of the A/B-ring system, C-16 and C-17 are lost with high probability after water elimination.     

Catalyst control of selectivity in the C–O bond alumination of biomass derived furans

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C–O bond of the heterocycle. Specifically, the reaction of [{(ArNCMe)₂CH}Al] (Ar = 2,6-di-iso-propylphenyl, 1) with furans proceeded between 25 and 80 °C leading to dearomatised products due to the net transformation of a sp² C–O bond into a sp² C–Al bond. The kinetics of the reaction of 1 with furan were found to be 1st order with respect to 1 with activation parameters ΔH^‡ = +19.7 (±2.7) kcal mol⁻¹, ΔS^‡ = −18.8 (±7.8) cal K⁻¹ mol⁻¹ and ΔG^‡_{298 K} = +25.3 (±0.5) kcal mol⁻¹ and a KIE of 1.0 ± 0.1. DFT calculations support a stepwise mechanism involving an initial (4 + 1) cycloaddition of 1 with furan to form a bicyclic intermediate that rearranges by an α-migration. The selectivity of ring-expansion is influenced by factors that weaken the sp² C–O bond through population of the σ*-orbital. Inclusion of [Pd(PCy₃)₂] as a catalyst in these reactions results in expansion of the substrate scope to include 2,3-dihydrofurans and 3,4-dihydropyrans and improves selectivity. Under catalysed conditions, the C–O bond that breaks is that adjacent to the sp²C–H bond. The aluminium(iii) dihydride reagent [{(MesNCMe)₂CH}AlH₂] (Mes = 2,4,6-trimethylphenyl, 2) can also be used under catalytic conditions to effect a dehydrogenative ring-expansion of furans. Further mechanistic analysis shows that C–O bond functionalisation occurs via an initial C–H bond alumination. Kinetic products can be isolated that are derived from installation of the aluminium reagent at the 2-position of the heterocycle. C–H alumination occurs with a KIE of 4.8 ± 0.3 consistent with a turnover limiting step involving oxidative addition of the C–H bond to the palladium catalyst. Isomerisation of the kinetic C–H aluminated product to the thermodynamic C–O ring expansion product is an intramolecular process that is again catalysed by [Pd(PCy₃)₂]. DFT calculations suggest that the key C–O bond breaking step involves attack of an aluminium based metalloligand on the 2-palladated heterocycle. The new methodology has been applied to important platform chemicals from biomass.

Non-catalysed and catalysed reactions of aluminium reagents with furans, dihydrofurans and dihydropyrans were investigated and lead to ring-expanded products due to the insertion of the aluminium reagent into a C–O bond of the heterocycle.     

Facile synthesis of 4-deoxy-4-fluoro-α-d-talopyranoside, 4-deoxy-4-fluoro-α-d-idopyranoside and 2,4-dideoxy-2,4-difluoro-α-d-talopyranoside

The title compounds were prepared by two independent syntheses using inexpensive commercially available starting materials. 4-Deoxy-4-fluoro-α-d-talopyranoside served as a precursor to 4-deoxy-4-fluoro-α-d-idopyranoside, allowing for inversion of configuration at C-3 via a three-step protocol. The synthesis of 2,4-dideoxy-2,4-difluoro-α-d-talopyranoside is based on two nucleophilic fluorination events at C-2 then at C-4 using TBAF·3H₂O and TBAF·4tBuOH as a fluoride source. All compounds are prepared as pure stereoisomers and are therefore suitable probes for OH?F H-bonding studies by ¹H NMR spectroscopy.     

Fluorination of Hydrogen-containing with elemental fluorine

The hydrohalo-olefins cis and trans CHC1=CHC1, CHC1=CC1₂, CHC1=CH-CH₂C1 and CH₂=CC1-CH₂C1 have been fluorinated with elemental fluorine to give good yields of hydrohalofluoroalkanes. The best operational conditions for F₂ addition to the double bond rather than hydrogen and/or chlorine atom substitution, dimerization and oligomerization of radical intermediates have been studied. Preliminary studies on the reaction of Freon 12 and Freon 22 towards elemental fluorine have also been carried out.     

