Cleavage of the products

Cyclopropane 87, obtained from n-butyl vinyl ether, rearranges to dihydrofuran 88 only at elevated temperature, and also partly during work-up on silica gel113). The complete conversion of 87 into veratrole by the action of HCl/CH3OH gave rise to the analogous two-step synthesis of hydrourushiol monomethyl ether from l-diazo-3,3-dimethoxy-2-nonadecanone 89113). Ether cleavage of the product yields hydrourushiol, one of the vesicant components of, inter alia, poison ivy. 

For a better overview, examples of endo-linkers and the enzymes used for the cleavage of the product from the soHd phase which have been described in the literature so far are given in Tab. 10.1. 

Split synthesis of the library using four amino acids, four aldehydes, and five olefins in the presence of four mercaptoacyl chlorides (Scheme 3.110) generated the required proline library that was screened, after TEA cleavage of the products from the solid support, for inhibition of angiotensin converting enzyme ACE. 

In late 1975, Enders et al.156) started a research project directed towards the development of a new synthetic method for asymmetric carbon-carbon bond formation. A new chiral auxiliary, namely the (S)-proline derivative SAMP (137), was allowed to react with aldehydes and ketones to give the hydrazones (138), which can be alkylated in the a-position in an diastereoselective manner 157,158). Lithiation 159) of the SAMP hydrazones (138), which are formed in excellent yields, leads to chelate complexes of known configuration 160). Upon treatment of the chelate complexes with alkyl halogenides the new hydrazones (139) are formed. Cleavage of the product hydrazones (139) leads to 2-alkylated carbonyl compounds (140). 

Alternatively, the so-called mix-and-split method [17-22] can be used to prepare mixtures of support particles (beads, paper disks, etc.) or of small portions of support (e.g., tea bags ) with a well-defined quantity of one discrete compound linked to each portion of support. These compound libraries can be screened either directly on the support, or in solution after partial or total cleavage of the product from the support. 

N-Arylations of amines have also been realized with support-bound heteroaromatic halides (Entries 9-11, Table 10.4). Several examples of the synthesis of substituted 1,3,5-triazines [83-85], purines [78,85-93], and pyrimidines [77,85,94—96] have been reported. The reactivity of these arylating agents depends strongly on their precise substitution pattern, and generally increases with decreasing electron density of the het-eroarene. Illustrative examples are given in Table 10.4. The arylation of amines with simultaneous cleavage of the product from the support is discussed in Section 3.8. 

A small library of oxazolidinones was then synthesized using the robotics of the Smith synthesizer to run sequentially each new boronic acid in the Suzuki reaction. Cleavage of the products and filtration through a small plug of silica provided excellent yields and purities of the desired oxazolidinones, including compound 12, the previous clinical candidate E3656, in 96% yield and 96% purity (Table II). 

In contrast to reactions in solution, solid-phase synthesis has the advantage that excess amounts of reactants can be used and the yields thus increased. Work-up and purification processes - which often prove difficult in homogeneous solution - are rationalised as straightforward washing or filtration. Recycling of the support material after cleavage of the product from the solid phase also has cost benefits. 

Combinatorial chemistry can be carried out in solution or on solid support. Most solution combinatorial chemistries are typically limited to one-step reactions, whereas solid-phase chemistries often involve multistep processes that include resin manipulation, washing, drying, cleavage of the products from the resin, etc. 

Hydrolytic cleavage of the products formed by addition of Grig-nard reagents to a-oxo esters of optically active alcohols affords optically active acids. 

The foundation of combinatorial synthesis was laid with the development of solid phase peptide synthesis by Merrifield in the 1960s. This allowed a rapid and convenient way for the elimination of reagents from products by simple washing after each step of the synthesis followed by cleavage of the product from the solid support. 

In the second example, optimization of a Suzuki coupling on SP was carried out. Two boronic acids were coupled with resin-bound iodide 6.56 (Fig. 6.24) at 90 °C for increasing reaction times of 1, 3, 6, and 10 h and the yields of the products 6.58 and 6.59 were calculated after cleavage of the product from the resin. The results are shown in Table 6.3. The less hindered thiophene boronic acid reacted completely after 1 h, while the more hindered tolyl derivative required 3 h to drive the reaction to completion. In this ease it was found that while 3 h was an optimal length of time for both substrates, longer reaction times tended to decrease the reaction yields. 

Nitriles are also formed in excellent yields by the decarboxylation and dehydration of oximino acids with warm acetic anhydride. A good route for obtaining the starting materials consists in the condensation of aldehydes with rhodanine followed by cleavage of the product with alkali and treatment with hydroxylamine. 

The solid-phase synthesis of peptide aldehydes can be carried out from either protected amino aldehydes or common protected amino acids. While the first kind of method requires prior synthesis of a convenient aldehyde derivative, in the second type the final cleavage of the product is performed in the presence of a reducing reagent. 

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