Tetraponerine synthesis

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. 

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 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>. 

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). 

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). 

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>. 

Figure 9.11 The formation of two examples of the tetraponerines from ants. Glutamic acid, ornithine and y-aminobutyric acid uniformly labelled with 0, sodium acetate labelled in C-1 and C-2 with Q and [l,4- C]putrescine were all used to show the synthesis is as shown...

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