Dysidiolide, synthesis

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. 

Scheme 70 Traceless removal of polymer 364 by RCM in the synthesis of 6-epi-dysidiolide (363) [153]...

In a total synthesis of cdc25A protein phosphatase inhibitor dysidiolide (46) [37], substitution on an sp carbon center by vinyl cuprate was used to accom-... 

Corey, E.J. Roberts, B.E. (1997B) Total synthesis of dysidiolide. J. Am. Chem. Soc., 119, 12425-31. Corey, E.J. Lazerwith, S.E. (1998) A direct and efficient streocontrolled synthetic route to the pseudopterosins, potent marine anti-inflammatojy agents. J. Am. Chem. Soc., 120, 12777-82. 

Takahashi, M. Dodo, K. Hashimoto, Y. Shirai, R. (2000) Concise asymmetric synthesis of dysidiolide. Tetrahedron. Lett., 41, 2111-4. 

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... 

The above-described problem demonstrates the first enantioselective synthesis of dysidiolide, a C25 isoprenoid antimitotic agent. The central transformations are the sulfenylation-dehydrosulfenylation sequence to prepare an a,/5-tnone, the biomimetic cationic 1,2-rearrangement to form stereoselectively the bicyclic scaffold, vinyl cuprate displacement of an iodide furnishing the C-l side chain and the photochemical oxidation of furan to generate the j hydroxy-butenolide functionality. 

As a representative example, the rather complex natural-product dysidiolide was synthesized by methods amenable to combinatorial synthesis (30). Using a cycloaddition-based approach to the dysidiolide core, a solid-phase synthesis of epi-dysidiolide (Fig. 4) and analogs thereof was developed. 

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. 

Waldmann et al. have synthesised a library of analogues of the anti-tumor active phosphatase inhibitor dysidiolide (16) [18]. A notable feature of this 11-step reaction sequence on solid-phase is that a wide range of transformations with vastly differing requirements could successfully be developed. Key transformations of the synthesis include an asymmetric... 

Scheme 4. Synthesis of a library of analogs of 6-epi-dysidiolide by Waldmann et al.

Corey and Roberts reported a total synthesis of the dysidiolide 46, a marine sponge metabolite with biological activities against A-549 human lung carcinoma and P388 murine leukemia cancer cell lines20 (Scheme 4.3p). The unwanted alcohol (47) was converted to the ketone 48 via Dess-Martin periodinane oxidation. The asymmetric reduction of 48 with the CBS catalyst 28b efficiently gave the alcohol 49, which was transformed into the dysidiolide 46 via photochemical oxidation. 

Scheme 14.3 Solid-phase synthesis of 6-ep/-dysidiolide. Dysidiolide is a naturally occurring inhibitor of Cdc25A.

Scheme 14.4 Dysidiolide analogs obtained by solid-phase synthesis. The IC50 values shown refer to inhibition of Cdc25C.

E.J. Corey and co-workers synthesized the cdc25A protein phosphatase inhibitor dysidiolide enantioselectively. In the last phase of the total synthesis, the secondary alcohol functionality of the side-chain was established with a highly diastereoselective oxazaborolidine-catalyzed reduction using borane-dimethylsulfide complex in the presence of the (S)-6-methyl CBS catalyst. Finally, a photochemical oxidation generated the y-hydroxybutenolide functionality. This total synthesis confirmed the absolute stereochemistry of dysidiolide. 

Dysidiolide is the first compound found to be a natural inhibitor of protein phosphatase cdc25A that is essential for cell proliferation. Y. Yamada et al. develcyed a novel total synthesis of this natural product using an intramolecular Diels-Alder cycloaddition as the key step. Deoxygenation of the advanced bicyclic intermediate at the C24 position was achieved under Woiff-Kishner reduction conditions to afford the C24 methyl group. 

Danishefsky and coworkers used a dioxolenium mediated Diels-Alder reaction between 83 and 85, generated from 84, in their total synthesis of dysidiolide (87) (equation 26). The Diels-Alder reaction, using trimethylsilyl triflate as the dioxolenium generating species, proceeded with high facial, endo and regioselectivity affording 86 as the main product, together with 5% of a yet unidentilied stereoisomer. 

An impressive example using this strategy is the recently published synthesis of analogues of dysidiolide [137], After a rriullislep synthesis pathway involving a diverse set of demanding chemical transformations, the desired compounds were obtained after a traceless release by metathesis using 101, as illustrated for one specific example in Scheme 54. 

Scheme 6.260 shows an example of the application of photooxygenation in the total synthesis of dysidiolide (539), a cdc25A protein phosphatase inhibitor, involving regioselective oxidation of the furan moiety of 540 in nearly quantitative chemical yield in the last step of the synthetic procedure.1447... 

Classic Wacker-Tsuji oxidation was used in the total synthesis of copalol (80— 81)63 and a formal total synthesis of dysidiolide (82— 83).64... 

There are many synthetic applications that involve enolate alkylation. In the Yamada and co-workers synthesis of dysidiolide, cyclohexenone 66 was treated with LDA to generate the enolate anion.Addition of TBDMS protected 3-iodo-l-propanol gave the alkylated product 67 in 76% yield. Notice that HMPA... 

The diene and/or the alkene components can be part of a very complex structure. An example is the reaction of ( )-butenal with 71 to give an 83% yield of 72 in Shirai s synthesis of dysidiolide. Note the regioselectivity and stereoselectivity of the reaction. Note also that it is catalyzed by a Lewis acid which, as mentioned, will be discussed in Section 11.6.A. 

The 1,5-diketone 21 is prepared by 3-butenylation of ketones to give 20 via Pd-catalyzed hydrogenolysis of the allylic acetate 19, followed by Pd-catalyzed oxidation, and is used for annulation to form the cyclohexenone 22 [19]. In this method, the 3-butenyl group is a masked methyl vinyl ketone. Preparation of the 1,7-diketone 24 was performed by oxidation of 23, and applied to the synthesis of dysidiolide (25) [23]. 

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