Sulfur-containing linkers

Another sulfur-containing linker was described by Hunt and Roush in 1996 (Scheme 4.6).4... 

Sulfur-containing linkers (Fig. 14) [91,270,271] are a widely used class of linkers not at least because of the large amount of mild cleavage methods. Release of target compounds from sulfur linked resins depends strongly on... 

There are a few routes to synthesize sulfone functionalities for solid phase chemistry. One possibility is the reaction of lithiated polystyrene beads with sulfur dioxide to deliver polymer-bound lithium phenyl sulfinate as a linker system to which allylic compounds can be easily attached [286]. Other syntheses start from the corresponding thioether linkage followed by oxidation to the sulfone. Mostly, sulfur-containing ether-linkers that are oxidized just before cleavage from the resin are presented separately from those which are directly bound to the resin in their oxidized form. This differentiation is not done in this review because it does not make any difference concerning the cleavage possibilities that are shown in Scheme 66. 

Scheme 9.10 Linkers containing sulfur shown with a pentasaccharide and the tetramannoside (the latter before its deprotection).

Sulfur has been used in linkers such as thioethers, sulfoxides, sulfones, sulfonic acids and their corresponding derivatives. A safety-catch linker for amines is based on 2-(thiobenzyl)ethylcarbamates [44]. Linkage is performed with preformed handles containing ethenyloxycarbonyl-protected amines 37. Attachment to thiomethyl-ated polystyrene 38 is performed under conditions involving radicals. Cleavage was performed with an oxidizing agent, which forms the retro Michael substrate (Scheme 6.1.11). 

When materials contain sulfur in addition to C, H, and 0, the process is more complex because sulfur may form three kinds of bonds (27). One kind acts as oxygen does by forming before the semi-coke stage another kind is unstable between 1300°C and 1700°C and, for some products, there is a third kind of residual sulfur that remains firmly fixed to the carbon above 1700°C. In the latter case, the sulfur acts as a strong cross-linker. In contrast, unstable sulfur acts as a modifier between 1300°C and 1700°C, suddenly transforming carbon into graphite (31). Therefore, the material is not cross-linked. For thdse products, we calculated an atomic ratio factor F MCT... 

The phenol-sulfide SC linker 1.28 (85) attached to Merrifield resin has been used to support peptides, with the exclusion of S-containing aminoacids. Oxidation of the sulfur atom with hydrogen peroxide increases the reactivity of the linker towards amines and allows the facile cleavage of the ester bond to release the final compounds into solution as amides. 

Sulfur analogs of some of the described hydroxy linkers and resins (Figure 15.2) have been employed to synthesize resin-bound thioesters that can then be cleaved with alcohols, amines and organometallic reagents to furnish esters, amides, ketones, aldehydes and alcohols [50]. Secondary amines react sluggishly with linker 9 and, therefore, more reactive thioester-linker derivatives were developed, such as 17 and 18. Yields for a hindered amine such as Pro-OMe were in the order of 60-70%. Thiol-containing PS-DVB resin 7 has been used for the obtention of P-hydroxyacids by hydrolysis with 0.2 M NaOH in aqueous dioxane [51],... 

The strategies described in Schemes 4.6.S-4.6.9 thus combine efficiently a novel sulfur-based safety-catch linker strategy, multigeneration construction of thio-linked pyrimidines with a multidirectional cleavage procedure. This approach should prove successful for the solid-phase synthesis of a whole range of nitrogen-containing heterocycles such as pyrimidines, triazines, imidazoles, benzimidazoles. 

It was found that by using succinic-sarcosinyl -type linker 9, the solid-phase automated synthesis of dodeca(deoxyadenosine phospho-rothioate) (d[(Aps)n A]) can be performed via the oxathiaphospholane method with an average of 95% effectiveness of a single coupling step. Purity of this material, as indicated by polyacrylamide gel electrophoresis and HPLC, is comparable with that of sample prepared by phosphoramidile-stepwise sulfurization or H-phosphonate-tandem sulfurization methods (35). P-NMR spectrum did not contain any signal within the phosphate region. The synthesis is outlined within Fig. 4, and synthetic protocol is given in Table 1. 

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