Analogues of Amphibian Alkaloids: Total Synthesis of (5R,8S,8as)-(-)-8-Methyl-5-Pentyloctahydroindolizine (8-Epi-Indolizidine 209B) and [(1S,4R,9as)-(-) -4- Pentyloctahydro-2H-Quinolizin-1-Yl]Methanol

Background e astonishingly diverse range of alkaloids isolated from the skins of amphibians includes numerous 1-azabicyclic systems belonging to the indolizidine (1-azabicyclo [4.3.0]nonane), quinolizidine (1-azabicyclo [4.4.0]decane) and lehmizidine (1-azabicyclo [5.3.0]decane) classes.[1,2] e rst of these classes is by far the most populous, and has commanded enormous attention from organic chemists stimulated by the challenges of designing novel total syntheses.[3] e more recently discovered amphibian quinolizidines constitute a smaller group of alkaloids; they embrace homopumiliotoxins (e.g. (+)-homopumiliotoxin 223G 1; Figure 1) and related systems, 4,6-disubstituted quinolizidines (e.g. rel-quinolizidine 195C 2) and 1,4-disubstituted quinolizidines (e.g. (-)-quinolizidine 217A 3). In the latter group, it appears that most of the well-characterised alkaloids have a 1,4-trans disposition of the substituents; the only alkaloid in which the substituents are unambiguously cis is (-)-quinolizidine 207I 4. Comparatively few syntheses of quinolizidine 207I, 217A and related compounds have been reported. [4-9]

As part of a long-standing investigation into the utility of pyrrolidinylideneand piperidinylidene-containing enaminones (vinylogous urethanes) 5 and 6 as key intermediates in the synthesis of alkaloids and other nitrogen-containing heterocycles,[10] we previously reported total syntheses of (-)-indolizidine 167B 7,[11,12] the 5,8-disubstituted indolizidine (-)-209B 8 and its racemic diastereomer (±)-9,[13] and the 5,6,8-trisubstituted indolizidines (+)-10 and (+)-11,[14] among other similar compounds (Figure 2). While our attempts to prepare quinolizidines have been less successful, we have synthesised two simple lupin alkaloids, lupinine 12 and epilupinine 13, in racemic form.[15] Although it might seem that reactions of the enaminones 5 and 6 should be directly comparable, we [15,16] and others [17,18] have previously found unexpected dierences in the preparation and reactions of cyclic enaminones of dierent ring sizes. In this article we report our progress in preparing 1,4disubstituted quinolizidine analogues of amphibian alkaloids by an extension of our approach to the synthesis of 5,8-disubstituted indolizidine alkaloids. [19]

Results and Discussion Steps in our reported total synthesis of (-)-indolizidine (-)-209B 8 [13] are shown in Scheme 1. Absolute stereocontrol resulted from use of the Davies protocol,[20,21] whereby the homochiral amine (+)-14 prepared from tert-butyl (E)-oct-2-enoate and (R)-N-benzyl-1-phenylethylamine, was converted into the primary amine (-)-15 and thence in several steps into the thiolactam (+)-16. Eschenmoser sulde contraction [22,23] with ethyl bromoacetate yielded the key enaminone intermediate (+)-17, chemoselective reduction of the saturated ester of which produced the alcohol (-)-18. e bicyclic core of the alkaloid was then constructed by a cycloalkylation that took advantage of the nucleophilic reactivity of the enaminone, following which a chemoselective and reasonably diastereoselective (88:12) reduction of the alkene bond of the bicyclic enaminone (+)-19 set up the desired stereochemistry at C-8 and C-8a. Epimerisation of the ester in the reduced compound (-)-20 produced (-)-21, reduction of which gave the alcohol (-)-22. Reduction of the corresponding methanesulfonate with lithium triethylborohydride, as described by Holmes et al.,[24] completed the total synthesis of (-)-indolizidine 209B 8.