Synthesis of sarcodictyin

The addition of LiCl and Cul, and triphenylarsine as ligand are required to suppress side-reactions in the carbonylative cross-coupling of geminally substituted alkenyl triflate in the synthesis of sarcodictyin. Stereochemical configuration of the double bond of organotin compound was completely lost in this reaction (Equation (5)). " ... 

Gennari and his group reported a more sophisticated palladium-catalyzed carbonylative coupling of vinyl stannanes with electron-poor enol triflates [61]. The effect of ligands and additives was tested, and a combination of Pd2dba3, AsPh3, LiCl, Cul and NMP proved to be the optimal system. Later, this methodology was applied to the total synthesis of sarcodictyins [62]. 

A total synthesis of sarcodictyins was reported by Cennari and colleagues... 

Some research groups have derivatized biological active and very important natural products (Scheme 3.30) like Indolactam V (207) [297], Sarcodictyin (208) [298] Taxol (209) [299] and Vancomycin (210) [123]. For example, the soHd-phase synthesis of Indolactam derivatives (213) with three points of diversity has been reported by Waldmann et al. in 1999 (Scheme 3.31) [297]. 

The 4,7-oxaeunicellane skeleton of the eleutherobins is also found in the eleuthosides (2, 3), the sarcodictyins (4), and the valdivones (5) (Figure 1) [4-6]. While the arabinosyl residue is not required for an antitumor effect, the methylurocanic acid ester side chain bound to C8 is part of the pharmacophore. Recent progress in the total synthesis of eleutherobin is discussed together with the identification of a common pharmacophore for tubulin-binding natural products, and a combinatorial way to determine the structure/activity relationship and drug optimization. 

During a synthesis of the marine antitumour agent Sarcodictyin A, selective removal of a secondary and a tertiary TES ether in the presence of a primary TIPS ether was effected by treatment with 5 equivalents of triethylamine trihy-drofluoride (Et3N 3HF)26 in THF at room temperature [Scheme 4,21 ].6... 

The total synthesis of the marine-derived diterpenoid sarcodictyin A was accomplished in the laboratory of K.C. Nicolaou. The most challenging part of the synthesis was the construction of the tricyclic core, which contains a 10-membered ring. This macrocycle was obtained by the intramolecular 1,2-addition of an acetylide anion to an a, 3-unsaturated aldehyde. This unsaturated aldehyde moiety was installed by utilizing the Knoevenagel condensation catalyzed by (3-alanine. The Knoevenagel product was exclusively the ( )-cyanoester. 

FIGURE 11.48 Solid- and solution-phase sarcodictyin libraries, and SAR of sarcodictyin A. (From Nicolaou, K.C. et al., Solid and solution phase synthesis and biological evaluation of combinatorial sarcodictyin libraries,... 

Jagtap, P.G. et al.. Design and synthesis of a combinatorial chemistry library of 7-acyl, 10-acyl, and 7,10-diacyl analogs of pacUtaxel (taxol) using solid phase synthesis, J. Nat. Prod., 65, 1136, 2002. D Ambrosio, M., Guerriero, A., and Pietra, R, Sarcodictyin A and sarcodictyin B, novel diterpenoidie alcohols esterified by ( l-Alll-methylurocanic acid isolation from the Mediterranean stolonifer... 

Nicolaou, K.C. et al.. Synthesis of the tricyclic core of eleutherobin and sarcodictyins and total... 

The synthesis of eleutherobin, which has antitumor activity and cytotoxic properties similar to those of taxol, has also been reported (Scheme 41) [181, 182], The carvone-derived acceptor was stereoselectively glycosylated with the arabinosyl trichloroacetimidate (a P = 8 1). The resulting glycoside intermediate was treated as for sarcodictyins A and B to yield eleutherobin and eleuthosides A and B. 

Ceccarelli, S Piarulli, U and Gennari, C. (1999) Synthetic studies on sarcodictyins and eleutherobin synthesis of fiiHy fimctionaIi2ed cyclization precursors. Tetrahedron Lett., 40,153-156. 

Telser, J., Beumer, R., Bell, A.A.. CeccareUi, S.M., Monti, D., and Gennari, C. (2001) Synthesis of a simplified sarcodictyin analogue which retains microtubule stabilising properties. Tetrahedron Lett., 42, 9187-9190. 

Fig. 4. Attachment of the pharmacophoric side chains to the sarcodictyin core structure by combinatorial synthesis.

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