Tetraponerines

Dicarbonate 14 was used as the starting material to achieve both cis-and trans- ring rearrangement precursors 15 and 16. ROM-RCM of the five-membered carbocycles 15 and 16 leads to 17 and 18. These compounds contain a terminal double bond at position 9, which can be easily functionalised and are set up to form the tricyclic tetraponerines. 

In a similar manner, the dihydropyrrole derivatives were investigated. The Ns protected cis- precursor 15b underwent ring rearrangement to give 23 in an 89% yield in a ratio of 15b 23 of 1 10. However, only a ratio of 2.5 1 was observed in the metathesis of the trans-precursor 16b. The Ns protection group was replaced with CBz to give 25. The subsequent RRM to yield 26 proceeded with complete conversion. 

In the case of both the Ns protected five- and six-membered heteocycles, the cis-conflgurated precursors were obtained more efficiently than the trans-configurated precursor. However, the introduction of the Cbz protecting group in the trans-derivatives resulted in quantitative conversion to the desired products. 

We found that under the conditions of the Wacker oxidation,27 the terminal double bonds of the metathesis products were cleanly transformed to the corresponding aldehydes. While the regioselective oxidation of protected allylic alcohols has been reported,28 the selective Wacker oxidation of an allylic amine derivative to the aldehyde is unprecedented. The Ns protected precursor 19 produced only the starting amine (NsN(H)CH2CH2CH2CH(OEt)2). Consequently, the Ns protecting groups were exchanged with Cbz (27) which successfully led to the desired aldehyde 28. 

This aldehyde intermediate was then olefinated using the Takai olefination.29 This step was also attempted using the Wittig olefination, but the basic conditions lead to retro-Michael side reactions, hence resulting in low yields. The Takai olefination avoids the use of basic conditions and produced 29 and 30 in good yields. 

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Four members of the tetraponerine family (the major constituents of the contact poison of the New Guinean ant Tetraponera sp.) were prepared by RRM methods [156]. The key step leading to tetraponerine T7 (374) from the readily available cyclopentene precursor 372 is shown in Scheme 72. When compound 372 was exposed to catalyst A in the presence of ethylene, the desired ROM-RCM sequence proceeded smoothly to furnish heterocycle 373 with complete conversion, whereas the corresponding di-nosyl (2-nitrophenylsulfonyl)-protected analog of 372 led only to a 1 2 equilibrium mixture of starting material and RRM product. 

Gevorgyan s approach toward tetraponerine 37 utilized a reduction reaction of 36 as the last step in a synthetic sequence, which relied on addition of a hydrogen atom on the correct face to generate the natural product (Equation 2). Accordingly, they carried out an analysis of the diastereoselective installation of the last stereogenic center <2004JOC5638, 2002OL4697>. 

In an approach toward a synthesis of tetraponerine 37, Gevorgyan first synthesized the fully aromatic tricyclic system 49 and then reduced it over two steps, first via hydrogenation under pressure (50 psi) to give 36 followed by a second reduction by lithium aluminium hydride of the amidinium salt (Scheme 1) <2002OL4697, 2004JOC5638>. 

In an approach toward the tetraponerine family of alkaloids, Piehiers and co-workers utilized base hydrolysis of the ester 90 followed by acid-catalyzed decarboxylation to obtain the corresponding amide 91 in good yield (Equation 19) <2000CJC1030>. 

In an approach toward the synthesis of tetraponerine, Gevorgyan and co-workers explored the double pyrrolization of pyrimidine derivatives 276 via a copper-catalyzed cyclization to give tricycles 277 (Equation 76) <2002OL4697, 2004JOC5638>. 

T. rufonigra from India and T penzigu T. clypeata and T. sp. cf. emeryU all three from Africa, had no tetraponerines. Surprisingly, the extract from another collection of T. allaborans was also devoid of alkaloids. Thus, the presence or absence of tetraponerine alkaloids cannot be considered a taxonomic marker for the genus until the genetic or environmental factors responsible for their production are uncovered and understood [131]. 

Since the discovery of tetraponerine-8 in 1987 by Braekman et al. [195] the tetraponerines, the defensive alkaloids of ants of the genus Tetraponera, have been the target of considerable synthetic efforts and have served to demonstrate the utility of various synthetic methodologies [114]. Recently a few further syntheses of these unusual tricyclic alkaloids have been reported. 

