A new mechanism for the Favorskii rearrangement

The title reaction was investigated by the use of ONIOM-RB3LYP calculations. A reaction system composed of alpha-chlorocyclohexanone, a methoxide ion and 8 MeOH solvent molecules was adopted. Two reaction channels, the semibenzilic acid mechanism (A) and cyclopropanone mechanism (B), were compared. B is found to be more favorable than A. The rate-determining step of B is the (MeOH)(3) addition transition state (TS3B) to the cyclopropanone intermediate. While TS3B involves a concerted function of MeO(-) addition and proton relays, it has a large activation energy. A new route was found, where the chloride ion evolved at the cyclopropane formation step (TS2B) works as a nucleophile to the cyclopropanone intermediate. Thus, a cyclopentane-carbonyl chloride intermediate is formed with a small activation energy. A new cyclopropanone mechanism is proposed.     

Theoretical study of the reaction from 6-methylidene penem to seven-membered ring intermediates

A sort of beta-lactamase inhibitor, 6-methylidene penem can inhibit both class A and class C serine beta-lactamase. Its inhibition mechanism involves yielding a seven-membered ring intermediate after acylation of the serine. Density functional theory (DFT) method was used on the molecular model to determine the mechanism of producing the seven-membered ring intermediate. Solvent effects were considered via polarizable continuum model (PCM). Moreover, a water-assisted process was considered in the hydrogen transfer process. The results show that the seven-membered ring intermediate can be obtained via two possible mechanisms, namely, concerted mechanism and stepwise mechanism. In stepwise mechanism, a new thiirane intermediate which has never been reported was found. The product of stepwise mechanism, e, has five tautomerics, and they can be tautomerized by hydrogen transfer.     

Nature of the intermediate formed in the reduction of O(2) to H(2)O at the trinuclear copper cluster active site in native laccase

The multicopper oxidases contain at least four copper atoms and catalyze the four-electron reduction of O(2) to H(2)O at a trinuclear copper cluster. An intermediate, termed native intermediate, has been trapped by a rapid freeze-quench technique from Rhus vernicifera laccase when the fully reduced form reacts with dioxygen. This intermediate had been described as an oxygen-radical bound to the trinuclear copper cluster with one Cu site reduced. XAS, however, shows that all copper atoms are oxidized in this intermediate. A combination of EXAFS, multifrequency EPR, and VTVH MCD has been used to understand how this fully oxidized trinuclear Cu cluster relates to the fully oxidized resting form of the enzyme. It is determined that in the native intermediate all copper atoms of the cluster are bridged by the product of full O(2) reduction. In contrast, the resting form has one copper atom of the cluster (the T2 Cu) magnetically isolated from the others. The native intermediate decays to the resting oxidized form with a rate that is too slow to be in the catalytic cycle. Thus, the native intermediate appears to be the catalytically relevant fully oxidized form of the enzyme, and its role in catalysis is considered.     

Infrared spectroscopy studies of the cyclic anhydride as the intermediate for the ester crosslinking of cotton cellulose by polycarboxylic acids. I. Identification of the cyclic anhydride intermediate

The mechanism of esterification of cotton cellulose by a polycarboxylic acid was investigated using Fourier transform infrared spectroscopy (FT-IR). The infrared spectroscopic data indicate that a polycarboxylic acid esterifies with cotton cellulose through the formation of an acid anhydride intermediate. A five-member cyclic anhydride intermediate was identified in the cotton fabric treated with poly(maleic acid). The five-member cyclic anhydride is a reactive intermediate and readily esterifies when reaction sites are available. We also found that those polycarboxylic acids, which form five-member cyclic anhydride intermediates, crosslink cotton cellulose more effectively than those polycarboxylic acids which form six-member cyclic anhydride intermediates. © 1993 John Wiley & Sons, Inc.     

The reversible addition‐fragmentation chain transfer process and the strength and limitations of modeling: Comment on “the magnitude of the fragmentation rate coefficient”

There is appreciable uncertainty concerning the magnitude of the fragmentation rate coefficient of the intermediate radical in reversible addition‐fragmentation chain transfer (RAFT) polymerizations. A large proportion of the experimental and theoretical evidence suggests that it is a stable species with a lifetime longer than 0.0001 s. This is particularly the case when the intermediate macro‐RAFT radical is stabilized by a phenyl group attached to the radical center or has a poor leaving group. Although the occurrence to some extent of irreversible termination reactions cannot be excluded, we argue that such reactions are more likely to be a result of slow fragmentation of the intermediate macro‐RAFT radical. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2828–2832, 2003     

Catalysis and specificity in enzymatic glycoside hydrolysis: a 2,5B conformation for the glycosyl-enzyme intermediate revealed by the structure of the Bacillus agaradhaerens family 11 xylanase.

