Linkers alkene functionalized

Linker 1 is immobilized through the carboxy function. Linker 2 is generated on solid support by a Wittig reaction. A second alkene is generated during or at the end of the synthesis to give the second olefin for metathesis. 

The functional group tolerance of the ruthenium-based metathesis catalysts has had a tremendous impact on solid-phase organic synthesis. The efficacy of the reaction in solution generally translates directly to solid-phase transformation and its potential has been harnessed in a number of library syntheses, solid-phase syntheses of natural products, or diversity-oriented syntheses. It enables the use of chemically robust alkenes as linkers which can be cleaved by RCM or CM. It, of course, provides new manifolds of diversification in diversity-oriented synthesis as has been elegantly shown in landmark examples by Schreiber and Nelson. Another metathesis application of paramount importance is in peptide chemistry where solid-phase synthesis is omnipresent. The ability to stabilize secondary structures in short peptide motifs and replace pharmacologically unsuitable disulfide bonds or simply restrict the conformation of a peptidic library has already been successfully implemented in a number of important examples. The orthogonality of the metathesis reaction to peptide chemistry provides a really powerful tool in this regard. 

The main strategies used for the preparation of alkenes by cleavage from insoluble supports are (3-elimination and olefin metathesis (Figure 3.35). Because some of these strategies enable the preparation of pure alkenes, devoid of additional functional groups, the linkers are sometimes also called traceless linkers, although the C=C double bond reveals the original point of attachment to the support. 

C-Alkylations have been performed with both support-bound carbon nucleophiles and support-bound carbon electrophiles. Benzyl, allyl, and aryl halides or triflates have generally been used as the carbon electrophiles. Suitable carbon nucleophiles are boranes, organozinc and organomagnesium compounds. C-Alkylations have also been accomplished by the addition of radicals to alkenes. Polystyrene can also be alkylated under harsh conditions, e.g. by Friedel-Crafts alkylation [11-16] in the presence of strong acids. This type of reaction is incompatible with most linkers and is generally only suitable for the preparation of functionalized supports. Few examples have been reported of the preparation of alkanes by C-C bond formation on solid phase, and general methodologies for such preparations are still scarce. 

Alkenes bound to cross-linked polystyrene can be epoxidized under conditions similar to those used in solution. The most commonly used reagent is m-chloroperbenzoic acid in DCM, but other reagents have also been used (Table 15.1). Because excess oxidant is usually required to furnish clean products, care must be taken with linkers or other functional groups prone to oxidation (ketones, amines, benzyl ethers, etc.). 

CM has been reported to provide a synthetic tool for immobilization of reagents. Polymer-supported synthesis with an allylsilyl unit as a linker was developed. Divinylbenzene cross-linked allyldimethylsilylpolystyrene has been reported to undergo highly efficient ruthenium-catalyzed CM with functionalized terminal alkenes (Eq. 45) [78]. Products have been liberated by proto-desilylation with trifluoroacetic acid. 

Starting from a vinyl-substimted resin, hydroboration with 9-BBN yields a homobenzylb-orane (Scheme 9). This intermediate can be coupled with various functionalized aryl iodides as well as vinyl and alkyl iodides giving rise to resins with amide, ester, or protected hydroxy functionaUties.t Similarly, bromostyrene could be coupled with functionalized boranes for the attachment of preformed handles, for example, for the construction of the silicon traceless linker.t i The carbometaUation of certain alkenes such as tropanes and the subsequent treatment with aryl boronic acid gives rise to two new C—C bonds (Scheme 10). 

Complex 33, containing a partially reduced 1,10-phenantroline-based monodentate NHC ligand led to 97% yield and 81% ee in the hydrogenation of methyl acetamidoacrylate (Figure 13.4). A bidentate NHC bearing a PPh2 unit with a chiral pseudo-o-[2.2]paracyclophane linker (34) was found to be a selective catalysts for non-functionalized trisubstituted alkenes, although functionalized alkenes were found to be sensitive to the H2 pressure. Also, the... 

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