Competent intermediate

Rh2(OAc)4 to afford 60% of oxathiazinane 103 and 40% of recovered sulfamate 100. Although the yield for this process is significantly below that obtained under conditions employing Phl(OAc)2 and MgO, this result does establish 101 as a chemically competent intermediate. From these data, it is reasonable to conclude that a small concentration of iodinane 101 may exist in equilibrium when Phl(OAc)2 and substrate are combined. This material is rapidly converted by the rhodium catalyst to oxathiazinane 103. Such a proposal would explain the absence of any detectable amount of 101 (or a related species) in the aforementioned control experiments. 

The accepted mechanistic scheme for metal catalyzed oxidations with peroxides is sketched in Scheme 1. The features of the active oxidant depend on the nature of the oxygen donor and on its interaction with the metal precursor in several examples high-valent peroxo metal species have been recognized as competent intermediates ... 

Although the two competing intermediates, the hypothetical ketyl-aryl radical pair (4) and the oxaspirooctadienyllithium (3), are not the rate-determining transition states, they should lie at almost the same energetic level. The rearrangement is in accord with the intramolecular nucleophilic addition/elimination mechanism rather than with homolytic cleavage/recombination. 

Kt = 0.84 and at pH 7, KT = 0.36. The rate of ring-chain interconversions obtained from temperature-jump kinetic experiments appears to be hydro-nium-ion-catalyzed in the pH range 11.5-13, with rate constants reaching about 105 s 1. It was presumed that the cyclic tautomers 54 can serve as kinetically competent intermediates for transimination sequences at the active sites of pyridoxal-P-dependent enzymes. 

The main problem with predictions of kinetic preferences based on force-field calculations of relative stabilities of reaction intermediates arises from the fact that the energies of the competing intermediate structures usually differ by amounts smaller than the accuracy of the energy calculations. These calculations are inherently inexact, since the force-field parameters for the intermediates are mostly unknown (high-level ab initio calculations would be needed to determine them). Moreover, the probability that a reaction passes via a given intermediate depends not only on its enthalpy, but also on entropy thus, a dynamic description of the solvated intermediate would be required. Finally, even if we knew the structure of a reaction intermediate perfectly, it would always remain an approximation for the geometry of the transition state, whose free energy is the real determinant of the reaction kinetics. 

Gerfen, G. J., Licht, S., Willems, J. P., Hoffman, B. M., and Stubbe, J., 1996, Electron paramagnetic resonance investigations of a kinetically competent intermediate formed in ribonucleotide reduction Evidence for a thiyl radical-Cob(II) alamin interaction. J. Am. Chem. Soc. 118 819298197. 

Evidence later became available that indicated that the lack of isotope incorporation from solvent in enzymic experiments is misleading. Trapping experiments have established quite conclusively that an enediol (38) is a kinetically competent intermediate. Hydride transfer occurring through a transition state like (39 equation 22) is therefore not required. ... 

Zirconocene metallacycles are invoked as key intermediates in the catalytic cyclomagnesiation of dienes. To probe for the intermediacy of metallacycles, zirconacyclopentane derivative 658 was synthesized from the reaction of Cp2ZrCl2 and 9,9-diallylfluorene in the presence of 2equiv. of BunLi482 (Scheme 154). This structurally characterized zirconacyclopentane is a catalytically competent intermediate for the cyclization of dienes. For example, cyclomagnesiation of 1,7-octadiene occurs smoothly in the presence of 10mol% of 658. 

Additional aspects of regioselectivity which arise for substituted methylenecyclopropanes are closely related to both the thermodynamic stability or kinetic availability of competing intermediates within the cycloaddition sequences. A variety of products can, in principle, be expected from a [3 + 2] cycloaddition between a monosubstituted MCP and a nonsymmetrical, disubstituted alkene (XHC = CHY). This can be attributed to variability arising in several different steps of the overall reaction. From a topological point of view, these structural features of the product methylenecyclopentanes can be classified as shown in Table 1. Only one selected example for the specific type of isomerism is given in each case. 

