Silyl linkers

Silyl linkers (Tab. 3.5) have successfully been used for the synthesis of natural products [96, 97], oligosaccharides [98], oligonucleotides [99] and in peptide synthesis [100]. 

Silyl linkers are very common in solid phase chemistry in their function as alcohol-protecting groups [332-338]. Cleavage from those silyl ether resins 

A few sihcon-containing linkers have been synthesized on sohd phase and are used to tether diverse aryl moieties without former preloading of the linker. Elhnan et aL attached aromatic and heteroaromatic compounds directly to a sihcon-substituted support for the first time. The nature of the resin anchoring of those silyl hnkers has to be chosen carefully because cleaving conditions for the release of non-alcohohc compounds may induce destruction (and therefore release) of the sihcon hnker as well. Ellman et al. synthesized a heteroatom free, masked and therefore stable silyl hnker 650 starting from allylsilanes and bromo-substituted polystyrene that can be eas- 

Appropriate allylic linker systems can be obtained with a three-step synthetic procedure starting from polystyrene. Selective Uthiation of polystyrene 604 (1%DVB crosslinked) was achieved by addition of Buli in combination with TMEDA and subsequent conversion with allyldimethylsilyl chloride gave resin 666 with an average siUcon content of 1.3 mmol/g. Diversity could 

673 as electrophilic compounds. For the use of acetaldehyde, yields of 54% over three steps could be achieved whereas for aldehydes bearing more bulky substituents the yield decreased to 34% for the allylation of isopropylalde-hyde. Diastereoselectivities for the formation of the desired sy -homoallylic alcohols 663 are in any case better than the values achieved in solution phase. Suginome and Ito used a very similar methodology to synthesize oxacyclo-heptenes 664 as well. The reaction of resin 672 with aldehydes 673 or acetals 

To the best of our knowledge only two groups have been working on the investigation of dialkylsilyloxy linkers up to now [349,350,353]. The synthesis of the linker core is performed in both cases in solution phase and is later on transferred to the resin. 

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Newlander KA, Chenera B, Veber DF, Yim NCF Moore ML. Simple silyl linker for the solid phase organic synthesis of aryl-containing molecules. J Org Chem 1997 62 6726-6732. 

Scheme 2.3 Glycal attachment to a polystyrene resin via a silyl linker.

Scheme 4.11 Application of the traceless silyl linker strategy.

Glycosyl Trichloroacetimidates Attached to the Solid Support via Silyl Linkers... 

To our knowledge, only one attempt has been made toward the preparation and use of a fixed glucosyl trichloroacetimidate.9 Takahashi et al. described the synthesis of an attached O-glucosyl trichloroacetimidate and extended the use of the well known traceless silyl linker strategy (Scheme 4.11). 

Many other linkers besides those listed above have been developed for two-phase synthesis of oligosaccharides on insoluble supports, and it can be expected that at least some of them will be tested on soluble supports. It should be kept in mind that MPEG-supported syntheses can be easily scaled up therefore, any relationship between both types of polymer supports will be cooperative rather than mutually exclusive. Such linkers will most probably include dialkyl- or diaryl-silyl linkers,10,41 3 and linkers cleavable by photolysis such as the o-nitrobenzyl group and its modifications.44 16... 

R. Duboc, M. Savignac and J. P. Genet, Palladium cross-coupling reactions on solid support using a new silylated linker, J. Organomet. Chem., 2002, 643, 512-515. 

Veber et al.88 used Suzuki couplings on a solid support to generate simple biphenyls (Scheme 38), in the presence of a silyl linker, which was cleaved to release these structures without trace of the linkage position. 

Usually, it is different to make a clear distinction between linker and spacer. The linker is the minimum part of the resin required for the functional cleavage (for silyl linkers it is the silyl group, for trityl linkers it is the triphenylmethyl moiety, and for the triazene linker it is the 1-aryltriazenyl group, etc.). The spacer is, therefore, the part between the linker and the resin as depicted in Figure 6.1.1. 

The first traceless linkers for arenes were silyl linkers. This linker type was used in the synthesis of a benzodiazepine library, a milestone in the solid-phase synthesis of small organic molecules (Scheme 6.1.9). Synthesis of the linker involves lithium-halogen exchange and, after chlorosilane attachment, coupling with an... 

Scheme 6.1.9. Synthesis of a benzodiazepine library using a silyl linker.

Cleavage reagents Benzyl- type linkers Ketal/ acetal linkers Esters/ amide linkers Silyl linkers Triazene linkers Selenium/ sulfur/ stannane linkers... 

Fluoride ions Silyl linkers Hydrocarbons, alcohols... 

The most prominent anchors for traceless linkage of arenes are based on silyl linkers. Generation of a diverse benzodiazepine library [40] has clearly shown the advantages of this type of detachment because no additional functionality, which might bias the library, was preserved in the final molecules (Scheme 6.1.33). 

Liao, Y., Fathi, R., Reitman, M., Zhang, Y., Yang, Z. Optimization study of Sonogashira cross-coupling reaction on high-loading macrobeads using a silyl linker. Tetrahedron Lett. 2001, 42,1815-1818. 

A support material bearing a silyl linker (50) can be prepared from polystyrene, according to Farrall and Frechet [59]. This has been successfully applied to the synthesis of diverse prostaglandins [60]. One example of such a synthesis is outlined in Scheme 25. 

Two new silyl linkers (61 and 62, Fig. 5) have been synthesized starting from Merrifield resin, 3-methyl-l,3-butanediol, and diphenyldichlorosilane or dimefhyl-dichlorosilane [64]. Linker 61 was used for the attachment of primary and secondary alcohols as well as for phenols, whereas tinker 62 was designed for the binding of tertiary alcohols. 

Despite these efforts, the carbonylahon reachons were still rather sluggish and proceeded only on a timescale of a few days. Stoichiometric amounts of PdCl2(PPh3)2 had to be used, and the co-reagent CBr4 caused partial cleavage of the silyl-linker. 

A new silyl linker was attached to a Merrifield resin through a MW-assisted O-alkylation followed by O-silylation. In order to test its versatility, methyl lactate was immobilized on this linker through the hydroxy group and then reacted with phenylmagnesium bromide. TBAF-medi-ated cleavage afforded the corresponding diol in good yield. 

A chiral aldehyde, attached through a silyl linker to a hydroxymethyl Merrifield resin, was employed for expanding polyketide diversity. Aldol reaction with preformed (H)-enol borinate derived from a suitable chiral (R)-ketone afforded the anti-anti aldol product. Titanium-mediated enolization of the enantiomer (S)-ketone afforded the syn-syn product. 

Scheme 16.27 Synthesis of a benzodiazepine library with the aid of a silyl linker by Ellman et al.

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