An iron-catalysed C-C bond-forming spirocyclization cascade providing sustainable access to new 3D heterocyclic frameworks.
Heterocyclic architectures offer powerful creative possibilities to a range of chemistry end-users. This is particularly true of heterocycles containing a high proportion of sp3-carbon atoms, which confer precise spatial definition upon chemical probes, drug substances, chiral monomers and the like. Nonetheless, simple catalytic routes to new heterocyclic cores are infrequently reported, and methods making use of biomass-accessible starting materials are also rare. Here, we demonstrate a new method allowing rapid entry to spirocyclic bis-heterocycles, in which inexpensive iron(III) catalysts mediate a highly stereoselective C-C bond-forming cyclization cascade reaction using (2-halo)aryl ethers and amines constructed using feedstock chemicals readily available from plant sources. Fe(acac)3mediates the deiodinative cyclization of (2-halo)aryloxy furfuranyl ethers, followed by capture of the intermediate metal species by Grignard reagents, to deliver spirocycles containing two asymmetric centres. The reactions offer potential entry to key structural motifs present in bioactive natural products.
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
Kirsty
K
Adams
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
Anthony K
AK
Ball
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
James
J
Birkett
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
Lee
L
Brown
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield SK10 4TG, UK.
Ben
B
Chappell
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
Duncan M
DM
Gill
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
P K Tony
PK
Lo
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
Nathan J
NJ
Patmore
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
Craig R
0000-0002-0630-4860
CR
Rice
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
James
J
Ryan
AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield SK10 4TG, UK.|AstraZeneca Pharmaceuticals, Oncology Chemistry, Hodgkin Building, c/o Darwin Building, Unit 310, Cambridge Science Park, Milton Road, Cambridge CB4 0FZ, UK.
Piotr
P
Raubo
Department of Chemical Sciences, University of Huddersfield, Huddersfield HD1 3DH, UK.
Joseph B
0000-0001-7593-9598
JB
Sweeney
D000588:Amines / Q000737:chemistry; D002384:Catalysis; D003500:Cyclization; D004987:Ethers / Q000737:chemistry; D005290:Ferric Compounds / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D008968:Molecular Conformation; D013141:Spiro Compounds / Q000737:chemistry*; D013237:Stereoisomerism
D000588:Amines; D004987:Ethers; D005290:Ferric Compounds; D006571:Heterocyclic Compounds; D013141:Spiro Compounds