The enzyme 2-C-methyl-D-erythritol-4-phosphate synthetase appears to catalyse a Bilik reaction (Figure 6.10) the substrate l-deoxyxylulose-5-phosphate is converted to the title compound via an intermediate aldehyde, whose carbonyl derives from C3 of the substrate. The first step is thus a Bilik reaction and the aldehyde is subsequently reduced by the enzyme using NADPH as reductant, The X-ray crystal structure of the Escherichia coli enzyme in complex with the promising antimalarial Fosmidomycin (a hydroxamic acid) reveals a bound Mn " coordinated to oxygens equivalent to the substrate carbonyl and 03. The stereochemistry and regiochemistry follow the normal Bilik course, although the crystallographers favour an alkyl shift rather than a reverse aldol-aldol mechanism. The intermediate aldehyde has been shown to be a catalytically competent intermediate. 

A related Lewis acid-catalyzed intramolecular formation of a bridged [4 + 2] cycloadduct derived from an in situ generated alkene a,/8-unsaturated ketone had been previously observed (Table 7-II, entry 3).132 The reversible, Lewis acid-catalyzed formation of intramolecular Diels-Alder [4 + 2] cycloadducts have been observed as competing intermediates generated in the Lewis acid-catalyzed irreversible ene reactions of a,/8-unsatu-rated ketones133 (Table 7-II, entry 4). 

If Hisl79 is replaced in the E. coli enzyme, the bond between C-8 and N-9 can be cleaved, but the resulting formamide derivative (27) cannot be hydrolyzed. However, the resulting intermediate can be converted into DHNTP (7) by wild-type GTP cyclohydrolase 1." ° In fact, 27 can be shown to fulfill the criteria for a kinetically competent intermediate. " ... 

The second finding was that the pentacyclic intermediates formed by the trimeric E. coli enzyme and the pentameric M. jannaschii riboflavin synthase are diastereomers, as shown in Figure 19. These pentacyclic diastereomers are formed by the condensation of two molecules of 6,7-dimethyl-8-ribityllumazine with the same regiochemistry in both enzymes. " This difference clearly results from the fact that these are different enzymes with different active sites. Each of the diastereomers is a catalytically competent intermediate for its respective enzyme but does not serve as a substrate for the other enzyme. ... 

In summary, these studies have led to the isolation and characterization of two kinetically competent intermediates a covalent phospholactoyl-enzyme adduct and a phospholactoyl-UDP-GlcNAc tetrahedral intermediate." " Further work is required to definitively establish whether the two intermediates are formed along a sequential or branched pathway as shown in Scheme 5, pathways a and b, respectively. 

Figure 3 Single turnover experiment for Mur Z-competent intermediates.

The nucleophilic substitution reactions, involving halide displacment in this five-membered system, bear clear similarity to the reaction studied by Corriu (1983), which led to the proposal of the equatorial-entry pathway. Equatorial-entry mechanisms (pathway D) may account for the epimeriza-tion reactions observed by Cullis et al. (1987) and Mikolajczyk and Witczak (1977). Pathway D can only be discounted if [33e] is shown to be a kinetically competent intermediate, or chloride ion is shown to be rigorously excluded from the reaction mixture. 

This chapter focuses on the role of organocobalt and organonickel species as competent intermediates in a range of enzymatic transformations. The text is organized by enzyme, with each section beginning with a summary of the relevant structural biology (where available) and enzymology to frame the discussion for the structural and reactivity model chemistry that follows. 

Scheme 4.8 Synthesis and characterization of catalytically competent intermediates in bis(imino)pyridine iron-catalyzed hydrogenation and hydrosilylation reactions.

Antibiotic biosynthetic enzymes are generally believed to possess low substrate specificity. This can be rationahzed fi-om an evolutionary point of view reduced substrate specificity increases the probability of a chain of enzymes to yield a product, even when the enzymes form new combinations (Fig. 1). When the intermediates are structurally distinct from the intermediates of primary metabolism, there is little need for stringent selectivity (and thus httle evolutionary pressure to increase it) as no competing intermediates are present. Since the evolutionary advantage in antibiotic biosynthesis originates from the diversity of the compounds produced and is rather indifferent to the quantity of production, many pathways have converged such that a long chain of enzymes with broad substrate specificity yields a specific product. 

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