O

Scheme 8

Procedure

An appropriate N-Fmoc-protected amino acid resin (100 mg, c. 0.06 mmol) on Sasrin support (method A) or TentaGel S NH2 resin (150 mg, c. 0.03 mmol), functionalized with a-

methyl-6-nitroveratryl alcohol photolinker (method B), was deprotected with 20 % (v:v) piperidine in DMF for 30 min.The resin was filtered, washed liberally with DMF, MeOH, and DCM, and dried under vacuum.The deprotected resin was suspended in a solution of an appropriate aldehyde (1 mmol) in DCM (0.5 mL), and trimethylorthoformate (0.5 mL, 4.57 mmol) with catalytic AcOH (10 |_tL) were added, and the mixture was agitated by gentle shaking for 5 h.The resulting imine resin 27 was filtered, washed with DMF, MeOH, and DCM, and dried under vacuum. Anhydrous pyridine (0.080 mL, 1.0 mmol) was added, under inert atmosphere, to a suspension of the above ¡mine. THF (2.0 mL) precooled to -78° C was added, followed by dropwise addition of an appropriate chlorosulfonylacetate (0.86 mmol) in THF (0.4 mL).The mixture was stirred at -78° C for 3 h, and allowed to warm to rt over ~ 24 h. MeOH (~ 5 mL) was added and the resin 28 was filtered off, washed with MeOH and DCM, and dried under vacuum. Photolinker-tethered compounds were released by photolysis (365 nm, 12 h) in /'-PrOH (2.0 mL). Sasrin-supported sultams were cleaved with 2 % (v:v)TFA in DCM (~ 2 mL, rt, 20 min). In the latter case, MeCN (7 mL) and toluene (~ 3 mL) were added (to prevent concentration of the labile products inTFA), and the solvent was removed under high vacuum.

3.4.6 Imidazoles

Five-membered ring heterocycles are common in numerous pharmaceuticals. In particular, the imidazole core structure, an element of histidine and its decarboxylation metabolite histamine, is often found [41], The exceptional properties and wide applicability of the imidazole pharmacophore is due to its hydrogen bond donor acceptor capabilities and its high affinity for metals (present in many protein active sites, e.g., Zn, Fe, Mg) [42^46], In addition, peptide-based protease inhibitors with improved pharmakokinetics and bioavailability have been obtained by replacing an amide bond with an imidazole [47],

The chosen example of imidazole synthesis on solid support relies on a new linking method, where attachment is achieved through an imidazole core nitrogen [48], The key reaction of the sequence utilizes a miinchnone [3+2]-cycloaddition, as shown in Scheme 9 [49]. Adaptation of this chemistry to polystyrene-poly(ethyleneglycol) grafted copolymer resin ArgoGel-MB-CHO includes a standard reductive alkylation protocol with an amino acid methyl ester. The resin-bound amino ester was acylated with a carboxylic acid chloride in the presence of Huenig base. KOH hydrolysis afforded the caboxylic acid 29. Treatment of the resin-bound acid under modified conditions with EDC and tosylimine led initially to the intermediate miinchnone 30. Subsequent cycloaddition of the miinchnone with the tosylimine, followed by elimination of toluenesulfinic acid and C02, afforded the polymer-bound imidazole 31. Interestingly, the yield of the corresponding reaction in solution is generally low, which is (at least in part) due to self-condensation of miinchnones [50]. It is well known that immobilization on a solid support can reduce the potential for self-condensation. The authors took advantage of the high stability of the 4-alkoxy-2-methoxybenzylic type linkage by washing the resin with 90 % (v:v) TFA/H20 for 1 h to remove unreacted starting materials and non-imidazole byproducts. During this purification step the desired imidazole was not cleaved from the resin. The actual cleavage was achieved by treatment with glacial acetic acid at 100° C for 2 h. The synthesis proceeds in high overall yields (49-99 %; 12 examples) and excellent purity (94-98 %).

X = polyethylene glycol grafted polystyrene

ArgoGel-MB-CHO

X = polyethylene glycol grafted polystyrene

ArgoGel-MB-CHO

3. KOH, dloxane/HjO

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