complanadine-a and lycodine

Valuable synthetic routes to the Lycopodium alkaloid lycodine (1) and its unsymmetric dimers, complanadines A (4) and B (5), have been developed. Regioselective construction of the bicyclo[3.3.1]nonane core structure of lycodine was achieved by a remote functionality-controlled Diels-Alder reaction and subsequent intramolecular Mizoroki-Heck reaction. A key coupling reaction of the lycodine units, pyridine N-oxide (66) and aryl bromide (65), through C-H arylation at the C1 position of 66 provided the unsymmetric dimer structure at a late stage of the synthesis. This strategy greatly simplified the construction of the dimeric architecture and functionalization. Complanadines A (4) and B (5) were synthesized by adjusting the oxidation level of the bipyridine mono-N-oxide (67). The diverse utility of this common intermediate (67) suggests a possible biosynthetic pathway of complanadines in Nature. Both enantiomers of lycodine (1) and complanadines A (4) and B (5) were prepared in sufficient quantities for biological evaluation. The effect on neuron differentiation of PC-12 cells upon treatment with culture medium, in which human astrocytoma cells had been cultured in the presence of 1, 4, or 5 was evaluated.

Topics: Alkaloids; Animals; Cell Line, Tumor; Crystallography, X-Ray; Cycloaddition Reaction; Dimerization; Heterocyclic Compounds, 4 or More Rings; Humans; Molecular Conformation; Neuronal Outgrowth; Oxidation-Reduction; PC12 Cells; Pyridines; Rats; Stereoisomerism

A synthetic approach to complanadine alkaloids is described which employs a Kondrat'eva reaction to construct the pyridine rings. The viability of this approach is demonstrated by its application to a model substrate accessed from unfunctionalized decalin. The key transformation affords the desired tetracyclic architecture with unprecedented incorporation of substituents on the pyridine ring, implicating the oxazole α-hydroxy group as an active participant in the cycloadduct fragmentation process.

Topics: Alkaloids; Alkenes; Cycloaddition Reaction; Heterocyclic Compounds, 4 or More Rings; Molecular Structure; Naphthalenes; Oxazoles; Pyridines

The dimeric alkaloid complanadine A has shown promise in regenerative science, promoting neuronal growth by inducing the secretion of growth factors from glial cells. Through the use of tandem, cobalt-mediated [2 + 2 + 2] cycloaddition reactions, two synthetic routes have been developed with different sequences for the formation of the unsymmetric bipyridyl core. The regioselective formation of each of the pyridines was achieved based on the inherent selectivity of the molecules or by reversing the regioselectivity through the addition of Lewis bases. This strategy has been successfully employed to provide laboratory access to complanadine A as well as structurally related compounds possessing the lycodine core.

Topics: Cyclization; Heterocyclic Compounds, 4 or More Rings; Molecular Conformation; Stereoisomerism