SN2 Type Research Articles

Synthesis and antiviral activity of novel methylene cyclopropyl nucleosides.

Novel exomethylene cyclopropyl nucleosides were synthesized as potential antiviral agents. The key intermediate 5 was synthesized in 4 steps, from Feists acid 1 and was condensed with purine derivatives by the SN2 type reaction to give some cyclopropyl nucleosides. The synthesized nucleosides did not showed any significant antiviral activity against HSV-1, HSV-2, HCMV, HIV-1, HIV-2, and HBV up to 100 microM.

Ab initio MO study on the difference of solvent effect between exo and endo stereoisomers of aflatoxin B1 8,9-oxide for SN2 type nucleophilic ring opening

Ab initio MO calculation was performed to study the solvent effect for SN2 type nucleophilic oxirane ring opening of Aflatoxin B1 8,9-oxide (1) by using model compounds, (1aS, 2aS, 5aR, 5bR)-1a, 2a, 5a, 5b-tetrahydrofuro[2,3-b]oxireno[2,3-d]furan (I) and (1aR, 2aS, 5aR, 5bS)-1a, 2a, 5a, 5b-tetrahydrofuro[2,3-b]oxireno[2,3-d]furan (II). H2O was considered to be the coordinating molecule to oxirane oxygen, on which negative charge grows as the reaction proceeds. Stationary points including transition structures (TSs) were optimized with no geometrical constraint at the RHF/3-21G basis set. Relative energies were evaluated at Becke3LYP/3-21G level based on the RHF/3-21G geometries. Calculation clarified the following points. (1) In the reaction of I, H2O molecules can coordinate to oxirane oxygen with little steric congestion, however, TSs for the reaction of II suffers severe steric congestion for solvation. (2) For the reaction of II, approach of solvating H2O molecules to oxirane oxygen is sterically restricted to occur from only three directions (outside, backside, and frontside). Consequently, solvation must be accompanied with unfavorable reorganization of stable hydrogen bonding network in H2O solvent. (3) The energy difference between the most stable exo and endo-attacking TS tends to increase as the number (n=0–3) of coordinating H2O increases. These calculational results suggest that solvent effect clearly makes endo-attacking of nucleophile predominant.

Structural studies of human alkyladenine glycosylase and E. coli 3-methyladenine glycosylase

Human alkyladenine glycosylase (AAG) and Escherichia coli 3-methyladenine glycosylase (AlkA) are base excision repair glycosylases that recognize and excise a variety of alkylated bases from DNA. The crystal structures of these enzymes have provided insight into their substrate specificity and mechanisms of catalysis. Both enzymes utilize DNA bending and base-flipping mechanisms to expose and bind substrate bases. Crystal structures of AAG complexed to DNA suggest that the enzyme selects substrate bases through a combination of hydrogen bonding and the steric constraints of the active site, and that the enzyme activates a water molecule for an in-line backside attack of the N-glycosylic bond. In contrast to AAG, the structure of the AlkA–DNA complex suggests that AlkA substrate recognition and catalytic specificity are intimately integrated in a SN1 type mechanism in which the catalytic Asp238 directly promotes the release of modified bases.

Concentrated salt effects on solvolysis rates in 1,4-dioxane–H2O mixed solvent and the expansion of the use of the Hammett equation for salt effects