An Unusual Behavior of Methyl or Benzyl 3-Azido-5-O-Benzoyl-3,6-Di-Deoxy-α-L-Talofuranoside with (Dimethylamino)Sulfur Trifluoride; Migration of the Alkoxyl Group from the C-1 to the C-2 Position

The reaction of methyl or benzyl 3-azido-5-0-benzoyl-3,6-di-deoxy-α-L-talofuranoside with (diethylamino)sulfur trifluoride (DAST) in toluene at 60°C resulted in the formation of 3-azido-5-0-benzoyl-3,6-dideoxy-2-0-methyl (or 2-0-benzyl)-3β-L-galactofuranosyl fluoride in good yield. In this reaction the alkoxyl group at C-1 migrated to the C-2 position and a fluorine atom entered into the C-1 position. The furanosyl fluoride was converted, via reduction of the azido group followed by N-trifluoroacetylation, acetolysis, and O-deacetylation, into 3,6-dideoxy-2-0-methyl-3-trifluoroacet-amido-L-galactopyranose (2-methoxy-Daunosamine derivative).     

Synthesis, structure, and biological evaluation of C-2 sulfonamido pyrimidine nucleosides

The C-2 sulfonamido pyrimidine nucleosides were prepared by opening the 2,2′- or 2,3′-bond in anhydronucleosides under nucleophilic attack of sulfonamide anions. Reaction of the sodium salt of p-toluenesulfonamide or 2-(aminosulfonyl)-N,N-dimethylnicotinamide with 2,2′-anhydro-1-(β-d-arabinofuranosyl)cytosine gave the C-2 sulfonamido derivatives in excellent yields. Ring opening of the less reactive 2,2′-anhydrouridine and 2,3′-anhydrothymidine could be accomplished with DBU/CH₃CN activation of p-toluenesulfonamide, giving moderate yields for C-2 sulfonamido derivatives. The action of acetic acid or ZnBr₂/CH₂Cl₂ on 5-methyl-N²-tosyl-1-(2-deoxy-5-O-trityl-β-d-threo-pentofuranosyl)isocytosine led to the cleavage of both the protection group and the nucleoside bond, yielding 5-methyl-N²-tosylisocytosine as the major product. Structures of the prepared C-2 sulfonamido nucleosides were confirmed by the 1D and 2D NMR experiments, and X-ray structural analysis of 4-imino-N²-tosylamino-1-(β-d-arabinofuranosyl)pyrimidine. Both methods confirmed β-configuration and anti-conformation of the 2-sulfonamido nucleosides. The investigated compounds displayed moderate inhibition of tumor cell growth in vitro, as determined by the MTT assay using six different human tumor cell lines.     

Cyclobutane-bicyclobutane system—I : The relative reactivity of the central bond in bicyclobutanecarbonitrile and the double bond in crotononitrile in nucleophilic reactions

The ease of nucleophilic cleavage of the central bond of bicyclo[1.1.0]butanecarbonitrile 1 by alkoxides was compared to that of the double bond in crotononitrile 2. With both MeO^? /MeOH and i-PrO^?/PrOH, 2 reacts faster than 1 (by a factor of ca. 8 and 3 respectively). Analysis of the activation parameter reveals that in MeO^?/MeOH, both substrates have about the same activation energy and the reaction rate of 1 is markedly retarded by entropy effect. In i-PrO-/i-PrOH the entropy of activation is in favour of the reaction of 1 white its activation energy is higher than that of 2. Considering the steric and electronic effects of the substituents, it is concluded that the central bond of bicyclobutanecarbonitrile is more susceptible to nucleophilic attack than the analogous double bond.     

Double amination of 2-fluoroallylic acetates by palladium catalysts

We accomplished the palladium-catalyzed double substitution of 2-haloallylic acetates with nitrogen nucleophiles. During the Pd₂(dba)₃/DPPE-catalyzed reaction of 2-fluoroallylic acetates with N-substituted-p-toluenesulfonamide, two equivalents of nitrogen nucleophiles were introduced to the allyl unit with a Z-selectivity through the carbon–fluorine bond cleavage. We further demonstrated the reaction of 2-chloroallylic acetates, and succeeded in obtaining the same doubly-substituted products in good yields with a high Z-selectivity.     

