Modification of 1-substituents in the 2-azabicyclo[2.1.1]hexane ring system; approaches to potential nicotinic acetylcholine receptor ligands from 2,4-methanoproline derivatives.
Successful nucleophilic substitution at a methylene attached to the bridgehead (1-) position of the 2-azabicyclo[2.1.1]hexane ring system opens the way to construction of novel derivatives having a wider range of functional groups attached to the 1-position via a methylene "spacer" (including the beta-amino acid homologue of 2,4-methanoproline) and provides access to epibatidine analogues containing heterocyclic substituents and also to further homologation at the 1-position. Displacements with loss of a nucleofuge (e.g., loss of mesylate anion from the 1-mesyloxymethyl derivative) require thermal activation but proceed without the rearrangement initially anticipated in such a strained bicyclic ring system. A novel tricyclic carbamate intermediate 17 has been isolated; nucleophilic attack on 17 leads directly to the isolation of N-deprotected substitution products (with concomitant decarboxylation).
Malpass
John R
JR
Department of Chemistry, University of Leicester, Leicester LE1 7RH, United Kingdom. jrm@le.ac.uk
Patel
Anup B
AB
Davies
John W
JW
Fulford
Sarah Y
SY
D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C450189:2,4-methanoproline; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D008024:Ligands; D018722:Nicotinic Agonists; D011392:Proline