Roseophilin

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

Roseophilin (273), a deeply red-colored pentacyclic compound isolated from the culture broth of Streptomyces griseoviridis, is a novel antitumor antibiotic. Compound 273 possesses a topologically unique pentacyclic skeleton, consisting of a 13-membered macrocycle incorporated in an ansa-bridged azafulvene, which in turn is linked to a conjugated heterocyclic ring system. The absolute stereochemistry of roseophilin, as depicted in Fig. 9, was unknown until the first total synthesis published by Tius and Harrington in 2001 [125]. All syn-... 

Fig. 9 Various RCM substrates used in total syntheses of roseophilin (273)...

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>. 

These studies paved the way for numerous synthetic applications, in particular total syntheses. Thus, the low-tech PtCl2, PtCl4, or PtBr4 systems, as named by Fiirstner, proved superior and more reliable compared to Trost s TCPCtfe system288 for the reactions of the cyclooctene substrate as shown in Scheme 81.300 These reactions, which could be run in a multi-gram scale, proved useful, for instance, for the formal total synthesis of streptorubine B. Similarly, a formal total synthesis of roseophilin was devised, based on a nearly quantitative transformation of an enyne moiety into a bicyclic diene system (Scheme 81).301... 

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). 

Fttrstner has employed the Trost pyrrole synthesis in the first total synthesis of roseophilin, wherein this A-benzylpyrrole-ring forming step occurred in 70% yield [23]. Backvall has found that primary amines react with dienes under the guidance of Pd(II) to form pyrroles 170 in variable yields [121]. The intermediate Jt-allyl-palladium complexes are quite stable. 

Reactions of this type have been used in the construction of the pyrrolylfuran derivatives (309) (R = H, 57% and R = C1, 24%) using nitrile ylides generated by the imidoyl chloride-KOf-Bu method (191). This reaction was a key step en route to simplified analogues of roseophilin, however, the reaction failed for the derivative with a methoxy group at the 4 position of the furan ring. 

For an excellent review on chemistry and biology of roseophilin and the related prodigiosin alkaloids, see Furstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582-3603. 

Trost succeeded in formal total synthesis of roseophilin. Macrocyclic compound 118 is synthesized from enyne 117 by platinum-catalyzed skeletal reorganization reaction and is converted into 119, which is further converted into pyrrole derivative 120 (Scheme 43). ... 

Despite the unrivaled easy access to 1,4-dicarbonyl compounds, only a few examples of the application of Stetter reactions in the synthesis of natural products have been reported to date [55]. Tius et al. have employed a diastereoselective in-termolecular Stetter reaction and a ring-closing metathesis reaction as the key steps in their elegant synthesis of roseophilin (58 Scheme 9.16) [56]. The 1,4-... 

Roseophilin (53) was isolated [37] from S. griseoviridis and found to exhibit cytotoxicity against leukemic and epidemoid cells at a concentration of 10=0.5 pM. 

The furanylcerium that was generated from lithiation/transmetallation of furan 40 as shown in Equation (28) was a highly nucleophilic species that added readily to the sterically hindered ketopyrrole to provide the penultimate intermediate during the total synthesis of roseophilin <1998JA2817>. 

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. 

The formal total synthesis of roseophilin was accomplished by B.M. Trost et al. who used the Paal-Knorr pyrrole synthesis to install the trisubstituted pyrrole moiety.The 1,4-diketone substrate was reacted with various primary amines to obtain A/-substituted pyrroles. The best yield was obtained when benzylamine was used as the amine component, but the A/-deprotection of the product proved to be problematic. This forced the researchers to prepare the otherwise unstable A/-unprotected pyrrole under carefully controlled conditions and protect it immediately with SEM-chloride. 

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. 

The absolute stereochemistry of natural roseophilin was determined by means of asymmetric total synthesis by M.A. Tius and co-workers. The trisubstituted pyrrole moiety of the natural product was installed using the Paai-Knorr pyrrole synthesis starting from a macrocyclic 1,4-diketone. This diketone was prepared by reacting an exocyclic a, 3-unsaturated ketone with excess 6-heptenal in the presence of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride as the catalyst. The major product was the trans diastereomer and the macrocyclization was achieved via aikene metathesis. It is worth noting that when the aldehyde was tethered to the cyclopentenone, all attempts to close the macrocycle in an intramolecular Stetter reaction failed. 

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