Synthesis eleutherobin

Eleutherobin Synthesis, Structure/Activity Relationship, and Pharmacophore... 

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. 

Scalabrino, G., Sun, X.W., Mann, J., and Baron, A. (2003) A convergent approach to the marine natural product eleutherobin synthesis of key intermediates and attempts to produce the basic skeleton. Org. 

For a tandem Diels-Alder/fragmentation approach to the eleutherobin aglycone, Winkler et al. used Marshall s protocol in an early step of the synthesis. The building block 95 was prepared in that way (Scheme 15.24) [56]. 

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. 

Scheme 2. Complete total synthesis of eleutherobin (1) by Nicolaou et al.

During a synthesis of Eleutherobin, Danishefsky and co-workers15 achieved the silylation of a hindered tertiary alcohol using TMSOTf and 2.6-lutidine at -78 °C [Scheme 4.12]. 

The similarity in the mechanisms of action of paclitaxel (Section 1.1), the epothilones (Section 1.3), discodermolide and eleutherobin (section 1.2) has led to proposals that these structurally dissimilar substances possess common pharmacophores which could lead to the design and synthesis of analogs having substantially different structures and superior activities. 

Nicolaou s total synthesis of a marine antitumor agent, eleutherobin [22] (Scheme 12.24), involves the attachment of D-arabinose to the aglycon intermediate. Thus, the glycosidation of the (-F )-carvone-derived hydroxy aldehyde 210 and the trichloroacetimidate 211, derived from... 

In the laboratory of J.D. Winkler, the synthesis of the carbon framework of the eleutherobin aglycon was developed using a tandem Diels-Alder reaction and a Grob fragmentation as key steps.The tricyclic fragmentation precursor was subjected to potassium carbonate in DMF at 75 °C to afford the fragmentation product in 68% yield via a dianion intermediate that underwent a spontaneous hemiketalization. 

In a similar vein, in a bold application of Stille chemistry, Danishefsky completed the synthesis of eleutherobin by the remarkable coupling of triflate 125 with (trimethylstannylmethyl)arabinose donor... 

Scheme 5.4.25 Synthesis of eleutherobin by alkyl-alkenyl coupling...

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