Synthesis of ( S, Z)-3-[(1 H-indol-3-yl)methylidene]hexahydropyrrolo[1,2- a]pyrazin-4(1 H)-one: an alternative, enaminone based, route to unsaturated cyclodipeptides

Abstract

A series of racemic and enantiopure ( S, Z)-3-[(1 H-indol-3-yl)methylidene]hexahydropyrrolo[1,2- a]pyrazin-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.