Cleavage strategies

F. Guillier, D. Grain and M. Bradley, Linkers and Cleavage Strategies in Solid-phase Organic Synthesis and Combinatorial Chemistry, Chem Rev 100 2091-2157 2000. 

C-6—N bond cleavage strategy was applied to a synthesis of corydamine (Section V,A,7). 

Allylic amination is important for the solid-phase organic synthesis.15 The solid-phase allylic aminations are devised into the G-N bond formation on solid support and the deprotection of allyl ethers. As a novel deprotection method, the palladium-catalyzed cyclization-cleavage strategy was reported by Brown et al. (Equation (4)).15a,15b The solid-phase synthesis of several pyrrolidines 70 was achieved by using palladium-catalyzed nucleophilic cleavage of allylic linkages of 69. 

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). 

Scheme 3. Cyclative cleavage strategies for the synthesis of (a) benzodiazepines and (b) hydantoins.

The proper choice of a suitable linker is a therefore a key consideration in the design of a solid-phase chemical route. Linkers have to be developed in order to be stable in the presence of reagents and to permit orthogonal cleavage under mild conditions. Often, cleavage conditions dictate the requirements for work-up and purification steps of the released compound. Different cleavage strategies have been developed such as photocleavable, safety catch and traceless linkers as mentioned in Section 3.2.2 [20]. 

The development of sulfone linkers, the exploration of sulfone based chemical transformations and cleavage strategies are an important objective in soHd-phase organic synthesis. This kind of Hnker (Tab. 3.7) has been used with thioethers [108], sulfoxides [109], sulfones [110], sulfonic acids and their corresponding derivatives [111]. Because carbon-sulfur bonds can be cleaved under very mild conditions, some Hnkers have been based on this effect. They can be cleaved under reductive conditions ]112, 113], photolytic conditions [114, 115] or with strong bases [116]. Various safety catch Hnkers have been developed based on the fact that thiols can be oxidized to sulfoxides and sulfones [112, 113]. 

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). 

The cyclative-cleavage strategy is different to the cases in which the cycUzation occurs in solution after the cleavage (Scheme 3.6). This is true for most acidic cleavage conditions in these cases the uncyclized reactant is also found in the hquid-phase. Examples of this strategy are the synthesis of benzofurans [184], imidazo-quinoxalinones [185, 186] and diketopiperazines [187]. 

Campbell J, Blackwell HE (2009) Efficient constmction of diketopiperazine macroarrays through a cyclative-cleavage strategy and their evaluation as luminescence inhibitors in the bacterial symbiont Vibrio fischeri. J Comb Chem 11(6) 1094-1099... 

An elegant cyclization-cleavage strategy has been devised for the removal of resin-bound 1,3-amino alcohol derivatives 392 as l,3-oxazin-2-ones 393 upon treatment with lithium hexamethyldisilazide (LiHMDS) (Equation 42) <20010L3177>. 

An interesting variant of electrophilic cleavage is intramolecular attack at the linking carboxylic acid derivative by a substrate-bound electrophile (Figure 3.23). This cleavage strategy generally produces lactones. 

A series of special linkers and cleavage strategies has been developed for the release of amines from insoluble supports (Table 3.23). These include the attachment of amines as triazenes, enamines, aminals, amidines, sulfonamides, sulfinamides, hydrazines, or amides. 

Linkers have been developed that enable the release of amines or other compounds by base-induced [3-elimination these linkers are thereby converted into alkenes (Chapter 3). Similarly, the (1-elimination of resin-bound leaving groups has been used as a cleavage strategy for the release of alkenes from supports (Section 3.15.1). 

Cyclative Cleavage Strategies for the Solid-Phase Synthesis of Heterocycles and Natural Products... 

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