In the mixed solvent system 50 vol% 1,4-dioxane and H2O, the concentrated salt effects of alkali metal (M+) and alkaline earth metal (M2+) perchlorates on the solvolysis rates of aliphatic halides (RX) and related compounds were investigated. The “pseudo” first-order reaction rates (k/s−1) of typical SN1 substrates, 1-adamantyl chloride and bromide and tert-butyl chloride, increased exponentially with increasing concentration of metal salt. The effects of M2+ on the reaction rates were larger than those of M+: Na+, Li+ < Ba2+ < Mg2+. A non-metallic salt, Et4NBr, at concentrations of ≥1.0 mol dm−3 caused the log k value to decrease, although the log k was slightly increased by lower concentrations of the salt (<1.0 mol dm−3). Raman spectra of D2O containing high concentrations of Et4NBr suggested a complete distortion of the solvent structure. The increase in log k values in the presence of metal ions was explained by direct “chemical” interaction between halide ions and metal ions with the concentrated salts in the modified media: X−⋯M+ or X−⋯M2+. The solvolysis rates of typical SN2 substrates, ethyl bromide and methyl tosylate, were much decreased by the addition of concentrated LiClO4. The log k values of borderline SN1–SN2 reacting substrates, isopropyl bromide and benzyl halides, remained almost constant, however, more positive slopes in log k in the presence of LiClO4 were caused by the introduction of methyl substituents on benzyl halides; negative slopes were observed upon the introduction of strong electron-withdrawing substituents, such as NO2 and CN. We observed a correlation (of two different slopes) between the σ+ values in the Hammett equation and the Δlog k for substituted benzyl halides upon the addition of 1.0 mol dm−3 LiClO4, as well as between the log (kx/kH) values themselves. We propose here an expansion of the use of the Hammett equation for the concentrated salt effect.

Reactions of Alkylidene-Bridged Cobaltadithiolene Complexes with Lewis Bases. Formation of M−S Sulfur Ylide Structure

The reactions of a malonate (C(COOMe)2)-bridged complex with Lewis bases give novel sulfur ylide (M−S sulfur ylide) complex due to the cleavage of Co−C bond as determined by X-ray sturucture analysis. Acetate (CHCOOEt)- and methylene-bridged complexes, on the other hand, reacted with Lewis bases via an SN2 type reaction to give unstable M−S sulfur ylide complexes and stable six-membered-ring complexes.

Local chain configuration dependence of the mechanisms of analogous reactions of PVC-5. Novel results on substitution reaction with sodium 2-mercaptobenzothiazolate

The nucleophilic substitution reaction on poly(vinyl chloride) (PVC) with sodium 2-mercaptobenzothiazolate has been carried out in solution in cyclohexanone at different temperatures. The kinetic parameters indicate the occurrence of one process having an activation energy of 63KJ.mol−1. The evolution of unreacted iso, hetero and syndiotactic triad contents with degree of substitution has been followed by 13C n.m.r. spectroscopy. By comparing quantitatively the microstructural changes with degree of substitution and taking into account that the reaction is of SN2 type only the mechanisms of substitution through the mm triad of mmr tetrad and the rm of rrmr pentads are proved to react. On the contrary, owing to steric hindrance the reaction by the mr triad in the mmr tetrad is quite unlikely, thus enhancing the stereoselective nature of the reaction. This conclusion was confirmed on the basis of the FTi.r. results and is more feasible than using other nucleophiles to study the effect of the aforementioned structures on the polymer properties and therefore provides new approaches to better comprehension at the molecular level of the structure–property relationships. These novel contributions are an original approach to the prominent role of the microstructure-dependent local conformation in the mechanisms of analogous reactions of PVC.

エキソおよびエンドＡｆｌａｔｏｘｉｎ Ｂ１ ８，９‐Ｏｘｉｄｅの求核開環反応に対するＡｂ Ｉｎｉｔｉｏ法による解析

The difference of the reactivity for SN2 type oxirane ring opening of exo and endo Aflatoxin B1 (AFB1)8, 9-oxide (exo-1 and endo-1, respectively) was analyzed with ab initio molecular orbital theory. All stationary points including transition-state structures were optimized with no geometry constraint at the RHF/3-21G basis set, and energies were evaluate at Becke3LYP/3-21G level based on the RHF/321G geometries. The caluculation clarified the following three points: (1) the activation energy (ΔE≠)for endo attacking of NH3 molecule (the reaction with exo derivatives containing exo-1) is considerably smaller than those for exo attacking (the reaction with endo ones containg endo-1) (2) the reactivity for nucleophilic oxirane ring opening is controlled by the distortion of LUMOc-o of oxirane ring, which is probably caused by exo/endo relationship between oxirane ring and five-membered dihydrofurano ring (B) with respect to A ring, and (3) the remaining part (inclusing coumarin skeleton) of AFB1oxide has little influence on the geometry around the reaction center and the activation energy.

