title: Synthetic approaches to the polycyclic alkaloid stemofoline.
abstract: Preliminary studies of a synthetic approach to the alkaloid stemofoline 1 are reported. Stereoselective cyclisation of the ketoester 14 gave the 1-butyl-2,8-bis(methoxycarbonyl)-8-azabicyclo[3.2.1]octane 21 in which the 2-methoxycarbonyl group is in the axial position. The analogous ketones 15, 18, and 19 were also cyclised to give the 8-azabicyclo[3.2.1]octanes 22-24 with axial electron-withdrawing 2-substituents. The structure of the bicyclic ketosulfone 22 was confirmed by X-ray diffraction. Conversion of ester 21 into the tricyclic lactams 31 and 39, in which the amide fragments are significantly distorted from planarity, was achieved by treatment of the iodides 29 and 38 with tert-butyllithium. The structure of the deprotected tricyclic hydroxylactam 40 was confirmed by X-ray diffraction, which showed the non-planar geometry of the lactam fragment and the distortion induced into the bicyclo[3.2.1]octane by the additional two-carbon bridge. This meant that the endo hydrogen at C9 was significantly closer to the 5-hydroxyl group than the endo hydrogen at C8. This structural feature was utilised to direct a regioselective remote oxidation of the hydroxylactam 40 using lead tetraacetate, which was accompanied by selective insertion into the closer endo C-H bond to give the tetracyclic ether 41. Lactam 39 was converted into the tricyclic aminoketone 49 by reduction to the aminol 44 using lithium aluminium hydride and reduction of the intermediate, possibly the chloride 46, formed from aminol 44 using thionyl chloride, with more lithium aluminium hydride, followed by O-deprotection and oxidation. The bicyclic ketoester 21 was also protected as its ketal 50, which was taken through via the tricyclic lactam 54 into the ketoamine 49. Finally, allylation of the tricyclic lactam 42 and amine 49 gave the axial allylated products 60 and 58, but further elaboration for incorporation of C10 and C11 (of stemofoline) was not straightforward. Alkylation of the protected hydroxyketone 64, which was prepared from the bicyclic ketoester 21, gave the axial alkylated products 65 and 69, and the ketoester 69 was converted into the tricyclic hydroxylactone 73. However, the formation of a tetracyclic lactam by treatment of the iodide 75 with tert-butyllithium was not successful.
authors: The School of Chemistry, The University of Manchester, Manchester, UK.
authors: Alison M
authors: AM
authors: Baylis
authors: Michael P H
authors: MP
authors: Davies
authors: Eric J
authors: EJ
authors: Thomas
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis*; D000478:Alkylation; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D006576:Heterocyclic Compounds, 4 or More Rings; C430220:stemofoline