Intramolecular reactions activation

Optically active dihydro-2-methylene-2(3//)-furanones fused to 5- and 6-membered carbocyclic rings were synthesized with 64-92% ee using the intramolecular reaction between chiral 2-alkoxy-carbonylallylsilanes and aldehydes80. 

A series of theoretical studies of the SCV(C)P have been reported [38,40,70-74], which give valuable information on the kinetics, the molecular weights, the MWD, and the DB of the polymers obtained. Table 2 summarizes the calculated MWD and DB of hyperbranched polymers obtained by SCVP and SCVCP under various conditions. All calculations were conducted, assuming an ideal case, no cyclization (i.e., intramolecular reaction of the vinyl group with an active center), no excluded volume effects (i.e., rate constants are independent of the location of the active center or vinyl group in the macromolecule), and no side reactions (e.g., transfer or termination). 

The activating capacity of boronate groups can be combined with the ability for facile transesterification at boron to permit intramolecular reactions between vinyl-boronates and 2,4-dienols. 

These reactions have very low activation energies when the intermediate is a free carbene. Intermolecular insertion reactions are inherently nonselective. The course of intramolecular reactions is frequently controlled by the proximity of the reacting groups.113 Carbene intermediates can also be involved in rearrangement reactions. In the sections that follow we also consider a number of rearrangement reactions that probably do not involve carbene intermediates, but lead to transformations that correspond to those of carbenes. 

Effective charge and transition-state structure in solution, 27, 1 Effective molarities of intramolecular reactions, 17,183 Electrical conduction in organic solids, 16,159 Electrochemical methods, study of reactive intermediates by, 19, 131 Electrochemical recognition of charged and neutral guest species by redox-active receptor molecules, 31, 1... 

Obelin is a Ca2+-activated bioluminescent photoprotein that has been isolated from the marine polyp Obelia longissima. Binding of calcium ions determines a luminescent emission. The protein consists of 195 amino acid residues [264] and is composed of apoobelin, coelenterazine, and oxygen. As aequorin, it contains three EF-hand Ca2+-binding sites and the luminescent reaction may be the result of coelenterazine oxidation by way of an intramolecular reaction that produces coelenteramide, C02, and blue light. As for aequorin, the luminescent reaction of obelin is sensitive to calcium and the protein was used in the past as an intracellular Ca2+ indicator. More recently, the cloning of cDNA for apoobelin led to the use of recombinant obelin as a label in different analytical systems. 

Cationic ruthenium complexes of the type [Cp Ru(MeCN)3]PF6 have been shown to provide unique selectivities for inter- and intramolecular reactions that are difficult to reconcile with previously proposed mechanistic routes.29-31 These observations led to a computational study and a new mechanistic proposal based on concerted oxidative addition and alkyne insertion to a stable ruthenacyclopropene intermediate.32 This proposal seems to best explain the unique selectivities. A similar mechanism in the context of C-H activation has recently been proposed from a computational study of a related ruthenium(ll) catalyst.33... 

In the direct transfer mechanism, the metal ion coordinates both reactants enabling an intramolecular reaction, and activates them via polarization. Consequently, strong Lewis acids including Alln and the Lnln ions are the most suitable catalysts in this type of reactions. In the hydride mechanism, a hydride is transferred from a donor molecule to the metal of the catalyst, hence forming a metal hydride. Subsequently, the hydride is transferred from the metal to the acceptor molecule. Metals that have a high affinity for hydrides, such as Ru, Rh and Ir, are therefore the catalysts of choice. The Lewis acidity of these metals is too weak to catalyze a direct hydride transfer and, vice versa, the affinity of Alm and Lnm to hydride-ions is too low to catalyze the indirect hydrogen transfer. Two distinct pathways are possible for the hydride mechanism one in which the catalyst takes up two hydrides from the donor molecule and another in which the catalyst facilitates the transfer of a single hydride. 

An attractive alternative is to study intramolecular reactions. These are generally faster than the corresponding intermolecular processes, and are frequently so much faster that it is possible to observe those types of reaction involved in enzyme catalysis. Thus groups like carboxyl and imidazole are involved at the active sites of many enzymes hydrolysing aliphatic esters and amides. Bimolecular reactions in water between acetic acid or imidazole and substrates such as ethyl acetate and simple amides are frequently too slow to... 

