Roseophilin core, synthesis

The reaction produced a 1 1 mixture of arylated and dehalogenated 238 and 239. Knight (99TL6117) also used a 3-pyrrolyl radical in this synthesis of the roseophilin core (Scheme 66). 

As will be discussed later, the novel pentacyclic antitumor alkaloid roseophilin continues to attract much synthetic effort and several approaches relied on the venerable Paal-Knorr condensation for construction of the pyrrole moiety. For instance, Trost utilized this reaction upon diketone 1 to afford the tricyclic core 2 of roseophilin in a strategy featuring an enyne metathesis as a key step <00JA3801>, while another formal synthesis of this alkaloid utilized a radical macrocyclization to produce the ketopyrrole core <00JCS(P1)3389>. 

A good example for such a situation is a recent report on the synthesis of the macrotricyclic core 63 of roseophilin [40,41]- RCM was able to form the rather strained ansa chain of this target molecule only after the cyclization had been biased by a conformational control element X which helps to bring the unsaturated chains closer together and lowers the enthalpic barrier during ring formation (Scheme 18). 

The first synthesis of the macrotricyclic core of roseophilin was carried out by A. Furstner and co-workers. intramolecular Friedel-Crafts acylation was used to close the third ring of the macrotricycle. 

M.A. Tius et al. reported a formal total synthesis of the macrocyclic core of roseophilin. The aliphatic five-membered ring of this core was prepared via a variant of the Nazarov cyclization. The precursor for this cyclopentannelation reaction is an ( )-a, 3-unsaturated aldehyde, which was prepared using the Peterson ole nation on the f-butylimine of 5-hexenal. First the a-TMS derivative of the imine was generated then after a second deprotonation, the additon of isobutyraldehyde gave the ( )-a, 3-unsaturated imine upon aqueous work-up. Acidic hydrolysis of this imine gave the desired ( )-a,(3-unsaturated aldehyde in good yield. 

Furstner, A., Weintritt, H. Total Synthesis of the Potent Antitumor Agent Roseophilin A Concise Approach to the Macrotricyclic Core. J. Am. Chem. Soc. 1997, 119, 2944-2945. 

Harrington, P. E., Tius, M. A. A Formal Total Synthesis of Roseophilin Cyclopentannelation Approach to the Macrocyclic Core. Org. Lett 1999, 1, 649-651. 

Jin, Z., Kim, S.H. and Fuchs, PL. (1996) Phosphazene base P2-Et mediated isomerization of vinyl sulfones to allyl sulfones. Tetrahedron Letters, 37, 5247-5248 Jin, Z. and Fuchs, PL. (1996) Use of phosphazene base and phase-transfer conditions for regiospecific alkylative isomerization of vinyl capable of undergoing P-elimination reactions. Tetrahedron Letters, 37, 5249-5252 Kim, S.H., Figueroa, 1. and Fuchs, P.L. (1997) Application of the Grubbs ringclosing metathesis for the construction of a macrocyclic ansa-bridge. Synthesis of the tricyclic core of roseophilin. Tetrahedron Letters, 38, 2601-2604. 

Due to the prevalence and diversity of pyrrole and indole alkaloids and the limitations of space, no attempt will be made to describe all of the synthetic efforts in this area. Of those syntheses wherein the construction of a pyrrole ring was of major importance, most efforts were devoted to the marine polycyclic aromatic lamellarin class of alkaloids and total syntheses of lamellarins-D, -G, -K and -O <97X5951, 97AGE155, 97CC2259, 97CC207> were reported Although not a total synthesis, Furstner reported a Pd-mediated route to the macrotricyclic core of the anti-leukemia alkaloid, roseophilin <97JA2944>. 

Trost BM, Doherty GA. An asymmetric synthesis of the tricyclic core and a formal total synthesis of roseophilin via an enyne metathesis. J. Am. Chem. Soc. 2000 122 3801-3810. 

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