BACKGROUND: The enzymatic hydrolysis of glycosides involves the formation and subsequent breakdown of a covalent glycosyl-enzyme intermediate via oxocarbenium-ion-like transition states. The covalent intermediate may be trapped on-enzyme using 2-fluoro-substituted glycosides, which provide details of the intermediate conformation and noncovalent interactions between enzyme and oligosaccharide. Xylanases are important in industrial applications - in the pulp and paper industry, pretreating wood with xylanases decreases the amount of chlorine-containing chemicals used. Xylanases are structurally similar to cellulases but differ in their specificity for xylose-based, versus glucose-based, substrates. RESULTS: The structure of the family 11 xylanase, Xyl11, from Bacillus agaradhaerens has been solved using X-ray crystallography in both native and xylobiosyl-enzyme intermediate forms at 1.78 A and 2.0 A resolution, respectively. The covalent glycosyl-enzyme intermediate has been trapped using a 2-fluoro-2-deoxy substrate with a good leaving group. Unlike covalent intermediate structures for glycoside hydrolases from other families, the covalent glycosyl-enzyme intermediate in family 11 adopts an unusual 2,5B conformation. CONCLUSIONS: The 2,5B conformation found for the alpha-linked xylobiosyl-enzyme intermediate of Xyl11, unlike the 4C1 chair conformation observed for other systems, is consistent with the stereochemical constraints required of the oxocarbenium-ion-like transition state. Comparison of the Xyl11 covalent glycosyl-enzyme intermediate with the equivalent structure for the related family 12 endoglucanase, CelB, from Streptomyces lividans reveals the likely determinants for substrate specificity in this clan of glycoside hydrolases.     

Synthesis of the Epimeric Secosteroids Strophasterols A and B

Two epimeric rearranged ergostanes, strophasterols A and B, with an unprecedented carbon skeleton were synthesized from ergosterol, both in 17 steps via a common secosteroidal intermediate. The conversion of ergosterol into the pivotal intermediate involved an efficient acid‐catalyzed double‐bond migration from ring B to ring D, oxidative cleavage of the double bond, and a completely diastereoselective acyl radical cyclization to form an isolated cyclopentanone ring unique to this recently discovered family of steroidal compounds produced by mushrooms. The intermediate was transformed stereodivergently into two epimeric cyclopentane derivatives through hydrogenation using two types of catalysts. One epimer was elaborated into strophasterol B by utilizing peracid oxidation of an iodide to provide an epoxide directly, and the other epimer was elaborated into strophasterol A, which is known to be a suppressor of endoplasmic reticulum stress.     

Nonnative interactions in the FF domain folding pathway from an atomic resolution structure of a sparsely populated intermediate: an NMR relaxation dispersion study

Several all-helical single-domain proteins have been shown to fold rapidly (microsecond time scale) to a compact intermediate state and subsequently rearrange more slowly to the native conformation. An understanding of this process has been hindered by difficulties in experimental studies of intermediates in cases where they are both low-populated and only transiently formed. One such example is provided by the on-pathway folding intermediate of the small four-helix bundle FF domain from HYPA/FBP11 that is populated at several percent with a millisecond lifetime at room temperature. Here we have studied the L24A mutant that has been shown previously to form nonnative interactions in the folding transition state. A suite of Carr-Purcell-Meiboom-Gill relaxation dispersion NMR experiments have been used to measure backbone chemical shifts and amide bond vector orientations of the invisible folding intermediate that form the input restraints in calculations of atomic resolution models of its structure. Despite the fact that the intermediate structure has many features that are similar to that of the native state, a set of nonnative contacts is observed that is even more extensive than noted previously for the wild-type (WT) folding intermediate. Such nonnative interactions, which must be broken prior to adoption of the native conformation, explain why the transition from the intermediate state to the native conformer (millisecond time scale) is significantly slower than from the unfolded ensemble to the intermediate and why the L24A mutant folds more slowly than the WT.     