Reactivities of Stable Rotamers. XLI. Reactions of 1-(9-Fluorenyl)-2-(1-methylethenyl)naphthalene Rotamers with Chalcogenyl Halides and Observation of Coloration During the Reaction of Methanesulfenyl Chloride and the ap-Rotamer

Abstract Reactions of p-toluenesulfenyl chloride with the title olefins in carbon tetrachloride afforded an addition product and sp-1-(9-fluorenyl)-2-[1-(p-tolylthiomethyl)ethenyl]naphthalene in the case of ap, whereas the only product was ap-1-(9-fluorenyl)-2-[1-(p-tolylthiomethyl)ethenyl]naphthalene in the case of sp. No cyclized compounds, which are commonly observed in the reactions of the sp-isomer with halogens or halogen chloride, were detected. Various unsuccessful attempts, including use of methanesulfenyl chloride to take advantage of different sulfur acidity, use of a soft anion to retard deprotonation or a polar solvent to accelerate cyclization by stabilizing the intervening cations, have been made to find conditions for formation of the cyclized compound. Similar unsuccessful results were obtained with benzeneselenenyl halides. Such results are attributed to the effective participation of a chalcogen atom in stabilizing a β-carbocation, which opens momentarily but is less vulnerable to the SN2 type attack of the existing nucleophile. Coloration was observed in the reaction of the sp form with methanesulfenyl chloride.

Ring opening reactions of thiiranes by alkoxo- and aryloxo-gold(I) complexes

Alkoxo- and aryloxo-gold(I) complexes [Au(OR)L] [R = CH(CF3)2, L = PPh3 1a or PCy3 1b; R = Ph, L = PPh3 1c, PCy3 1d or PMe3 1e] smoothly reacted with ethylene sulfide to give the corresponding 2-(alkoxy- or -aryloxy)ethylsulfanylgold(I) complexes [Au(SCH2CH2OR)L] 2 at room temperature. Similar treatments of 1a–1e with propylene sulfide, isobutylene sulfide, or styrene sulfide selectively cleaved the less hindered C–S bond of thiiranes to give corresponding 2-(alkoxy- or -aryloxy)ethylsulfanylgold(I) complexes. Reactions of 1a with cis- and trans-2-butene sulfide gave syn- and anti-[Au(SCHMeCHMeOR)L], respectively, suggesting a mechanism involving an SN2 type trans addition of alkoxogold(I) complexes toward thiiranes.

The role of mutation frequency decline and SOS repair systems in methyl methanesulfonate mutagenesis.

Methyl methanesulfonate (MMS) is an SN2 type alkylating agent which predominantly methylates nitrogen atoms in purines. Among the methylated bases 3meA and 3meG are highly mutagenic and toxic. The excision of these lesions leads to the formation of apurinic (AP) sites and subsequently to AT-->TA or GC-->TA transversions. The in vivo method based on phenotypic analysis of Arg+ revertants of Escherichia coli K12 and sensitivity to T4 nonsense mutants has been used to estimate the specificity of MMS induced mutations. In the E. coli arg-his-thr- (AB1157) strain MMS induces argE3(oc)-->Arg+ revertants of which 70-80% arise by supL suppressor formation as a result of AT-->TA transversions. The remaining 20-30% arise by supB and supE(oc) suppressor formation as a result of GC-->AT transitions. The level of AT-->TA transversions decreases during starvation. This is a consequence of action of the repair mechanism called mutation frequency decline. This system which is a transcription coupled variant of nucleotide excision repair was discovered in UV induced mutations. We describe the mutation frequency decline phenomenon for MMS mutagenesis. MMS is a very efficient inducer of the SOS response and a umuDC dependent mutagen. In MMS treated E. coli cells mutated in umuDC genes the class of AT-->TA transversions dramatically diminishes. A plasmid bearing UmuD(D')C proteins can supplement chromosomal deletion of umuDC operon: a plasmid harbouring umuD'C is more efficient in comparison to that harbouring umuDC. Moreover, plasmids isolated from MMS treated and transiently starved E. coli AB1157 cells harbouring umuD(D')C genes have shown the repair of AP sites by a system which involves the UmuD'C or at least UmuD' protein.

