Complementary asymmetric routes to fused tricyclic (R)-2, 3, 4, 4a, 5, 6-hexahydro-1H-pyrazino[1, 2-a]quinolines and (R)-1, 2, 3, 4, 5, 5a, 6, 7-octahydro-[1, 4]diazepino[1, 2-a]quinolines. Issue 42 (19th October 2016)

• Record Type: Journal Article
• Authors: Schrader, Thomas O.; Kasem, Michelle; Sun, Qi; Wu, Chunrui; Ren, Albert; Semple, Graeme
• Is Part Of: Tetrahedron letters. Volume 57:Issue 42(2016)
• Page Start: 4730
• Page End: 4733
• Publication Date: 2016-10-19
• Subjects: GPCR ligand -- Asymmetric synthesis -- Dilithiation -- Tetrahydroquinoline -- Fsp3 -- CNS drugs; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tetlet.2016.09.025
• Languages: English
• ISSNs: 0040-4039

Abstract

Graphical abstract: Highlights: Unique tricyclic amines with high degrees of molecular complexity are reported. Ligands target centrally expressed GPCRs. Two distinct asymmetric syntheses of tetrahydroquinoline-based tricyclic amines. Dilithiation approach to enantiopure 2-substituted-1, 2, 3, 4-tetrahydroquinolines. Convergent route to tricyclic scaffold via coupling and intramolecular SN Ar reaction. Abstract: Two distinct enantioselective approaches to ( R )-2, 3, 4, 4a, 5, 6-hexahydro-1 H -pyrazino[1, 2- a ]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 SN 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 SN Ar reaction to form the tricycle. Both synthetic routes were valuable for preparing and identifying ligands targeting GPCRs expressed in the central nervous system (CNS).