Ungesättigte Zucker. Eine milde Sulfonat-β-Eliminierung bei Aminohexopyranosiduronat-Derivaten

Substituted 2-deoxy-2-acylamino-4-O-methanesulfonyl-hexopyranosiduronates yield, by mild alkaline mesylate (a, e)-β-elimination, the corresponding 4,5-unsaturated 4-deoxyhexopyranosiduronates VIII. This type of aminosugars proved to be the cyclic enol-ether acetal form of the 2,4-dideoxy-2-acylamino-hexos-5-ulosuronates. The structural principle of the latter can be found e.g. in neuraminic acid. These 4,5-unsaturated 4-deoxy-acylamino-hexopyranosiduronates give by reduction with NaBH₄ the corresponding 4,5-unsaturated 2,4-dideoxy-2-acylamino-hexopyranosides IX (with an endocyclic double bond on the glycosidic C atom 5). The isomeric 5,6-unsaturated 2,6-dideoxy-2-acylamino-hexopyranosides XVI (with an exocyclic double bond) are furthermore synthesized according to the method of HELFERICH [14] by elimination of a molecule of HI from the corresponding 2,6-dideoxy-2-acylamino-6-iodo-4-O-acylhexopyranoside derivatives XV. The ring stability of the two types of isomeric unsaturated hexopyranosides mentioned (bearing respectively an exo- and an endocyclic 5-enol-ether linkage) has been examined. In accordance with the stability principle of BROWN [16] – on the base of our preliminary experimental indications – the hexopyranosides with endocyclic double bond have been shown to be more stable than those with an exocyclic double bond: the latter (1) decompose slowly at 20°; (2) the α-glycosidic linkage is very easily split by dil. acetic acid at 20° within a few hours, giving 2, G-dideoxy-2-acyl-amino-D -xylo-hcxofuranos-5-ulose derivatives XX. On the other hand, the hcxopyranosides with endocyclic double bond show in the mass spectrometer, besides other fragmentations, a retro-dien decomposition. Some data on the NMR. spectra (100 and 220 MHz) of the above isomeric unsaturated acylamino-hexopyranosides (and hexopyranosiduronates, resp.) are furnished. The ORD./CD. spectra of the 4,5-unsaturated 2,4-dideoxy-2-acylamino-hexopyranosiduronates, which have two «COTTON centres», have been measured.     

β-Mannosidase and β-hexosaminidase inhibitors: synthesis of 1,2-bis-epi-valienamine and 1-epi-2-acetamido-2-deoxy-valienamine from d-mannose

A partially protected C-5C-5a unsaturated carbasugar with α-lyxo configuration is synthesised in five steps and 26% overall yield from a known mannose-derived hemiacetal, using ring-closing metathesis as a key step. This carbasugar is converted into valienamine derivatives with β-lyxo (i.e., corresponding to β-manno at C-1–C-4), α-lyxo (i.e., corresponding to α-manno at C-1–C-4) and β-2-acetamido-2-deoxy-xylo (i.e., corresponding to β-GlcNAc at C-1–C-4) configurations. This is the first report of the synthesis of the β-lyxo compound, 1,2-bis-epi-valienamine, which was found to inhibit Cellulomonas fimi β-mannosidase (CfMan2A) with K_i 140 μM. We report the crystal structures of three protected C-5C-5a unsaturated carbasugars with lyxo configuration.     

Formic acid reduction—XVII : Kinetic studies on the formic acid reduction of N-benzylideneaniline

The formic acid reduction of azomethine which has been reported² to proceed nearly quantitatively by the use of the formate reagent, 5HCO₂H·2NEt₃, was kinetically investigated by the carbon dioxide trapping and UV spectroscopic methods, using N-benzylideneaniline as a representative. Rate data gave the rate equation, v = (k + k′ [NEt₃])[N-benzylideneaniline][HCO₂H], indicating two-path mechanism. By the technique of using deuterated formic acids, it was found that the hydrogen bound to the carbon of formic acid is transferred as hydride to the carbon of the CN double bond in the rate determining step. The reaction is facilitated by the electron-releasing substituents of the two benzene rings of N-benzylideneaniline. On the bases of these results a possible mechanism is proposed.