Solid-Phase Organic Syntheses

70 Solid-Phase Synthesis of Di- -peptoids

total program, 7 min.; flow rate, 2 mL/min.; UV detection at 210 nm.

DISCUSSION

Solid-phase synthesis is the most convenient method for preparation of oligomeric N-substituted -aminopropionic acids or - peptoids.1 The acrylate and acrylamide resins are reactive toward a wide variety of primary amines, allowing introduction of a diverse set of substituents.1,2 Use of primary amines is essential for chain extension by acylation with acryloyl chloride, although secondary amines can be used as a chain-terminating step for the amine end of an oligomer. -Peptoids can be prepared by standard peptide couplings of N-substituted -amino acids, however this approach requires the preparation of each of the -amino acids before solid-phase synthesis. The solid-phase approach also eliminates the formation of bis-addition products (addition of two equivalents of acrylate or acrylamide to the amine); a common side product of solution phase synthesis.3 Standard coupling of Fmoc amino acids is compatible with the solid-phase procedure for preparation of oligomeric -aminopropionic acids, as previously shown for inclusion of Fmoc -alanine and nipecotic acid in a trimer series,1 allowing the formation of ‘‘mixed peptide or peptoid’’ chains. Reaction of acrylate resins that are not TFA cleavable with secondary amines has been investigated as a means of preparing tertiary amines by Michael addition of the amine, alkylation, and Hoffman elimination from the resin.4 In this case, the acrylate resin is used as a linker, and the threecarbon unit is not incorporated in the final product.

Addition of amines 8a–k to acrylamide 3 resulted in good yields (71–92%) of di- -peptoids 9a–k, with conversions of the starting resin being >95% in all cases except 9i, j, and l (Table 6.1). The -branched amines typically required longer reaction times for completion. Because double treatments were used in

72 Solid-Phase Synthesis of Di- -peptoids

REFERENCES

1.Hamper, B. C.; Kolodziej, S. A.; Scates, A. M. et al. J. Org. Chem. 1998, 63, 708.

2.Kolodziej, S. A.; Hamper, B. C. Tetrahedron Lett. 1996, 37, 5277.

3.Zilkha, A.; Rachman, E. S.; Rivlin, J. J. Org. Chem. 1961, 26, 376 and Stork, G.; McElvain, S. M. J. Am. Chem. Soc. 1947, 69, 971.

4.Ouyang, X.; Armstrong, R. W.; Murphy, M. M. J. Org. Chem. 1998, 63, 1027 and Brown, A. R.; Rees, D. C.; Rankovic, Z.; Morphy, J. R. J. Am. Chem. Soc. 1997, 119, 3288.

5.Appella, D. H.; Christianson, L. A.; Klein, D. A. et al. Nature 1997, 387, 381 and Seebach, D.; Overhand, M.; Kuhnle, F. N. M. et al. Helv. Chim. Acta 1996, 79, 913.

74

LIBRARY SYNTHESIS ROUTE

Procedure 75

BUILDING BLOCKS

PROCEDURE

A TYPICAL PROCEDURE FOR THE PREPARATION OF INDIVIDUAL BENZOXAZOLE 4

Preparation of Carboxylfunctionalized Resin 1

To the Wang resin (100 mg, 0.070 mmol) in a 3-mL polypropylene filtration tube with polyethylene frit was added 1 mL 0.4 N CDI in anhydrous THF (note 1), capped with a yellow polyethylene cap, and shaken at room temperature for 6 h (note 2). The resin was thoroughly washed with CH2Cl2 (3 1 mL) and THF (3 1 mL) to remove the excess CDI and then treated with 1 mL 0.4 N piperazine in THF at room temperature for 15 h. The resulting resin was washed with DMF (3 1 mL), MeOH (4 1 mL),

76 Solid-Phase Synthesis of Benzoxazoles via Mitsunobu Reaction

and CH2Cl2 (4 1 mL) and dried in vacuo. To the aminofunctionalized resin was added 1 mL 0.4 N succinic anhydride in pyridine/CH2Cl2 (v/v ¼ 1:1) and 5 mg DMAP, and the resulting slurry was shaken at room temperature for 4 h. The resulting carboxylfunctionalized resin 1 was washed with DMF (3 1 mL), MeOH (4 1 mL), and CH2Cl2 (4 1 mL) and dried in vacuo.