Synthesis, Structure, and Properties of {(Me3Si)2CH}2SnH(OH)

The Lappert stannylene SnR2, R = CH(SiMe3)2, adds water and methanol to yield the low-melting-point, crystalline hydroxy- and methoxydiorganostannanes R2SnH(OH) (1) and R2SnH(OMe) (2). The corresponding deuterated derivatives R2SnD(OD) (1-d2) and R2SnD(OCD3) (2-d4) have also been prepared. Compounds 1 and 2 react with D2O with retention of the Sn−H bond to give R2SnH(OD) (1-d(SnOD)). The reaction is thought to proceed by an SN2 type mechanism via a [R2SnH(OR‘)2]- (R‘ = H, D, or Me) intermediate or transition state. Consistent with this, 2-d4 is hydrolyzed to R2SnD(OH) (1-d(SnD)). A single-crystal X-ray structure analysis of 1 reveals that individual molecules form Ci-symmetrical dimers in the solid with short O−H···O* hydrogen bridges (O···O* = 2.854(2) A). Reaction of 1 with (iPr2PC2H4PiPr2)Pd(C2H4) results in oxidative addition of the Sn−H bond to Pd0 to give the known (iPr2PC2H4PiPr2)Pd(H)−SnR2(OH) (3).

Concentrated Salt Effects on the Solvolysis Reaction Rates in Methanol–Water Solution

Abstract The solvolysis rates of aliphatic halides and related compounds (RX) were determined in an 80 vol% MeOH–20 vol% H2O solvent in the presence of very highly concentrated salts (0.25—5.0 mol dm−3) at 25—75 °C. For typical SN1 substrates, such as 1-adamantyl bromide and t-butyl chloride, the pseudo-first-order reaction rates (k/s−1) increased exponentially with increasing concentration of LiClO4, NaClO4, Mg(ClO4)2, and Ba(ClO4)2. The cation effects increased as Na+ &amp;lt; Li+ &amp;lt; Ba2+ ≤ Mg2+. A nonmetallic salt, Et4NBr, caused the k/s−1 value for 1-adamantly bromide to be slightly increased at lower concentrations ( &amp;lt; 1.0 mol dm−3), but to be greatly decreased at higher salt concentrations ( ≥ 2.0 mol dm−3). The large positive effects of metal perchlorates were explained by a change in the solvent structure and the formation of “stable” carbocations through a “chemical” interaction between X− (Cl−, Br−, or I−) and M+ (Li+, Na+) or M2+ (Mg2+, Ba2+) in the “modified” solvent. On the other hand, for SN1–SN2 intermediates, the solvolysis reaction rates were decreased by a decrease in the activity of the solvent containing a large amount of salts. The apparent rate constant (“k/s−1”) for isopropyl bromide at 75 °C remained an almost constant value in the presence of 0—5.0 mol dm−3 LiClO4. The rate constant for ethyl bromide was decreased substantially by the addition of the alkali metal and alkaline-earth metal perchlorates. A good linearity was observed between log (k1/k0) and the m values for RX by Grunwald and Winstein, where k1 and k0 are the solvolysis rates in the presence of 1.0 mol dm−3 LiClO4 and in the absence of the salt, respectively. Upon the solvolysis of neophyl chloride (1-chloro-2-methyl-2-phenylpropane), the change in the reaction scheme (e.g., methyl shift) was suspected during the increase in the LiClO4 or Ba(ClO4)2 concentration.

Concentrated salt effects on the rates of solvolyses involving carbocations as reaction intermediates in acetone–water mixed solvents

