Dysidiolide derivatives

An illustrative example of an alternative strategy (cf Fig. 11c) involving the use of a novel traceless linker is found in the multistep synthesis of 6-epi-dysidiolide (363) and several dysidiolide-derived phosphatase inhibitors by Waldmann and coworkers [153], outlined in Scheme 70. During the synthesis, the growing skeleton of 363 remained attached to a robust dienic linker. After completion of intermediate 362, the terminal olefin in 363 was liberated from the solid support by the final metathesis process with concomitant formation of a polymer-bound cyclopentene 364. Notably, during the synthesis it turned out that polymer-bound intermediate 365a, in contrast to soluble benzoate 365b, produced diene 367 only in low yield. After introduction of an additional linker (cf intermediate 366), diene 367 was released in distinctly improved yield by RCM. 

An illustrative example for the alternative strategy, (cf Figure 7c) by the use of a traceless linker, is found in the multi-step synthesis of 6- f-dysidiolide 434 and several dysidiolide-derived phosphatase inhibitors by Waldmann and co-workers outlined in Scheme 83. During the synthesis, the growing skeleton of 434 remained attached... 

Brohm, D., Metzger, S., Bhargava, A., Muller, O., Lieb, F., and Waldmann, H. (2002) Natural products are biologically validated starting points in structural space for compound library development solid phase synthesis of dysidiolide-derived phosphatase inhibitors. Angew. Chem. Int. Ed. 41, 307-311. 

Fast binary filtering methods can also be used for scaffold ranking, i.e., the prioritization of combinatorial scaffolds based on predicted properties. Privileged scaffolds were selected to demonstrate this idea [82], Piperazines SI, benzodiazepines S2, and spiroindolines S3 have been described as GPCR-privileged scaffolds [83], Scaffold S4 represents a SPIKET motif for tubulin binding which is effective for inhibiting cellular proliferation [84], Dysidiolide-derived compounds... 

Brohm D, Phihppe N, Metzger S, Bhargava A, Muller O, Lieb F, Waldmann H. Sohd-phase synthesis of dysidiolide-derived protein phosphatase inhibitors. J. Am. Chem. Soc. 2002 124 13171 13178. 

Dysidiolide is a terpene of current interest in medicinal chemistry. Its structure invites creative approaches. The first synthesis by the Corey group [21] (Scheme 11.16) starts from a readily available chiral building block with one stereogenic center. The striking fact is that this stereogenic center appears nowhere in the target structure. It serves as an auxiliary to derive the other stereogenic centers and ultimately it had to be removed in an impressive way. 

The first of these examples was reported (Scheme 136) by the group of E. J. Corey (566). In 1997, this group published the total synthesis of the neo-isolabdanoid sesterterpene dysidiolide (655) from the Caribbean spraige Dysidea etheria (568). Dysidiolide was found to be the first naturally derived inhibitor of... 

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