Alkene linker

Alkenes can be considered as a class of protected carbonyl compounds since they can be converted into carbonyls by ozonolysis. Hall [69] demonstrated a practical strategy for solid phase synthesis of peptide aldehydes using an olefinic linker, which was constructed using Wittig chemistry. After normal peptide synthesis using the alkene linker, ozonolysis of the linker and subsequent workup with... 

Although 3 induced the potent Thl-type response in mice, it showed rather weak activities against human lymphocytes [50]. As an improved analog, Franck and coworkers [50] reported the synthesis of GCK152 (4 in Fig. 11) with both an -alkene linker and an aromatic acyl chain. This unsaturated C-galactoside analog 4 induced potent cytokine production against human lymphocytes. 

Scheme 111 Ozonolysis of alkene linkers to give aldehydes...

THE ALLYLSILYL LINKER SYNTHESIS OF CATALYTIC BINDING OF ALKENES AND ALKYNES TO AND CLEAVAGE FROM ALLYLDIMETHYLSILYL POLYSTYRENE... 

Recently, the semi-synthesis of Vancomycin (48) on solid supports was accomplished using an allylic linker (Scheme 3.2) [123, 124]. Polymer-bound chiral electrophilic selenium reagents have been developed and applied to stereoselective se-lenylation reactions of various alkenes (Tab. 3.9) [125]. 

Other sulfur linker give alkenes by cleavage with palladium catalyst [206, 207] or heterocycles by cleavage with nucleophiles [208]... 

Electrophilic alkenes have been appended to imidazolium-type ILs for use in the Diels-Alder cycloaddition, 1,4-addition, Heck and Stetter reactions.Electrophilic alkenes containing Wang-type linkers were alkylated to imidazole followed by ion exchange and esterification giving the desired TSIL. Diels-Alder cycloaddition was carried out with 2,3-dimethylbutadiene and cyclopentadiene to give corresponding adducts. After washing with ether, transesterification resulted in cyclohexene derivatives. Scheme 29. 

Schreiber and co-workers (436) prepared a library calculated to contain 2.18 million polycyclic compounds through the 1,3-dipolar cycloaddition of a number of nitrones with alkenes supported on TentaGel S NH2 resin (Scheme 1.83). (—)-Shikimic acid was converted into the polymer bound epoxycyclohexenol carboxylic acid 376 (or its enantiomer), coupled to the resin via a photolabile linker developed by Geysen and co-workers (437) to allow release of the products from the resin in the presence of live cells by ultraviolet (UV)-irradiation. A range of iodoaromatic nitrones (377) was then reacted with the ot,p-unsaturation of the polymer-bound amide in the presence of an organotin catalyst, using the tandem esterification/ dipolar cycloaddition methodology developed by Tamura et al. (84,85) Simultaneous cyclization by PyBrop-mediated condensation of the acid with the alcohol... 

The stereochemical outcome of such cycloadditions may be altered by substituents attached to the nitrile oxide-olefin linker. Hassner and co-workers (75,240,253-255) and Kurth and co-workers (256) examined the influence of a stereogenic center a to the dipole in the cycloaddition of alkene-tethered nitrile oxides that feature a sulfur or oxygen atom within the connecting chain (Table 6.13). As expected, the diastereofacial selectivity is increased in the presence of fragments with increasing steric demand. Cycloadditions of thioethers show lower... 

In a parallel study, Wipf and Fritch11041 have shown that also urethane-protected (Boc), and even amino acid segments, are tolerated as acyl compounds on the aziridine nitrogen. The best results were obtained with alkylcopper reagents derived from CuCN and an alkyl-lithium in the presence of boron trifluoride-diethyl ether complex. Some 6-alkylated compounds (11-15%) were isolated as well. This work was extended to a solid-phase procedure that resulted in resin-bound alkene isosteres that could immediately be used in further peptide synthesis.11051 For this purpose, the 2-nitrophenylsulfonyl (oNbs) group was used for nitrogen protection and aziridine activation. It could be readily cleaved with benzenethio-late, which was compatible with the acid-sensitive Wang linker used. 

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. 

Resin-bound selenium has been used as a linker for alkenes in two ways (a) as an oxidant-sensitive linker (selenoxides readily undergo [5-elimination at room temperature Entries 6-8, Table 3.43 [767-773]), or (b) as a linker cleavable by tin radicals (Figure 3.37 Entries 9 and 10, Table 3.43). The main advantages of selenides as linkers are their stability under a broad variety of (non-oxidizing) reaction conditions, including high temperatures and treatment with acids or bases, and the mild conditions required for their cleavage. 

Support-bound sulfonylhydrazones can also be used as linkers for alkenes. Cleavage is effected by heating in the presence of an alcoholate, whereby diazoalkanes are initially formed these then undergo thermal fragmentation into the alkene and nitrogen (Entry 12, Table 3.43 Bamford-Stevens reaction). Polystyrene-bound alkynyl... 

Linkers for Alkenes Cleavable by Olefin Metathesis and Miscellaneous Linkers for Alkenes... 

The C-Si bonds of aryl-, heteroaryl-, vinyl-, and allylsilanes are stable towards alco-holates or weak reducing agents, but can be cleaved under mild conditions by treatment with acids or fluoride to yield a hydrocarbon and a silyl ester or silyl fluoride. Several linkers of this type have been tested and have proven useful for the preparation of unfunctionalized arenes and alkenes by cleavage from insoluble supports. Typical loading procedures for these linkers are sketched in Figure 3.42. 

Support-bound silanes are useful linkers and intermediates, and can be prepared by several routes. The most versatile approaches include the reaction of resin-bound organolithium compounds with chlorosilanes [36,37] and the hydrosilylation of resin-bound alkenes (Figure 4.6). Further transformations of resin-bound silanes are discussed in Section 3.11.2. 

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. 

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). 

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