A further enantioselective synthesis of (+)-T-4 (125), T-6 (128), T-7 (129) and T-8 (126) has been reported by Stragies and Blechert [198]. Key steps are a Pd-catalyzed domino allylation and a Ru-catalyzed metathesis ring rearrangement. Their strategy represents a general approach towards all naturally occurring tetraponerines and will be illustrated here by the description of the syntheses of (+)-T-4 (125) and (+)-T-8 (126) (Scheme 9). 

In addition to the two asymmetric syntheses above described, two racemic syntheses of tetraponerines based on the 5=6-5 tricyclic skeleton have been published. Thus, Plehiers et al. [199] have reported a short and practical synthesis of ( )-decahydro-5Tf-dipyrrolo[l,2-a r,2/-c]pyrimidine-5-carbonitrile (238), a pivotal intermediate in the synthesis of racemic tetraponerines-1, -2, -5 and -6, in three steps and 24% overall yield from simple and inexpensive starting materials. The key reaction of the synthesis was a one-pot stereoselective multistep process, whereupon two molecules of A pyrroline react with diethylmalonate to afford the tricyclic lactam ester 239, possessing the 5-6-5 skeleton (Scheme 10). Hydrolysis of the carboethoxy group of 239 followed by decarboxylation yielded lactam 240, that was converted into a-aminonitrile 238 identical in all respects with the pivotal intermediate described by Yue et al. [200] in their tetraponerine synthesis. 

Another example of a natural product that we synthesised using a ROM-RCM sequence are tetraponerines.23 Tetraponerines (T1-T8) (Figure 6) were isolated from the venom of the New Guinean ant Tetraponera sp.24 These alkaloids represent the major constituents of the contact poison and contaminated enemies immediately show symptoms of nerve poisoning. 

Tetraponerines (T1-T8) each contain three stereocentres and differ from one another in the side chain and stereochemistry at C-9, and the size of ring A. Due to these features, a general procedure for the synthesis of these unusual alkaloids is challenging. A general strategy utilising RRM to synthesise tetraponerines T1-T8 was developed and can be seen in the retrosynthetic analysis (Scheme 5). 

After successful completion of all rearrangement reactions, the incorporation of the different side chains of the tetraponerines was attempted by employing a cross metathesis reaction. However, the cross metathesis of 19 and 22 with allyltrimethylsilane in the presence of 10% [Ru-1] was unsuccessful due to the formation of a carbene with low reactivity. The use of Schrock s molybdenum catalyst26 [Mo] (Figure 7) also failed to show any conversion. The terminal double bonds of 19 and 22 were assumed to be too hindered for cross metathesis. An alternative route to incorporate the different alkyl chains of the tetraponerines was necessary (Scheme 8). 

Other enantiopure tetraponerines that were synthesised by this route are T7 and T6 (Scheme 9). The synthesis of these representative tetraponerines demonstrates the high efficiency and flexibility of the metathesis rearrangement. 

Symmetrically substituted cydopentanones have proven to be very good substrates in allylic substitution chemistry [98]. This chemistry is elegantly exploited by Blechert and co-workers for the synthesis of the nerve poisoning tetraponerine... 

Scheme 12.29. Synthesis of tetraponerines using a three-component double allylic animation, by Stragies and Blechert [99] Ns = nosyl, dba = dibenzylideneacetone, dppb = 3,4-di(bisphenylphosphino)butane, Cy = cyclohexyl.

The synthesis of C-2-epi-hydromycin A [170] and tetraponerines [171] using a desymmetrization of 76 (bearing benzoates and carbonates respectively instead of acetate) has been reported. Finally, the first-generation and second-generation asymmetric syntheses of the aminocyclohexitol moiety of hygromycin A were reported [172]. 

Charette recently described an innovative activation protocol in which lactams, in the presence of triflic anhydride (33), react with pyridines to afford the pyridinium imidate 107 in good yield. Subsequent addition of metal enolates to this species leads to 2-substituted tricyclic dihydropyridines, advanced intermediates for the total synthesis of the natural alkaloid ( )-tetraponerine T4 (109, Scheme 16) [107]. 

Pyridinium salt 72 is generated by the treatment of the amide 71 with triflic anhydride in the presence of pyridine followed by treatment with the lithium enolate. Intermediate 72 was used to synthesize tetraponerine T4 in four steps in 38% overall yield. Comins and co-workers used addition of a zinc enolate to an Al-acylpyridinium salt in the synthesis of (+)-hyperaspine <05OL5227>. Additionally, they have studied cuprate addition to A/ -acyl pyridinium salts of nicotine, where addition occurs selectively at the 4-position <050L5059>. 

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