Cyclative cleavage nucleophile attack

Cyclative cleavage strategies release the final compound into solution following intramolecular attack of a nucleophile or electrophile upon the linkage site. Synthesis byproducts and intermediates do not incorporate the necessary nucleophile or electrophile therefore only the desired products are released into solution to yield high purity materials. Seminal examples of this approach are the library syntheses of benzodiazepines and hydantoins (Scheme 3). 

Cyclative-cleavage strategy is a process in which activation promotes the cleavage, while an intramolecularly located nucleophile, electrophile, radical or another group attacks, so that the product is released from the sohd support (Scheme 3.4). 

Besides nucleophilic attack, cyclative cleavage can be eaffected for example by Stille reactions [120], Wittig olefmation reactions [177], Wittig-Horner [178, 179] or metathesis reactions [180-183]. For more details of C-C-bond formation, see Section 3.3.2. 

The final example in this section features a rare instance where the electrophilic center is s -hybridized carbon, as most cyclative cleavages involve the attack of carbonyl derivatives. Oxazolidinones are formed cyclatively18 by the displacement of a sulfonate ester by an acylsulfonamide (Fig. 5). In a variant19 of this cyclization, a quasi-meso bis-sulfonate partitions into a pair of quasi-enantiomeric sulfonates, one resin bound and the other cleaved, depending on the direction of intramolecular cyclization. The resin-bound enantiomer can then be displaced by an external nucleophile. 

Carbon-carbon bond formation by reductive elimination from Ni, Pd, or Pt complexes is widespread. In many cases it is presumed to occur as the final step in a catalytic cycle, whereby the organic product is expelled from the metal center, but in others it is a well-defined, mechanistically studied reaction. Elimination takes place from Ni, Pd, and Pt complexes in their - - 2 or + A oxidation states, and it may be promoted by thermolysis, by photolysis, or by nucleophilic attack at the metal center. The reaction may proceed by heterolytic or homolytic metal-carbon bond cleavage, reductive elimination, or dinuclear elimination, and more than one mechanism may operate. 

Cleavage of the C-O bond in various allylic substrates by oxidative addition to M(0) species gives r 3-allylic complexes, which undergo nucleophilic attack to produce allylic compounds catalytically. A base is needed in most cases to remove HOX and to drive the catalytic cycle. There are a lot of synthetic reactions utilizing allylic oxygen bond cleavage catalyzed by palladium complexes [6, 7, 19-21]. 

Fig. 2. Schematic diagram of the catalytic mechanism of 20S proteasomes. A proton transfer from the hydroxyl group of Thrl of /3 subunits to its own terminal amino group initiates the nucleophilic attack (I). As a result of the nucleophilic addition to the carbonyl carbon of the scissile peptide bond, a tetrahedral intermediate is formed (II). By an N—O acyl rearrangement, an ester is formed (the acyl enzyme) and the amino-terminal cleavage product is released (III). Finally, hydrolysis of the acyl enzyme yields the carboxyl-terminal cleavage product and frees the enzyme for another reaction cycle (IV).

The subsequent coordination and insertion of CO into the metal-alkyl bond leads to a hable acyl complex. Finally, hydrolysis of the acyl complex with the nucleophile NuH gives off the corresponding carboxylic acid or carboxylic acid derivative and completes the catalytic cycle. Presumably, the acyl cleavage takes place by a nucleophilic attack on the carbonyl carbon of the acyl group. 

Macrocyclic polyamine Zn +-complexes not only were used as carbonic anhydrase models. They were also shown to promote hydrolytic cleavage of phosphate esters and in particular phosphate diesters as present in DNA. In Figure 3, the catalytic cycle for monometallic activation is shown. Dissociation of a metal-bound water molecule provides a metal hydroxide species, which nucleophilically attacks the phosphorus center of a phosphate diester, whereby finally the aUcoxide gets released and the product is formed. 

Water is a moderately reactive nucleophile and, as such, is involved in several well-known catalytic cycles, in which it (or its conjugate base, hydroxide ion) usually attacks either carbonyl ligands or other ligands in nucleophilic cleavage or reductive elimination steps. Such processes may be encountered, for example, in hydroxycarbonylation reactions ... 

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