Mechanistic Insights into the Pd‐Catalyzed Direct Amination of Allyl Alcohols: Evidence for an Outer‐Sphere Mechanism Involving a Palladium Hydride Intermediate

The mechanism of direct amination of allyl alcohol by a palladium triphenylphosphite complex has been explored. Labelling studies show that the reaction proceeds through a π‐allylpalladium intermediate. A second‐order dependence of reaction rate on allyl alcohol concentration was observed. Kinetic isotope effect studies and ESI‐MS studies are in agreement with a reaction proceeding through a palladium hydride intermediate in which both O–H bond and C–O bond cleavages are involved in rate‐determining steps. A stereochemical study supports an outer‐sphere nucleophilic attack of the π‐allylpalladium intermediate giving complete chiral transfer from starting material to product.     

Hydroxy-directed diastereoselective installation of a methyl group on indalone models and spiroketal potential precursors for the bafilomycin A(1) C15-C25 subunit

Current efforts devoted to the synthesis of Bafilomycin A(1) led us to investigate a synthetic route through a spiroketal intermediate for the construction of the C15-C25 subunit. Preliminary studies for the diastereoselective installation of the methyl-16 cis with respect to the vicinal OH-15 group through radical opening of either siloxafuran intermediate 7 or cyclopropyl compounds 9 and 13 have been carried out using model compounds derived from commercial Indalone 6. In each case the expected "cis" diastereoisomer was obtained in good to excellent yield. Application of these results to Bafilomycin A(1) synthon led to the opposite "trans" stereoselectivity when alpha-carboxy- or alpha-keto-substituted spiroketals 4 or 19 were used. However, the expected potential intermediate has been obtained from the alpha-hydroxymethyl cyclopropanated synthon 21. A Barton-Motherwell xanthate radical deoxygenation-cylopropane opening methodology, followed by a hydroboration-oxidation of the exovinylic intermediate, delivered the expected product 22cis in high yield and excellent stereoselectivity.     

Mechanistic studies of the biosynthesis of 2-thiosugar: evidence for the formation of an enzyme-bound 2-ketohexose intermediate in BexX-catalyzed reaction

The first mechanistic insight into 2-thiosugar production in an angucycline-type antibiotic, BE-7585A, is reported. d-Glucose 6-phosphate was identified as the substrate for the putative thiosugar biosynthetic protein, BexX, by trapping the covalently bonded enzyme-substrate intermediate. The site-specific modification at K110 residue was determined by mutagenesis studies and LC-MS/MS analysis. A key intermediate carrying a keto functionality was confirmed to exist in the enzyme-substrate complex. These results suggest that the sulfur insertion mechanism in 2-thiosugar biosynthesis shares similarities with that for thiamin biosynthesis.     

A concise synthetic route to the conduritols from pentoses

A short synthetic strategy for preparation of the conduritols is described. The key step employs a zinc-mediated fragmentation of protected methyl 5-deoxy-5-iodo-d-pentofuranosides followed by an allylation of the intermediate aldehyde in the same pot. The allylation is performed with 3-bromopropenyl benzoate and occurs with good diastereoselectivity. An amino group can be introduced in the product by trapping the intermediate aldehyde as the imine prior to the allylation. The functionalised 1,7-octadienes, thus obtained, are converted into protected conduritols by ring-closing olefin metathesis.     

动力学分析方法检测酶反应活性中间体的研究

提出了一种检测酶反应活性中间体的动力学新方法，利用中间体的反应活性，加入合适的竞争剂使中间体在转化产物的同时能与竞争剂反应，监测中间体与竞争剂反应的动力学过程的以获得中间体信息，该法既能研究自由基中间体，也能研究非自由基中间体，便于研究快反应和跟踪动态过程，用该法对辣根过氧化酶催经过氧化氢氧化去甲肾上腺素的中间过程进行了研究。     

Metal salt catalyzed carbenoid—XIII: On the mechanisms of cyclopropanation and allylic CH insertions by diazo esters in the presence of olefins and homogeneous copper catalysts

Evidence is presented demonstrating the existence of two paths to the title processes which arise from a common intermediate. A rationale involving catalyzed addition of the diazo compound to the olefin and carbenoid addition to the olefin is proposed. The penultimate intermediate has one new CC bond formed. It is partitioned between products by forming the second CC bond or formation of a hydrocarbenoid allyl complex which collapses to the allylic CH insertion products. Cyclopropanation occurs stereospecifically. The proposed mechanism accounts for the stereospecificity of cyclopropanation, the variance of syn/anti ratios with catalyst concentration when diazoacetic ester is employed and optical inductions with chiral catalysts. The question of whether the alleged carbenoid and/or the penultimate intermediate contain N₂ is not answered although it is felt that a cupro-cyclobutane intermediate is the most probable intermediate before product partitioning.     

