Cephalostatin

LaCour, T.G. Guo, C. Bhandaru, S. Boyd, M.R. Fuchs, P.L. (1998) Interphylal product splicing the first total syntheses of cephalostatin 1, the North hanisphere of ritterazine G, and the highly active hybrid analogue, rittaostatin GNl - J. Am. Chan. Soc., 120, 692-707. 

A twofold intramolecular Heck reaction of the dibromobenzene derivative 19 has been used to construct the heptacyclic skeleton 20 of cephalostatin analogs. This reaction required a precise control of the reaction time and temperature. The conversion proceeded best with a catalytic amount of the palladacycle from tris(< -tolyl)phosphine and palladium acetate, and gave exclusively (in 80% yield) the heptacycle 20 with an unusual m-annelation of the two newly formed rings (Scheme 10). ... 

Cephalostains 1-6 (507-512), powerful cell growth inhibitory substances against the PS cell line, were isolated from the marine worm Cephalodiscus gilchristi collected in the Indian Ocean 406-408). The structure of cephalostatin 1 (507) was determined by X-ray analysis. Cephalostatins apparently result from a biosynthetic condensation of 2-amino-3-oxosteroid units to yield dimeric steroidal molecules connected by a pyrazine ring. 

FIGURE 3.11 Selected metabolites from a polychaete and a hemichordate 3.11.1 Thelepin, from the poly-chaete Thelepus setosus.222 3.11.2 Cephalostatin 10, from Cephalodiscus gilchristi223... 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

The synthesis of the potent in vitro active compound, cephalostatin 1, isolated from a rare marine worm, Cephalodiscus gilchristi, has recently been reported, and scale-up... 

A bonanza of Heck reactions was used by Tietze25 in the synthesis of cephalostatin analogues. Corey-Fuchs reaction on the aldehyde 167 gives the alkene 168 from which the trans Br atom is stereoselectively removed by Pd-catalysed tin hydride reduction to give the Z-vinyl bromide 169. This reaction is discussed below under Stille coupling. 

Prominent amongst these marine discoveries are the bryostatins from the marine bryozoan Bugula neritincr, the dolastatins from the shell-less mollusc Dolabella auricularia the cephalostatins from the South African marine worm (a mere 5 mm long) Cephalodiscus gilchristi the sponge... 

Pettit et al. (24), working on the marine worm Cephalodiscus gilchristi (order Cephalodisicida, phyla Hemichordata, class Pterobranchia) collected from the Indian Ocean off Southeast Africa, have isolated a number of bioactive bis-steroidal pyrazine alkaloids, the cephalostatins 1-15 (11-25). 

With the complete X-ray structural assignment and completely interpreted NMR spectra of compound 11, it became easier to determine the structures of other members of this interesting series. Cephalostatin 2 (12), C54H74N2O11, [a]D 1110 (CH3OH), (M + H)+ m/z 927.5372, was crystallized from ethyl acetate-methanol. Compound 12 exhibited JH and 13C NMR spectra very similar to those of cephalostatin 1 (11). The structure was found to have one extra hydroxyl group at C-9. Cephalostatin 3 (13), CssHtsNzOh, [a]D 99° (CH3OH), (M + H)+, m/z 941.5546 was found to be a C-24 methyl derivative of cephalostatin 2 (12) as evidenced by a new 3H doublet in the H NMR spectrum of 13 (25). 

The right-side subunits of cephalostatins 5 and 6 (15 and 16) contain an aromatic ring C. Naturally occurring and synthetic steroids with ring A aromatized are well known, but steroids bearing an aromatic ring C are quite rare and examples of biosynthetic origin are essentially unknown (26). 

A sequence (using P-388 guided bioassay) of steric exclusion and partition-type chromatographic separations of the active butanolic fraction by reversed-phase semipreparative HPLC led to the isolation of cephalo-statin 12 (22), CaHyeNzOjz, [a]D 157° (CH3OH), (M + H)+ m/z 945.5444, and cephalostatin 13 (23), [a]D 108° (CH3OH), (M + H)+... 

Cephalostatin 14 (24), C54H72N2O12, [o ]d 80.9° (CH3OH), (M + Na)+ m/z 963.4983, was found to have an identical right-side subunit, as in cephalostatin 1 (11), as inferred from ID and 2D NMR data. Furthermore, it was found that the rings A, E, and F in the left-side subunit corresponded to those of cephalostatin 1 (11). However, two downfield olefinic signals and the upheld... 

---