Complementary asymmetric routes to fused tricyclic (R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-α]quinolines and (R)-1,2,3,4,5,5a,6,7-octahydro-[1,4]diazepino[1,2-α]quinolines

Two distinct enantioselective approaches to (R)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-alpha]quinolines and (R)-1,2,3,4,5,5a,6,7-octahydro-[1,4]diazepino[1,2-a]quinolines, low MW tricyclic organic scaffolds with a high degree of molecular complexity, are described. The key transformation in route 1 is the lateral lithiation of an N-Boc-o-toluidine and dianion trap with (S)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane. An intramolecular S(N)2 cyclization then forms the optically pure tetrahydroquinoline core. Route 2 involves the coupling of (R)-2-(4-benzyl-1-(Boc)piperazin-2-yl)acetaldehyde or (R)-2-(4-benzyl-1(Boc)-1,4-diazepan-2-yl)acetaldehyde with an aryllithium and a subsequent intramolecular SNAr reaction to form the tricycle. Both synthetic routes were valuable for preparing and identifying ligands targeting GPCRs expressed in the central nervous system (CNS). (C) 2016 Elsevier Ltd. All rights reserved.