Total syntheses of the benzodiazepine alkaloids circumdatin F and circumdatin C

Total syntheses of circumdatin F and circumdatin C, which both possess a 3H-quinazolin-4-one as well as a 1,4-benzodiazepin-5-one moiety, are described. A tripeptide derivative was synthesized as a key intermediate and dehydrated to a benzoxazine by reaction with triphenylphosphine, iodine, and a tertiary amine. The natural products were attained via rearrangements to an amidine intermediate, deprotection with 45% HBr in acetic acid, and cyclization on silica gel.     

Solution-phase energy profiles for trigonal bipyramidal species postulated as intermediates for the hydrolysis of methyl ethylene phosphate

We present results of solution-phase ab initio and DFT investigations on the trigonal bipyramidal (TBP) intermediates postulated for the hydrolysis of methyl ethylene phosphate (MEP). A key intermediate for the hydrolysis would not be a TBP species with the hydroxyl group axial, but would be a TBP intermediate with the hydroxyl group equatorial. Considering the reaction pathways through this intermediate, not only exclusive ring opening in the dilute alkaline hydrolysis of MEP but also significant amount of exocyclic cleavage in the strong alkali can be rationalized. This interpretation is in accord with the mechanisms proposed by Lim et al. and by Lönnberg et al.     

Simple and Efficient Process for the Large-Scale Preparation of Agomelatine: An Antidepressant Drug

A simple and efficient process for the large-scale preparation of agomelatine (1), an antidepressant drug is, described. Agomelatine was prepared in a linear manner starting from readily available, inexpensive 2-naphthol. Key steps in the synthesis are Friedel–Crafts acylation of 2-naphthyl acetate with chloroacetyl chloride, reduction of keto intermediate, and nucleophilic displacement of chloro intermediate with sodium diformylamide. A systemic approach was described to streamline the process into a robust scalable process by controlling the impurities.     

利用一个通用的方法全合成Fuscinarin和Fuscins

通过一个共同的中间体6,首次全合成了fuscinarin (1)和全合成了fuscins,它们都是戊烯酮(pentaketide)的代谢物,在亲近闪烁检测(scintillation proximity assay)中显示具有抗CCR5的活性。这一合成主要是利用微波辅助的 ortho-Claisen/Cope 重排的串联反应更合成中间体10。     

A second-generation synthesis of the C1-C28 portion of the altohyrtins (spongistatins)

A practical second-generation synthesis of an advanced intermediate in our total synthesis of altohyrtin C (spongistatin 2) has been developed. A new approach to the C1-C15 (AB) portion features a vinyllithium addition to an aldehyde followed by a palladium-catalyzed allylic reduction to install the troublesome C13-C15 segment. Our general approach to the C16-C28 (CD) spiroketal has been retained, but some improvements have been made. Most notably, the kinetically controlled CD-spiroketalization reaction now proceeds in high yield with excellent diastereoselection. This new strategy uses the anti-aldol coupling used in our first-generation synthesis to join AB and CD fragments. A total of 9.6 g of intermediate 57 has been produced using this improved route.     

Synthesis of 6-thia analogs of the natural neurosteroid allopregnanolone

A procedure is described for the preparation of 6-thiapregnanes in five steps from pregnenolone via a 5-oxo-7-iodo-secopregnane intermediate. The 6-thiasteroid obtained was converted into 6-thia-allopregnanolone and its sulfoxide and sulfone derivatives. The trans stereochemistry at the A/B ring junction was accomplished by stereoselective reduction of an intermediate hemithioketal with triethylsilane/BF₃·Et₂O. The compounds synthesized are analogs of natural neurosteroids, and exhibited GABA_A receptor activity comparable to allopregnanolone.