Preparation of Benzoxazole 4

To resin 1 (0.070 mmol) was added PyBOP (182 mg, 0.35 mmol) and 2-aminophenol (38 mg, 0.35 mmol) in 1 mL DMF, followed by N-methylmorpholine (NMM) (38 mL, 0.35 mmol). The mixture was shaken at room temperature for 3 h. The resulting resin 2 was washed extensively with DMF (3 1 mL), MeOH (4 1 mL), and CH2Cl2 (4 1 mL) and dried in vacuo. To the mixture of resin 2 and Ph3P (92 mg, 0.35 mmol) in 1 mL anhydrous THF was added diethyl azodicarboxylate (DEAD) (55 mL, 0.35 mmol). The reaction mixture was shaken at room temperature for 17 h, followed by washing with DMF (3 1 mL), MeOH (4 1 mL), and CH2Cl2 (4 1 mL). The resulting resin 3 was dried in vacuo, treated with a solution of 50% TFA in CH2Cl2 (1.5 mL) at room temperature (note 3) for 30 min to release the polymer-bound benzoxazole and washed with CH2Cl2 (2 1 mL). Removal of the volatiles under a stream of nitrogen followed by drying under high vacuum overnight afforded the crude compound 4, which was submitted to HPLC, mass spectrum, and NMR analyses (notes 4 and 5).

A DIRECTED LIBRARY SYNTHESIS OF

BENZOXAZOLES

As described above, a small library containing 27 benzoxazoles was synthesized by using three diamines, three dicarboxylic anhydrides, and three 2-aminophenols (Table 7.1). Wang resin

was distributed into twenty-seven 3-mL filtration tubes (100 mg / tube, 0.070 mmol) followed by adding 1 mL 0.4 N CDI in THF. After shaking at room temperature for 6 h, the resins were washed with CH2Cl2 (3 1 mL / tube) and THF (3 1 mL / tube) to remove the excess CDI. A solution of piperazine in THF (310 mg in 9 mL THF) was dispensed into 9 tubes of row A, row B, and row C at 1 mL / tube; a solution of homopiperazine in THF (361 mg in 9 mL THF) was dispensed into 9 tubes of row D, row E, and row F at 1 mL / tube; and finally, a solution of trans- 1,4-diaminocyclohexane in THF (411 mg in 9 mL THF) was dispensed into 9 tubes of row G, row H, and row I at 1 mL / tube. The resulting mixtures were shaken at room temperature for 15 h, and the resins were washed with DMF (3 1 mL / tube), MeOH (4 1 mL / tube), and CH2Cl2 (4 1 mL / tube) and dried in vacuo. Succinic anhydride solution (360 mg succinic anhydride, 45 mg DMAP, 4.5 mL pyridine, and 4.5 mL CH2Cl2) was dispensed into 9 tubes of column 1 at 1 mL / tube; diglycolic anhydride solution (418 mg diglycolic anhydride, 45 mg DMAP, 4.5 mL pyridine, and 4.5 mL CH2Cl2) was dispensed into 9 tubes of column 2 at 1 mL / tube; and finally, 3-methylglutaric anhydride solution (461 mg 3-methylglutaric anhydride, 45 mg DMAP, 4.5 mL pyridine, 4.5 mL CH2Cl2) was dispensed into 9 tubes of column 3 at 1 mL / tube. The reaction mixtures were agitated at room temperature for 4 h. The resulting carboxylfunctionalized resins (1) were then washed with DMF (3 1 mL / tube), MeOH (4 1 mL / tube), and CH2Cl2 (4 1 mL / tube) and dried in vacuo.

Next, PyBOP (4.914 g, 9.45 mmol) in 13.5 mL DMF was dispensed into all the reaction tubes at 0.5 mL / tube and 2- aminophenol (344 mg, 3.15 mmol) in 4.5 mL DMF was dispensed into 9 tubes of row A, row D, and row G at 0.5 mL / tube; 2-amino- p-cresol (388 mg, 3.15 mmol) in 4.5 mL DMF was dispensed into 9 tubes of row B, row E, and row H at 0.5 mL / tube; and finally, 2- amino-4-tert-butylphenol (521 mg, 3.15 mmol) in 4.5 mL DMF was dispensed into 9 tubes of row C, row F, and row I at 0.5 mL /