Stereochemistry group transfer reactions

In this primer, Ian Fleming leads you in a more or less continuous narrative from the simple characteristics of pericyclic reactions to a reasonably full appreciation of their stereochemical idiosyncrasies. He introduces pericyclic reactions and divides them into their four classes in Chapter 1. In Chapter 2 he covers the main features of the most important class, cycloadditions—their scope, reactivity, and stereochemistry. In the heart of the book, in Chapter 3, he explains these features, using molecular orbital theory, but without the mathematics. He also introduces there the two Woodward-Hoffmann rules that will enable you to predict the stereochemical outcome for any pericyclic reaction, one rule for thermal reactions and its opposite for photochemical reactions. The remaining chapters use this theoretical framework to show how the rules work with the other three classes—electrocyclic reactions, sigmatropic rearrangements and group transfer reactions. By the end of the book, you will be able to recognize any pericyclic reaction, and predict with confidence whether it is allowed and with what stereochemistry. 

Group Transfer Reactions. There are so few of these reactions that a fully general rule for them can wait until the next section, where we see the final form of the Woodward-Hoffmann rules. For now, we can content ourselves with a simplified rule which covers almost all known group transfer reactions. When the total number of electrons is a (4 +2) number, group transfer reactions are allowed with all-suprafacial stereochemistry. 

When the total number of electrons is a (4 +2) number, group transfer reactions are allowed with all-suprafacial stereochemistry. 

Stereochemistry of Enzyme-Catalyzed Methyl Group Transfer Reactions... 

Table III summarizes how the atoms move around in the conversion of diols to aldehydes. Very interesting stereospecificity becomes apparent here. If we start out with the R isomer, containing deuterium at C-1, the deuterium appears in the C-2 position of the product (3). If we start with the S isomer, the deuterium is not transferred and remains at C-1. A similar experiment was done by Arigoni (4). When he started out with the R isomer with in the C-2 position, all of the (within experimental error) ended up in C-1. This, of course, establishes that this is a group transfer reaction, just like the other reaction, because whatever else is going to happen now, the oxygen from C-2 ends up at C-1. If one starts out with the S-isomer and labels with then the disappears and is released into the solvent. The stereochemistry of this...

The phase-transfer-catalyzed asymmetric alkylation of 1 has usually been performed with achiral alkyl halides, and hence the stereochemistry of the reaction with chiral electrophiles has scarcely been addressed. Nevertheless, several groups have tackled this problem. Zhu and coworkers examined the alkylation of 1 with stereo-chemically defined (5S)-N-benzyloxycarbonyl-5-iodomethyl oxazolidine using 4d to prepare (2S,4R)-4-hydroxyornithine for the total synthesis of Biphenomycin. Unexpectedly, however, product 7 with a 2 R absolute configuration was formed as a major isomer, and the diastereomeric ratio was not affected by switching the catalyst to pseudoenantiomeric 2d and even to achiral tetrabutylammonium bromide (TBAB), indicating that the asymmetric induction was dictated by the substrate (Scheme 2.3) [21]. 

The use of perfluoroalkyliodide in group transfer tandem additions has been examined by Wang and Lu for the preparation of butyrolactones [95T2639]. The mild reaction conditions, high chemical yield, and excellent control of alkene stereochemistry are the highlights of this methodology. 

The stereochemistry of the reaction in which C-4 is oxidized to give intermediate 41 is difficult to envisage, because the hydride abstraction and addition would have to take place from opposite sides of the carbonyl group. Various solutions to this problem have included (a) a double binding-site for the substrate, which can transfer from one site to the other as the intermediate 4-ulose,146... 

The nature of the ligand donor atom and the stereochemistry at the metal ion can have a profound effect on the redox potential of redox-active metal ions. What, we may ask, is the redox potential In the sense that they involve group transfer, redox reactions (more correctly oxidation—reduction reactions) are like other types of chemical reactions. Whereas, for example, in hydrolytic reactions a functional group is transferred to water, in oxidation-reduction reactions, electrons are transferred from electron donors (reductants) to electron acceptors (oxidants). Thus, in the reaction... 

One special distinction you should master from now on is that stereo specificity has a different meaning. It refers to the specific transfer of stereochemistry during a reaction because the mechanism of the reaction demands this stereochemical outcome. An SN2 reaction goes with inversion, whether the molecule likes it or not, because an SN2 reaction is stereospecific. In the reduction of a ketone the molecule may select the stereochemistry of the new OH group this reaction is not stereospecific though it may be stereoselective. 

A sensitive probe applied to understand the nature of the reaction mechanism of group transfer is the stereochemistry of the overall reaction. The reaction at a phosphoryl center normally is a degenerate question, since a monosubstituted phosphate ester or anhydride is proprochiral at the phosphate center. Phosphate centers at a diester or disubstituted anhydride are prochiral. Two related methods to analyze the stereochemistry at a phosphate center have been developed by the generation of chirality at the phosphorus center. The first approach was developed by Usher et al. (24) and gave rise to the formation of isotopi-cally chiral [ 0, 0]thiophosphate esters and anhydrides (I). Isotopically chiral [ 0, 0, 0]phosphates (II) have also been synthesized and the absolute configurations determined. Two primary problems must first be addressed with respect to both of the methods that have been developed the synthesis of the isotopically pure chiral thiophosphates and phosphates and the analysis of the isotopic chirality of the products. An example of the chiral starting substrates, as developed for ATP, is schematically demonstrated. Ad = adenosine. 

The DNA and RNA polymerase reactions, as well as the reverse transcriptase and polynucleotide phosphorylase reactions, proceed with inversion of configuration at Pa of the nucleoside triphosphate (45-50). Thus, an uneven number of displacements at phosphoms is involved in the chemical reaction mechanism, and the stereochemistry provides no evidence for the involvement of a covalent nucleotidyl-enzyme as an intermediate on the catalytic pathway. No other evidence for such an intermediate is available. Therefore, it must be concluded that the physicochemical requirements for nucleotidyl group transfer, substrate recognition, and movement along the template are derived fiom binding interactions between the enzyme and its template and substrate rather than through nucleophilic catalysis. This is also true of polynucleotide phosphorylase and other nucleotidyltransferases that catalyze reactions of polynucleotides (51, 52). 

These enzymes are not classified as nucleotidyltransferases, although they catalyze nucleotidyl group transfers in the course of activating the S -phosphoryl groups for the ligation process. The activation mechanism involves a covalent adenylyl-enzyme as an intermediate and a double displacement on of ATP (or NAD+). The chemical mechanism of the RNA ligase reaction is similar. The stereochemistry of these reactions is known for RNA ligase and is consistent with the mechanism as formulated above (81, 82). 

Scheme III shows the experimental arrangement to study the second one-carbon transfer reaction we investigated, the formation of thymidylic acid from uridylic acid catalyzed by thymidy-late synthetase. In this reaction, the methyl group of thymidy-late is derived from the carbon and the two hydrogens of the methylene bridge plus H-6 of methylene-tetrahydrofolate. To study the stereochemistry of this reaction, we (5) synthesized serine stereospecifically labeled with tritium and deuterium at...

In the reaction proper, pyridoxamine phosphate transfers the amino group to the sugar residue and is itself converted back into pyridoxal phosphate. In some organisms one of the two possible 4-deoxy- 4-amino sugars forms, in others both form, which implies differences either in the nature of the intermediates formed or in the stereochemistry of the reaction sites on the enzyme. 

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