title: Stereoselective formation of fused tricyclic amines from acyclic aldehydes by a cascade process involving condensation, cyclization, and dipolar cycloaddition.
abstract: The preparation of tricyclic amines from acyclic precursors is described using a cascade of tandem reactions involving condensation of an aldehyde with a primary amine, cyclization (with displacement of a halide), and then in situ deprotonation or decarboxylation to give an azomethine ylide or nitrone followed by intramolecular dipolar cycloaddition. The methodology is straightforward, and the aldehyde precursors are prepared easily and quickly in high yield using nitrile alkylations followed by DIBAL-H reduction. The relative ease of reaction of various substrates with different tether lengths between the aldehyde and the halide or dipolarophile has been studied. Several primary amines including simple amino acids such as glycine, alanine, and phenylalanine and derivatives such as glycine ethyl ester and also hydroxylamine have been investigated. High yields are obtained in the formation of different tricyclic ring sizes; the dipolar cycloaddition necessarily creates a five-membered ring, and we have investigated the formation of five- and six-membered rings for the other two new ring sizes. In all cases, yields are high (except when using glycine when the tether to the terminal alkene dipolarophile leads to a six-membered ring), and most efficient is the formation of the tricyclic product in which all five-membered rings are formed. Examples with an alkyne as the dipolarophile were also successful. In all the reactions studied, the products are formed with complete regioselectivity and remarkably with complete stereoselectivity. The key step involves the formation of three new rings and potentially up to four new stereocenters in a single transformation. The power of the chemistry was demonstrated by the synthesis of the core ring systems of the alkaloids (+/-)-scandine and (+/-)-myrioneurinol and the total syntheses of the alkaloids (+/-)-aspidospermine, (+/-)-quebrachamine, and (+/-)-aspidospermidine.
authors.affiliation: Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK.
authors.forename: Adam J M
authors.initials: AJ
authors.lastname: Burrell
authors.forename: Iain
authors.initials: I
authors.lastname: Coldham
authors.forename: Luke
authors.initials: L
authors.lastname: Watson
authors.forename: Niall
authors.initials: N
authors.lastname: Oram
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Pilgram
authors.forename: Nathaniel G
authors.initials: NG
authors.lastname: Martin
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000470:Alkaloids / Q000138:chemical synthesis; D000588:Amines / Q000138:chemical synthesis*; D003500:Cyclization; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis*; D026121:Indole Alkaloids / Q000138:chemical synthesis; D011804:Quinolines / Q000138:chemical synthesis; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D000470:Alkaloids; D000588:Amines; D006575:Heterocyclic Compounds, 3-Ring; D026121:Indole Alkaloids; D011804:Quinolines; C409672:aspidospermidine; C091897:quebrachamine; C091896:aspidospermine