Extensive studies have been carried out on the concentrated salt effects on the solvolysis reaction rates of aliphatic halides and related compounds (RX) in acetone–water mixed solvents. In 90 vol% acetone– 10 vol% water solution, the pseudo-first-order rate constant (k/s–1) of a typical SN1 substrate, tert-butyl chloride, at 50 °C was increased exponentially by the addition of M+ClO4– (M+ = Li+, Na+: up to 4.0 mol dm–3) and M2+(ClO4–)2 (M2+ = Mg2+, Ba2+: up to 2.0 mol dm–3); the extent of the cation effects increased as Na+ ⩽⩽⩽ Li+ 1.0 mol dm–3 Et4NBr decreased the solvolysis rate markedly, whereas it was increased slightly by lower Et4NBr concentrations. The positive effects of metal ions for typical SN1 substrates were explained by the change of solvent structure and by a “chemical” interaction between the anions from the substrates (R+–X–) and M+ or M2+ in the presence of very concentrated salts; the negative effects of nonmetallic salts should have been brought about by the decrease in activity of H2O. The solvolysis rate of 2-adamantyl tosylate (C10H15OTs) in 50 vol% acetone–water solution at 50 °C was also increased exponentially by the addition of LiClO4, whereas those of typical SN2 substrates, methyl tosylate (CH3OTs) and ethyl bromide, were decreased by the addition of LiClO4. On the other hand, for isopropyl bromide and benzyl chloride, the solvolysis rates were not changed by the addition of LiClO4. A good linearity was observed between the increase in log (k/s–1) in the presence of 1.0 mol dm–3 LiClO4 and the m-values of the substrates (by Grunwald–Winstein). It is proposed that one could simply distinguish SN1 from SN2 reactions merely by observing a substantial increase in the solvolysis rate constant at 1.0 mol dm–3 LiClO4 in aqueous mixed solvents. The salt effects on the solvolysis rates of sulfonyl chlorides in 50% acetone–water at 35 °C were very different from those for substrates with carbocations as reaction intermediates.

アミン‐ｎＨＦをフッ素源として用いる新しいフッ素化反応の開発

Recently, Et3N-nHF complexes have been used for a variety of fluorination reactions instead of hazardous anhydrous HF. This review summarizes the recent progress in the fluorination reaction using Et3N-nHF complexes except Et3N-3HF. Et3N-HF and Et3N-2 HF have been used as nucleophilic fluorinating reagents in the SN2 type ring opening of terminal oxiranes and substitution with alkyl halides. On the other hand, Et3N-5 HF and Et3N-6 HF complexes, which are slightly more acidic than Et3N-3HF, have been used as 1) an electrolyte in electrochemical fluorination reactions 2) a hydrofluorination reagent of alkenes and alkenals and 3) a co-reagent of iodotoluene difluoride in the oxidative fluorination of β-dicarbonyl compounds, alkenes, and alkynes.

Synthesis of novel [formula omitted] nucleosides

Asymmetric synthesis of d-2′,3′- dideoxy-2′,3′-endo- methylene nucleosides was achieved via the intermediate 2,3- endo-methylene pentofuranoyl chloride 6, which was prepared from 1,2:5,6- Di-O- isopropylidene- D-mannitol 1 with high stereoselectivity (only α chlorosugar). The SN2 type condensation of 6 with sodium salt of adenine and silyated N 4-benzoylcytosine gave the desired β-nucleosides as major isomers ( β: α = 2.5:1 and 2:1, respectively).

Mitsunobu Reaction of Unbiased Cyclic Allylic Alcohols.

The stereochemical inversion of unbiased allylic alcohols using triphenylphosphine, diethyl azodicarboxylate, and benzoic acid, commonly known as the Mitsunobu reaction, was studied in three different solvents with specific attention toward the product composition. The results generated for the Mitsunobu reaction of (R)-3-deuterio-2-cyclohexen-1-ol and the cis and trans isomers of 1-deuterio-5-methyl-2-cyclohexen-1-ol, 1-deuterio-5-tert-butyl-2-cyclohexen-1-ol, and optically active cis and trans 5-isopropyl-2-methyl-2-cyclohexen-1-ol all gave similar product distributions with respect to inversion and retention at the carbinol center as well-as syn and anti S(N)2' type addition when THF or benzene was used as the solvent (CH(2)Cl(2) gave less selective product distributions). Interestingly, it was found that the quasi-equatorial and quasi-axial nature of the starting allylic alcohol does not appear to affect the product distribution for this reaction, nor does methyl substitution at the central carbon of the allylic alcohol. In all cases, significant amounts (8-28%) of non-S(N)2 type products were detected for these sterically unbiased allylic alcohols; only 72-77% of the product was from S(N)2 type reaction when sterically undemanding (R)-3-deuterio-2-cyclohexen-1-ol was subjected to Mitsunobu conditions.

