Concise, Enantioselective Total Synthesis of (−)-Alstonerine

Abstract

A novel enantioselective total synthesis of (-)-alstonerine has been completed that requires only 1 5 steps from L-tryptophan. The synthesis features the first application of a Pauson-Khand reaction t o synthesize an azabridged bicyclic skeleton.The macroline/sarpagine class of indole alkaloids is a rich source of biologically active natural products, some of which exhibit hypotensive, antiamoebic, and antimalarial activities. 1 For example, alstonerine (1) has recently been reported to exhibit cytotoxic activity against two human lung cancer cell lines. 2 The alkaloids of this family contain an azabicyclo[3.3.1] substructure that is annelated to an indole ring. It is thus fitting that a number of strategies have been devised to access this structural motif including sequential Pictet-Spengler and Dieckmann condensations, 3 ring-closing metathesis, 4 phosphine-catalyzed [4+2] annulation/ Friedel-Crafts cyclization, 5 or aza-Diels-Alder/intramolecular Heck reaction. 6 As a representative member of the macroline/sarpagine family, two total syntheses and one formal synthesis of 1 have been reported. 5, 7In the context of a longstanding interest in alkaloid synthesis, we have been intrigued by designing and developing novel and general strategies for the facile preparation of representative members of different alkaloid families. 8 We have recently explored a number of transition metal catalyzed reactions for the construction of ring systems common to a number of alkaloids. In the context of some investigations toward developing some new cascade reactions, 9 we became interested in examining the potential of the Pauson-Khand reaction (PKR) for alkaloid synthesis. The intramolecular version of the PKR has been applied to the syntheses of a few natural products, 10 but its use has overwhelmingly been limited to forming fused bicyclo-[3.3.0]octenones and bicyclo[4.3.0]nonenones. 11, 12Our ongoing efforts to develop concise routes for the elaboration of azabridged bicyclic structures led us to query whether the scope of the PKR might be extended to include cyclizations of cis-2,6-disubstituted piperidine enynes. Considering the absolute lack of precedent for such a PKR, the simple model substrate 4 was first prepared to explore the feasibility of such a construction (Scheme 1). Thus, by analogy with previous work in our laboratories, 4, 13 reaction of 4-methoxypyridine (2) with the anion derived from trimethylsilylacetylene in the presence of Cbz-Cl gave the unsaturated piperidinone 3. Lewis acid mediated conjugate addition of allyltribuyltin followed by treatment of the intermediate silyl acetylene with TBAF provided the enyne substrate 4 in >19:1 diastereoselectivity. To our delight, the ensuing PKR proceeded cleanly to give 5 as a single diastereomer. To our knowledge, this represents the first example of a PKR to provide an azabridged bicyclic product.Correspondence to: Stephen F. Martin. Having thus established the underlying viability of using PKRs to form azabicyclo[3.3.1] bicyclononanes fused with cyclop...

Simple indole alkaloids and those with a nonrearranged monoterpenoid unit

“…Enantioselective total synthesis of (À)-491 has been completed using Pauson-Khand reaction of 493 as the key step to assemble azabridged bicycle 494 (Scheme 96). 170 A new indole alkaloid, arbophylline (495), possessing an unprecedented heptacyclic system and incorporating an acetal unit, was isolated from the stem-bark extract of Kopsia arborea, and the structure was established by spectroscopic analysis. 171 A full account of the total synthesis of macrocaffrine (496) was presented, in which the key step was an intramolecular cycloaddition of the oxazole-olefin in 497 giving 498.…”

Copper‐Catalyzed Aerobic Oxidative Cyclization Cascade to Construct Bridged Skeletons: Total Synthesis of (−)‐Suaveoline

“…Cook and co‐workers have accomplished elegant synthesis of several indole alkaloids with this structural feature by using Dieckmann condensation to construct the bridged framework. Efficient strategies also include biomimetic synthesis and olefin metathesis from the Martin group,‐ a [4+2]‐annulation/Friedel–Crafts acylation from the Kwon group, and a [5+2]‐dipolar cycloaddition/ring enlargement from the Gaich group,– and other methods . Despite these advances, most of the existing methods require multiple functional‐group pre‐installations and transformations (Scheme b), whereas greener strategies, namely, C−H functionalization, that benefit from minimal functional‐group manipulations remain underexplored.…”

Toward the Total Synthesis of FR901483: Concise Synthesis of the Azatricyclic Skeleton

“…Attempts to improve this yield under other mild conditions were unfruitful, and the use of stronger bases such as NaHMDS gave complex mixtures. Subsequent reaction of 38 with 3butenylmagnesium bromide (7) in the presence of TMEDA gave 39 in 88% yield; when the reaction was conducted in the absence of TMEDA the yield of 39 was only 64%. The yields for preparing protected 2-pyrrolidinones related to 38 using other chloroformates 33 (R 3 = H; R 4 = Me, Pr, and i-Bu) were comparable (41-48%), whereas the yields of the corresponding ring opened products were either lower or no better than for the preparation of 39.…”

“…Toward this goal, the chiral lactam 23 was treated with the chloroformate 36 in the presence of DMAP and Et 3 N to give 40 in an unoptimized 36% yield (96% based upon recovered starting material) (Scheme 7). Reaction of 40 with 3butenylmagnesium bromide (7) in the presence of TMEDA gave the ketone 41 in 58% yield. Although the palladium-catalyzed removal of the Etalloc group in the presence of benzotriazole proceeded smoothly, all attempts to isolate and purify the resultant chiral imine 26 were unsuccessful owing to its acid-sensitivity and facile transformation to the pyrrole 27.…”