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trifluoroacetic acid/10% water. Reported HPLC purities ranged between 51 and 85%, with an average value of 70%.
A series of trisubstituted guanidines has been prepared by Drewry et al.19 a-Bromo-p-toluamide was converted to the azide by reaction with sodium
(i) PhNCS, THF Î
(ii) PPh3, THF H
95 % TFA,
H ?h N-^N
206 SOLID-PHASE ORGANIC SYNTHESIS ON RADIATION-GRAFTED POLYMER SURFACES
azide (Scheme 6). Treatment with an isothiocyanate followed by triphenyl-phosphine furnished the carbodiimide, most likely via a Staudinger/azaWittig reaction sequence. The order of addition was important to minimize side products from this step. Treatment of the intermediate carbodiimide with an amine provided the guanidine. Cleavage of the Rink linker was achieved using 95% TFA-H20. The reported model system had a purity of 96% by HPLC.
6.2.4. Polysaccharide Synthesis
Scheme 7 shows how trisaccharides were prepared on a radiation-grafted polymer surface.20 The photolabile 4-hydroxymethyl-3-nitrobenzamido handle21 and AModosuccinimide-triethylsilyltriflate coupling chemistry were used. Product purities were similar to those obtained using Tentagel macrobeads.
6.2.5. Hydroformylation and Hydrogenation
In an interesting application of a gaseous reagent to solid-phase synthesis, Takahashi and co-workers demonstrated hydroformylation of an unactivated alkene using synthetic gas (1:1 H2-CO) and a Rh(I) catalyst (Scheme 8).22 The reaction was typically performed at 40°C in toluene at a pressure of 75 atm. Conversions of 99% were obtained following careful reaction optimization. Variation in the concentration of catalyst could be used to alter the regioselectivity of the reaction.
SynPhase crowns can also be used as the polymer support for solid-supported reagents in solution-phase combinatorial chemistry. Gilbertson and co-workers used crowns to prepare a bank of 63 solid-supported peptide-based chiral phosphine ligands to investigate a rhodium-catalyzed hydrogenation (Scheme 9).23 The pentapeptide ligands each had two phosphine-containing residues, but the positions of these residues and the peripheral sequences were varied. Rhodium complexes of these ligands were formed in situ, and this library of catalysts was then used for asymmetric hydrogenation of dehydroalanine. Screening revealed that some conditions gave very high conversions. Although the enantioselectivity was low, it was dependent on the ligand used. Recycling of ligands attached to the crowns was possible.
6.2. SYNTHETIC APPLICATIONS OF SYNPHASE CROWNS 207
(i) NH2CSNH2, MeO(CH2)2OH, 80 °Ñ
(ii) NIS, TMSOTf
BzO BzO ^
MeO(CH2)2OH 70 °Ñ
(i) Ac20, DMAP pyr, CH2CI2 ^
(ii) hv, THF
208 SOLID-PHASE ORGANIC SYNTHESIS ON RADIATION-GRAFTED POLYMER SURFACES
ÎÑÍç --------- AcNK OCH,
good yield varied åå
6.3. LINKER DEVELOPMENT USING SYNPHASE CROWNS
Expanding the variety and properties of linker groups increases the scope of practical applications of radiation-grafted polymer surfaces for the parallel synthesis of organic compounds. Linker molecules have a bearing on the types of reactions that can be performed and the ease of isolation of products after cleavage.
A wide range of linker groups are currently used with SynPhase crowns. They accommodate formation of the following functional groups upon cleavage: carboxylic acids, primary and secondary amides, sulfonamides, alcohols, phenols, amines, anilines, anilides, hydroxymates, aldehydes, ketones, and thiols.
An important criteria in solid-phase synthesis is product purities immediately after cleavage from the support. Ideally, the target compound should be cleaved into a solvent-reagent system that can be easily removed, usually by evaporation. Solvents/cleavage reagents that are difficult to remove may compromise subsequent biological screening of the libraries. Consequently,
6.3. LINKER DEVELOPMENT USING SYNPHASE CROWNS 209
cleavage strategies featuring volatile acids (e.g., TFA) and scavengers are common.