α-KDOase Activity in Oyster and Synthesis of α- and β-4-Methylumbelliferyl Ketosides of 3-Deoxy-d-manno-octulosonic Acid (KDO)

Although alpha- and beta-linked 3-deoxy-D-manno-octulosonic acid (KDO) is found in lipopolysaccharides (LPSs) of Gram-negative bacteria, capsular polysaccharides of microorganisms, and plants, very little is known about its degradation. Using both thin-layer chromatography and the periodate-thiobarbituric acid reaction, we found that the hepatopancreas of oyster (Crassostrea virginica) contained an enzyme (alpha-KDOase) capable of releasing alpha-linked KDO from LPSs. To facilitate the studies of alpha-KDOase, we have carried out the synthesis of 4-methylumbelliferyl-alpha-KDO (alpha-KDO-MU) by conjugating the glycosyl chloride of the per-O-acetylated methylester of KDO with methylumbelliferone by the SN2 type reaction and the catalyzed phase-transfer. In both cases, the beta-anomer was obtained as the major product with a yield of about 80%, whereas the yield of alpha-anomer was only about 7%. Attempts to increase the yield of alpha-anomer were not successful. alpha-KDO-MU was used as substrate to follow the purification of alpha-KDOase from oyster hepatopancreas. The pH optimum for oyster alpha-KDOase was determined to be 4.5 using Re-LPS as substrate and 3.0 using alpha-KDO-MU as substrate. The enzyme was found to be stable in the pH range of 3-8. This enzyme released KDO from different LPSs, including Re-LPS from Escherichia coli and Salmonella minnesota, Rd-LPS from S. minnesota, and de-O-acyl-Re-LPS (Kiang, J., Szu, S. C., Wang, L.X., Tang, M., and Lee, Y. C. (1997) Anal. Biochem. 245, 97-101).

ChemInform Abstract: Lewis Acid‐Mediated SN2 Type Displacement by Grignard Reagents on Chiral Perhydropyrido(2,1‐b)pyrrolo(1,2‐d)(1,3,4)oxadiazine. Chirality Induction in Asymmetric Synthesis of 2‐Substituted Piperidines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The Mitsunobu Reaction: An Alternative Synthesis of 1-(Primary Alkyl)benzotriazoles

1-(Primary alkyl)benzotriazoles are obtained in convenient yields by treating the corresponding alcohol with triphenylphosphine, N-bromosuccinimide and benzotriazole. Under these conditions, the alcohols gave exclusively the corresponding 1-alkyl-benzotriazoles. Allyl and propargyl alcohols also reacted regiospecifically in a typical Sn2 manner, and no products derived from prototropic rearrangement were found.

Local chain configuration dependence of the mechanisms of analogous reactions of PVC. I. A conclusive study of the microstructure evolution in SN2 nucleophilic substitution

The nucleophilic substitution in poly(vinyl chloride) (PVC) with sodium benzenethiolate has been studied in two kinds of solvent differing in the molecular structure in the vicinity of the carbonyl group. From the evolution of the content of isotactic (mm), heterotactic (mr), and syndiotactic (rr) triads; and of mmmm, mmmr and rmmr isotactic pentads, in the unmodified parts of the polymer, as followed by 13C-NMR, it is unambiguously inferred that any chlorine but the central one of either the isotactic triad at mmr tetrads or the heterotactic triad at rmrr pentads is unreactive. Only a small fraction of mmr tetrads reacts occasionally by the central chlorine of its mr triad instead of the mm. Of those structures, the mmr, especially when located at the end of long isotactic sequences, proves to be highly reactive compared to the rmrr structure. By comparing quantitatively the microstructural changes with degree of substitution and taking into account that the reaction is of SN2 type, the mechanisms of substitution through the three foregoing reactive chlorines have been stated. They are found to be independent of the type of solvent and to account for all the changes in triad and pentad content as experimentally found. Instead, the solvent dependence of the ratio between the mmr- and rmrr-based processes of substitution is such that the depletion of mmr compared to that of rmrr structure may be controlled. The conformational sensitivity of this behavior is discussed on the basis of side work in our laboratory. As a whole, the results of the present work provide some original concepts as to the role of the tacticity dependent microstructure and the related local conformations in the chemical reactions of PVC. © 1996 John Wiley & Sons, Inc.