A series of racemic and enantiopure (
S,
Z)-3-(1
H-indol-3-yl)methylidenehexahydropyrrolo1,2-
apyrazin-4(1
H)-one (cyclic Pro–ΔTrp) dipeptide analogues were prepared. Racemic analogues
6a–
c were ...prepared by direct coupling of racemic cyclodipeptide enaminone (
R,
S)-
5 with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction in which acyclic (
S)-Pro–ΔTrp dipeptide analogues
20 and
21 were formed. Acyclic dipeptides were cyclized to enantiopure (
S)-Pro–ΔTrp dipeptide analogues
24 and
25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (
7), enaminone
8 was prepared and coupled with 2-methylindole and 2-phenylindole to give
9 and
10. Direct bromination of 3-(indole-3-yl)propenoates
9 and
10 at position 2 results in vinyl bromides
11 and
12. The Boc protecting group on the indole nitrogen 1′ in vinyl bromides
11 and
12 was introduced, before the copper(I) catalyzed coupling with
N-Boc prolinamide
18 was performed. Enantiomeric purity of chiral intermediates and final products was determined mostly by HPLC or
1H NMR spectroscopy and X-ray diffraction.
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