Polycyclic Indolizidines

Intermediate 49 was prepared from 48 in a large number of steps. The crucial tandem ene-yne-RCM process was also performed with [Ru]-I catalyst (10mol%), which afforded the tetracyclic product in 78% in a diastereomeric ratio of a-OAc-SO /S-OAc-50 as 63 37. Once more, separation of the products, followed by deacetylation of a-OAc-50 afforded erythravine (50) in an overall yield of 7.0%. 

The family of polyhydroxyindolizidine alkaloids is not the only target of interest in the field of natural product synthesis when it comes to application of RCM. Several approaches for the formation of the hindered 5,5-fused bicycHc (poly)hydroxypyrrolidines have been reported as well. The RCM methodology is, in some of these cases, applied to construct the second pyrrole, while on the other hand a larger number of cases exist for both natural and nonnatural products where the first cycle is created this way. 

Unfortunately, an identical approach failed for the synthesis of (-l-)-australine (96) since a Mitsunobu ring closure of the second ring did not take place. A few years later, however, Trost and coworkers pubhshed a different route that made an RCM-mediated synthesis of (-t-)-austrahne (96) possible. In a similar procedure as 

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Porif.> (hydro)pyrimidine, macroQ clic and oligomeric pyridine or pyridinium, naphthyridine, oxazole, pteridine, pyridoacridine, pyrrole, pyrroloimiiMquinone, (oxa)quinoli2idine, terpenoid indolizidine. ISOPR. Monotero. rare Sesouitem. . Ditero.. Sestertero. also degraded C>i Tritero.. POLYKET. macrolides, polyacetylenes, polycyclic (hydro)quinones, polyethers, (epidioxy)polyp ionates. ... 

The majority of published work on aza-ylides concerns their applications in synthesis, and here we report a selection of contributions from this area. The Staudinger reaction is a popular route to aza-ylides and has been used to prepare a series of perfluoroalkyl-tagged aza-Wittig reagents, e.g., (68), which were generated in situ (Scheme 22), and utilised in the synthesis of 3//-quinazolidine-4-ones in a fluorous biphasic system. A method for the preparation of aza-polycyclic compounds derived from pyrrolidine, indolizidine and indole has... 

Indolizines, indolizidines, indoles, and other bicyclic or polycyclic compounds containing a fused pyrrole or pyrrolidine moiety often possess potent and useful biological activities. There have been several approaches to the preparation of fluorinated analogues of these heterocycles, mainly based on 1,3-dipolar addition reactions using fluorinated synthons either as the dipole or as the dipolarophile. Several examples of this strategy are given below. 

Alkaloids with polycyclic skdetal frameworks are, when it comes to their synthesis, excellent candidates for RCM. Illustrative are the indolizidines rhynchophylline (43) and its C(7)-epimer ixo-rhynchophylhne (44), both isolated from the plant Uncaria rhynchophytta (Rubiaceae) [26]. Deiters total synthesis of 43 and 44 started with the efficient construction of diallylamine 39 via amide formation between indole-3-acetic acid (38) and diallylamine (Scheme 2.10). One-pot RCM-carbomagnesation of 39 was smoothly achieved with only 1 mol% of [Ruj-I catalyst and 4 equiv. of EtMgCl to afford the 2-ethyl-3-butene-amine derivative in 71% yield. It appeared that the electron-withdrawing carbonyl moiety was critical to the success of the RCM-carbomagnesation steps. Amide reduction and subsequent treatment with acryloyl chloride dehvered the second metathesis precursor 40. Cyclization with [Ruj-I (5 mol%) then furnished the a,j8-unsaturated lactam 41 in a high yield of 91%. Continuation of the total synthesis of alkaloids 43 and 44 included a Bischler-Napieralski cychzation (42) and subsequent rearrangement into the oxindole framework. 

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