Target bonding

Scheme 4.9 Synthesis plan for triclosan showing labelled atoms Involved in target bond forming steps.

If the degrading enzyme is extracellular, the target bonds in the molecule must be exposed to this... 

Step 1 Water molecules (HOH) are partially dissociated into hydroxyl groups (HO") and protons (H"). The first step in enzyme-catalyzed hydrolysis may involve the attack of a proton on the target bond. Molecules of phosphoric acid H3PO4) dissociate to give phosphate anions (FO, ) and protons. The first step in enzyme-catalyzed phosphorolysis may involve the attack of a proton. 

Step 2 The attack of the proton on the target bond results in the development of a positive charge, which attracts an electron from an adjacent atom of the polymer. In the case of the peptide bond, the electron is drawn away from the carbonyl carbon. In the case of the carbohydrate (sugar) bond, the electron is drawn away from the carbon adjacent to the oxygen. The result of this electron withdrawal is breaking of the bond, resulting in formation of a carbonium ion (shown at the left) and a stable byproduct (shown at the right). 

The selectivity of active sites on oxide catalysts have been assessed by conqtaring their ability to selective activate a C-H bond in a reactant rather than a milar C-H or C-C bond in a selective oxidation product. Active shes on oxide catalysts are capable of activating target bonds in reactants that are up to 30-40 kJ mole weaker than similar bonds in the selective oxidation product. Good selectivities are always recorded provided that selective oxidation reactions attenqited do not exceed the discriminating capacity of the active site. Evidence is also presented that C-C bonds, which are generally weaker than C-H bonds, are protected from rupture by steric factors. 

A basic operating principle of selective oxidation catalysis is the need to minimise the contact time between the selective oxidation product and the catalyst to prevent conversion of the product, typically, into oxides of carbon. Whereas this aspect of selective oxidation catalysis is well recognised, it has never been put on a quantitative basis, so that the ability of a particular active site to activate a target bond in a reactant in preference to a similar bond in the product. 

Figurel3.2 Percentage contributions to target bond-forming and sacrificial reactions for the nine synthesis plans to lysergic acid.

The order of plan performance given in Table 13.1 can be readily understood by categorizing all reaction steps in each plan into either target bond-forming or sacrificial reactions, and then determining the waste contribution of each category. 

Figures 13.2 and 13.3 show the percentage contributions and kernel E-factors for target bond-forming and sacrificial reactions in each plan, respectively.

Figure 13.6 Target bond-forming reaction profiles for various plans to lysergic acid. Ordinate is number of target bonds made per reaction stage.

From the target bond-forming reaction profiles in Figure 13.6, one can see that the Hendrickson, Ramage, Ortar, and Szantay plans are most productive in the late stages whereas, the Rebek, Kurihara, Woodward, Oppolzer, and Ninomiya plans are most productive in the early to middle stages. A Tanimoto pairwise structure comparison shows that the Woodward-Szantay, Ramage-Ortar-Rebek,... 

Figure 13.7 Target bond reaction maps of lysergic acid by plan showing which bonds were made and at what reaction step. Lists of reagents used that in whole or in part end up in the target structure are shown below each structure map.

Target bond frequencies for most common bonds... 

The Ortar and Rebek plans have the fewest number of target bonds made (seven). 

In Table A.l the chemical environment of each bond is normally defined by a linear formulation of the substructure. The target bond is set in bold type, e.g. Cgr-C N (aryl cyanides) C-CH2-0-Cgr (primary alkyl aryl ethers) (C-0)2-P( = 0)2 (phosphate diesters). Occasionally the chemical numbering of a functional group or ring system is used to define bond environment, e.g. in naphthalene, C(2)-C(3) in imidazole N1-C2. To avoid any possible ambiguity in these cases, we include numbered chemical diagrams in Figure A.4. A combination of chemical name and linear formulation is often employed to increase the precision of the definition, e.g. NH2-C=0 in acyclic amides C = C-C( = 0)-C(=0) in benzoquinones. Finally, for very simple ions the accepted conventional representation is deemed to be sufficient, e.g. in N03, S04, etc. 

If the chemical connectivity of a given system can be anticipated, as for example in the case of framework structured solids, reasonable bounds for first and second neighbour bond distances can be readily defined. Distance targets can, therefore, be set up for such a system and the resulting distance least squares procedure (Meier and Villiger, 1969) (DLS) takes as input a trial or random set of coordinates, the crystal symmetry and possibly site symmetry constraints, which, when combined with defined connectivity and target bond... 

In these approaches, the bonds chosen for disconnection maximize simplification of the target. Bonds are chosen that can easily be re-formed. A pool of known starting materials and chemical reactions is essential. Once the disconnection process begins, the chemical experience and interest of the chemist will usually determine which pathway is best suited for their purpose. 

It is also possible to brominate at the C bearing the SePh unit. To form the targeted bond requires displacement of bromide from a neopentyl carbon, which is very difficult... 

Substructure in which the bond is found. The target bond is set in boldface. Where X is not specified, it denotes any element type. C indicates any sp carbon atom, and C denotes an sp carbon whose bonds, in addition to those specified in the linear formulation, are to C and H atoms only. 

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