Complanadine

As is evident from its structure, complanadine A is comprised of two molecules of the natural product lycodine (2), which are joined at the 2 and 3 positions of the two monomers, respectively (see 1 for numbering). Although there are other examples of dimeric Lycopodium alkaloids, the pseudosymmetric variants are not very common. Therefore, a synthesis of complanadine A could offer opportunities to study the properties and intricacies of the reactivity of the pseudodimeric Lycopodium alkaloids. 

Scheme 11.2 Potential biosynthetic origin of pseudodimeric complanadines...

From a laboratory synthesis standpoint, it was difficult to envision a synthesis of complanadine A along the proposed biosynthetic lines, given the propensity with which compounds such as 15a and 15b undergo disproportionation or oxidation to afford 2 and 14 as recognized in the work of Schumann and coworkers [10]. 

While only a snapshot of the proposed biosynthetic picture for complanadine A has been presented above, we considered an alternative approach in our synthetic strategy analysis (as shown below in Fig. 11.3) that also put into focus the close connections between complanadine A, which would arise from a dimerization of the (S-obscurine precursor 21, and the Lycopodium alkaloids lycoposerramine R (23) and fastigiatine (25). The details of this strategic approach are the subject of this chapter. 

Scheme 11.3 Siegel approach to the pseudodimeric complanadine framework...

We recognized at the outset of our studies that the synthetic challenge in achieving a direct synthesis of complanadine A would be to identify ways to exploit two molecules of lycodine or a closely related precursor. With appropriately positioned functional handles (at C2 and C3, respectively see 36 and 37, Scheme 11.5), the coupling of the pyridine moieties would yield the complanadine skeleton. 

Scheme 11.12 Suzuki cross coupling to build the core of complanadine A...

Scheme 11.13 Acid-mediated Boc removal to afford complanadine A...

The Suzuki adduct 66 was subjected to 6 N HC1 to afford complanadine A as its HC1 salt in 80 % yield (Scheme 11.13). The 1H and 13C NMR spectral data of complanadine A were consistent with that which had been obtained by isolation (Kobayashi) and in Siegel s total synthesis. 

Similarly, we anticipate that boronic ester 52 should prove highly useful for the synthesis of other lycodine-derived Lycopodium alkaloid pseudodimers including complanadines D and E (see Scheme 11.2) as well as unnatural analogues for biological studies. This is the direction of our ongoing research in this area. 

Morita H, Ishiuchi K, Haganuma A, Hoshino T, Obara Y, Nakahata N, Kobayashi J (2005) Complanadine B, obscurumines A and B, new alkaloids from two species of Lycopodium. Tetrahedron 61 1955-1960... 

Yuan C, Chang C-T, Axelrod A, Siegel D (2010) Synthesis of (-t)-complanadine A, an inducer of neurotrophic factor excretion. J Am Chem Soc 132 5924-5925... 

Ishiuchi K, Kubota T, Ishiyama H, Hayashi S, Shibata T, Mori K, et al. Lyconadins D and E, a complanadine E, new Lycopodium alkaloids from Lycopodium complana-tum. Bioorg Med Chem 2011 19(2) 749-53. 

Scheme 16 A Kondrat eva appraoch to the pyridine ring in the complanadines.

Antifungal activity Lycovatine A isolated from L. clavatum var. robustum and complanadine C and D were shown to have antifungal effect on Cryptococcus neoformans (MIC 0.52, 0.52, and 0.26 pg ml , respectively) said Aspergillus niger (MIC 2.06, 2.05, and 4.16 pg ml respectively) [85]. 

Fischer, D. F. Sarpong, R. 2010. Total synthesis of (H-)-complanadine a ising an iridium-catalyzed pyridine C-H functionalization. J. Am. Ghem. Soc. 132 5926-5921. 

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