Baylis Alison M, Davies Michael P H, Thomas Eric J
The School of Chemistry, The University of Manchester, Manchester, UK.
Org Biomol Chem. 2007 Oct 7;5(19):3139-55. doi: 10.1039/b708910d. Epub 2007 Aug 14.
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.
报道了一种合成生物碱茎福林1的方法的初步研究。酮酯14的立体选择性环化得到了1-丁基-2,8-双（甲氧基羰基）-8-氮杂双环[3.2.1]辛烷21，其中2-甲氧基羰基处于轴向位置。类似的酮15、18和19也进行了环化，得到了带有轴向吸电子2-取代基的8-氮杂双环[3.2.1]辛烷22-24。双环酮砜22的结构通过X射线衍射得以确证。通过用叔丁基锂处理碘化物29和38，将酯21转化为三环内酰胺31和39，其中酰胺片段明显偏离平面。脱保护的三环羟基内酰胺40的结构通过X射线衍射得以确证，该衍射显示了内酰胺片段的非平面几何形状以及由额外的二碳桥引入双环[3.2.1]辛烷中的扭曲。这意味着C9处的内氢比C8处的内氢更靠近5-羟基。利用这一结构特征，使用四乙酸铅对羟基内酰胺40进行区域选择性远程氧化，同时选择性地插入较近的内C-H键，得到四环醚41。内酰胺39通过用氢化铝锂还原为氨基醇44，并还原由氨基醇44与亚硫酰氯形成的中间体（可能是氯化物46），再用更多氢化铝锂，随后进行O-脱保护和氧化，转化为三环氨基酮49。双环酮酯21也被保护为其缩酮50，通过三环内酰胺54转化为酮胺49。最后，三环内酰胺42和胺49的烯丙基化得到了轴向烯丙基化产物60和58，但进一步引入茎福林的C10和C11的过程并不简单。由双环酮酯21制备的受保护羟基酮64的烷基化得到了轴向烷基化产物65和69，并且酮酯69被转化为三环羟基内酯73。然而，用叔丁基锂处理碘化物75形成四环内酰胺的反应未成功。
