Flustramine

In a recently published report by MacMillan s group [121] on the enantioselective synthesis of pyrroloindoline and furanoindoline natural products such as (-)-flustramine B 2-219 [122], enantiopure amines 2-215 were used as organocatalysts to promote a domino Michael addition/cyclization sequence (Scheme 2.51). As substrates, the substituted tryptamine 2-214 and a, 3-unsaturated aldehydes were used. Reaction of 2-214 and acrolein in the presence of 2-215 probably leads to the intermediate 2-216, which cyclizes to give the pyrroloindole moiety 2-217 with subsequent hydrolysis of the enamine moiety and reconstitution of the imidazolid-inone catalyst. After reduction of the aldehyde functionality in 2-217 with NaBH4 the flustramine precursor 2-218 was isolated in very good 90 % ee and 78 % yield. 

Lindel T, Brauchle L, Golz G, Bohrer P (2007) Total Synthesis of Flustramine C via Dimethylallyl Rearrangement. Org Lett 9 283... 

Kawasaki T, Shinada M, Kamimura D, Ohzono M, Ogawa A (2006) Enantioselective Total Synthesis of (-)-Flustramines A, B and (-)-Flustramides A, B via Domino Olefination/ Isomerization/Claisen Rearrangement Sequence. Chem Commun 420... 

Flustra foliacea L., a marine bryozoan, or moss animal, contains29 two isomeric metabolites, flustramine A and flustramine B, which are eserine derivatives that contain one bromine and two isoprenyl substituents, at positions 6, 3a, and 8. In... 

Application of the pyrroloindoline-forming protocol in natural product synthesis was demonstrated by the first enantioselective synthesis of (—)-flustramine B (Scheme 3.16) [21]. Moreover, this amine-catalyzed transformation has also been extended to the enantioselective construction of furanoindoline frameworks, a widely represented substructure among natural isolates of biological relevance [21]-... 

B. Flustrarine B was also synthesised by oxidation of flustramine B with hydrogen peroxide [381. 

F. foliacea also occurs in the Bay of Fundy, Canada. Bioassay-guided fractionation based on antibacterial activity of the extract of this bryozoan has lead to the isolation of a different series of bromoal-kaloids of the physostigmine class, two of which were N-oxides (39]. The major alkaloids were dihydroflustramine C, 90, ( 60%), which had been reported previously by these authors [40) and flustramine D, 91, (-40%). Minor alkaloids found were dihydroflustramine C N-oxide, 92. flustramine D Af-oxide, 93, and isoflutramine D, 94. The JV-oxides were also synthesised by oxidation of the corresponding free bases with m-chloroperbenzoic acid. These alkaloids were shown to be responsible for the wide spectrum of antibacterial activity exhibited by this bryozoan extract. 

Kawasaki. T, Terashima, R., Sakaguchi, K.-E., Sekiguchi, H., and Sakamoto, M., A short route to reverse-prenylated pyrrolo[2,3-7>]indoles via tandem olefination and Claisen rearrangement of 2-(3,3-dimethyl-allyloxy)indol-3-ones. First total synthesis of flustramine C, Tetrahedron Lett., 37, 7525, 1996. Nasutavicus, W.A., Tobey, S.W., and Johnson, E, The cyclization of nitriles by halogen acids. Part 2. A new synthesis of substituted S/Z-azepines, J. Org. Chem., 32, 3325, 1967. 

The marine bryozoan Flustra foliacea collected in the North Sea has given rise to the isolation of a complicated mixture of alkaloids, twelve of which have so far been identified (32-36). The structures are depicted in Scheme 11 flustramine A (1)... 

Investigations of the same species from New Brunswick and Nova Scotia have yielded five structurally identified alkaloids depicted in Scheme 11 Dihydroflus-tramine C (I) (43), flustramine D (II), isoflustramine D (III, tentatively identified as the minor component in a 65 35 mixture with II), dihydroflustramine C N-oxide (IV), and flustramine D N-oxide (V) (44). 

As yet not one single compound has been found to co-occur in the two populations. The five compounds from the Canadian collection arc all characterized by the presence of the inverted isoprene unit (2-methyl-3-buten-2-yl) in the 3a position. Of the tricyclic structures from the Scandinavian collection only three compounds (1, 5, and 6) encompass this configuration. Therefore, even if I and 8 only differ in this aspect they are clearly biogenetically different. Likewise, even if the N-oxide of flustramine B (2-VI-oxide) participates in an acid-base catalyzed equilibrium with flustrarine B (9) (45) analogous to the geneserine and geneseroline equilibria with hexahydropyrrolo[2,3-6] indole V-oxides and hexahydro-1,2-oxazino[5,6-fe]indoles (46) there is no possibility of transforming IV to 9. 

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