J Steffans et al., 1973, 1975. The reference reaction is the attack of the anion of a carboxylic acid of pK, 3.91 on methyl 2,4-dinitrophenyl phosphate at 39° (Kirby and Younas, 1970). The intramolecular reaction is corrected for the better leaving group using y LO=1.26 (Khan et al., 1970), and to 39° using the activation energy measured for the intermolecular reaction with acetate (Kirby and Younas, 1970). 

Unfortunately, in many cases the reaction is not so straightforward it becomes complicated because of the nature of the activated component. There is another nucleophile in the vicinity that can react with the electrophile namely, the oxygen atom of the carbonyl adjacent to the substituted amino group. This nucleophile competes with the amine nucleophile for the electrophilic center, and when successful, it generates a cyclic compound — the oxazolone. The intermolecular reaction (path A) produces the desired peptide, and the intramolecular reaction (path B) generates the oxazolone. The course of events that follows is dictated by the nature of the atom adjacent to the carbonyl that is implicated in the side reaction. 

More /V-acylurea is generated if tertiary amine is present because the latter removes any protons that might prevent the rearrangement (see Section 2.12). The two intramolecular reactions also occur to a greater extent when interaction between the O-acylisourea and the /V-nucleophile is impeded by the side chain of the activated residue. This means that more 2-alkoxy-5(4//)-oxazolone and /V-acylurea are generated when the activated residues are hindered (see Section 1.4). A corollary of the above is that the best way to prepare an /V-acylurea, should it be needed, is to heat... 

The design of prodrugs that are activated by intramolecular reactions, i.e., prodrugs that are partly or completely activated without the need for enzymatic contribution, is an area of great current interest. As outlined in Chapt. 1, this approach can lead to a decrease in biological variability that facilitates the development of clinically useful prodrugs. One important condition, however, is that intramolecular catalysis should not be so fast that it results in poor bioavailability. 

A few examples of ester prodrugs that are activated by intramolecular reactions have been mentioned in Sect. 8.3.1, 8.5.1, and 8.5.2. Here, we discuss the special case of some carboxylic acid esters of active alcohols or phenols that are released following an intramolecular cyclization-elimination reaction [168], The general reaction scheme of such reactions is shown in Fig. 8.8. 

After five cycles of selection and ampHfication, a population of single-stranded DNAs was enriched that catalyzed the Pb +-dependent cleavage at the ribose residue. This intramolecular cleavage activity was transformed into an inter-molecular reaction by separating the 38-nucleotide long catalytic domain from the 21-mer substrate which was cleaved specifically and with high turnover rates. Remarkably, the deoxyribozyme can perform well only with the special DNA/RNA chimeric oHgonucleotide substrate and cannot cleave a pure RNA substrate of the same sequence. 

Intramolecular reactions of a phenolate were also reported (Scheme 9.33) [22a]. The preparation of a chromane derivative is described below, where the catalyst was activated with the base TBD. As in the case of intramolecular aminations, these cyclizations could be run at concentrations as high as 0.5-1 M. 

The intramolecular reaction of activated alkenes of the type 8 leads to the formation of 5- or 6-membered rings [26] and has been carried out only at a mercury cathode in a divided cell. In these processes, the activated alkene radical-anion is formed at a less negative potential than that required for cleavage of the carbon-bromine bond. Cyclization then occurs by nucleophilic substitution. 

Intramolecular reactions from organolithium reagents (Scheme 37) have also been reported. The organolithium reagent is produced through iodine-lithium exchange", through a carbometalation reaction or by deprotonation at a position activated by an aryl. 

The most spectacular application of the donor/acceptor-substituted carbenoids has been intermolecular C-H activation by means of carbenoid-induced C-H insertion [17]. Prior to the development of the donor/acceptor carbenoids, the intermolecular C-H insertion was not considered synthetically useful [5]. Since these carbenoid intermediates were not sufficiently selective and they were very prone to carbene dimerization, intramolecular reactions were required in order to control the chemistry effectively [17]. The enhanced chemoselectivity of the donor/acceptor-substituted carbenoids has enabled intermolecular C-H insertion to become a very practical enantioselective method for C-H activation. Since the initial report in 1997 [121], the field of intermolecular enantioselective C-H insertion has undergone explosive growth [14, 15]. Excellent levels of asymmetric induction are obtained when these carbenoids are derived... 

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