NH2 2. NaCNBH3 NH DIC
Scheme 9. Synthesis of diketopiperazines.
Cyclative cleavage:The resin 35 (200 mg) was shaken in toluene ortoluene/ethanol (1:1; 2 mL) in the presence of 1 % acetic acid or 4 % triethylamine at room temperature for several hours (8-12 h for acidic conditions, 2-5 h for basic conditions).The resin was washed several times with ethanol, the combined filtrates were concentrated to give 36 .
In a similar strategy, a-hydroxy acids were bound to substituted amino acids via a Ugi reaction. Cyclative cleavage resulted in the formation of diketomorpholines after cyclative cleavage with triethylamine/CH2Cl2 . Similar concepts were also presented by other groups ,
Introducing an a-ketoacid instead of a second amino acid moiety afforded almost planar 3-alkylidene-2,5-dioxopiperazines 37 after cyclization in toluene/acetic acid with ammonium acetate as source of ammonia (Scheme 10) ,
Scheme 10. Synthesis of virtually planar 3-alkylidene-diketo-piperazines.
A synthesis of biologically highly potent dihydropyridines (DHPs) is shown in Scheme 11. P-Ketoesters were bound to PAL or Rink resin to give the corresponding enamines 38. Reaction with aromatic aldehydes and p-diketones or P-ketoesters (R4 = OR) gave the precursors for cyclization 39. Cyclative cleavage was performed in a mixture of TFA/CH2C12- The authors assumed that the products 40 were formed by a cyclization of the precursors with a subsequent cleavage from the resin, although they did not exclude that cleavage from the resin might also occur before cyclization .
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