Discodermolide total synthesis

Discodermolide Total Synthesis of Natural Product and Analogues... 

Smith IIIAB, Freeze BS. (+)-discodermolide total synthesis, construction of novel analogues, and biological evaluation. Tetrahedron 2008 64 261-298. 

The utility of RCM methodology for the synthesis of open-chain building blocks from a,fi-unsaturated d-lactones is exemplified by the partial syntheses of Cossy aimed for (+)-methynolide (the aglycon of the methymicin family of macrolide antibiotics) [45], and the anticancer agent discodermolide [46], as well as during a recent total synthesis of the highly cytotoxic marine natural depsipeptide apratoxin A by Forsyth and Chen [47]. 

Smith, A.B. Ill, Freeze, B.S., Xian, M., Hirose, T. (2005) Total Synthesis of (-l-)-Discodermolide A Highly Convergent Fourth-Generation Approach. Organic Letters, 7, 1825-1828. 

Paterson, I., Delgado, O., Florence, G.J., Lyothier, I., Scott, J.P., Sereinig, N. (2003) 1,6-Asymmetric Induction in Boron-Mediated Aldol Condensations Application to a Practical Total Synthesis of (-F)-Discodermolide. Organic Letters, 5, 35-38. 

Nerenberg, I.B., Hung, D.T., Somers, P.K., Scheiber, S.L. (1993) Total Synthesis ofthe Immunosuppressive Agent (—)-Discodermolide. Journal of the American Chemical Society, 115, 12621-12622. 

The second chapter focuses on the total synthesis of the marine sponge-derived polyketide discodermolide. A comprehensive survey of the synthetic chemistry efforts of several groups over a 14-year period is provided together with a comparison of the different approaches. 

Schreiber and co-workers reported the first total synthesis of (-)-discodermolide (ent-1) in 1993, confirming the relative stereochemistry and establishing the absolute configuration [43, 44], In 1996, they reported the first synthesis of the natural... 

In the total synthesis of a polyketide natural product, (+)-discodermolide (22), Paterson and co-workers synthesized the C9-C16 fragment 27 using a Johnson-Claisen rearrangement9 (Scheme 1.2i). Evans-Tishchenko reduction10 of... 

Paterson, 1., Florence, G. j.,The development of a practical total synthesis of discodermolide, a promising microtubule-stabilizing anticancer agent, Eur. J. Org. Chem. 2003, 2193-2208. 

Finally, Paterson and Schlapbach employed the Corey-Winter olefination to generate a trisubstituted olefin in their studies toward a total synthesis of discodermolide.19 In this example, diols 42 and 43 were treated with thiocarbonyldi-imidazole to give the corresponding thionocarbonates. Exposure of this mixture of thionocarbonates to phospholidine 21 at 50 °C generated olefin 44 in 81% yield. 

Clinical development is hampered due to the extremely scarce supply of discodermolide from the natural source. Thus, total synthesis provides the only viable route to useful quantities of this novel cytotoxic polyketide. Consequently, there have been considerable synthetic efforts toward the total synthesis of discodermolide [16], Up to date, five total synthesis of (+)- and/or (-)-discodermolide have been reported, one by Schreiber [3], one by Smith [17], one by Myles [18], one by Marshall [19] and one by Paterson [20]. All the syntheses are convergent. Schreiber and Myles employed an analogous connection by using a Nozaki-Kishi addition of a C8 acetylenic or (Z)-vinylic chromium to a C7 aldehyde for the major... 

ADVENTURES IN NATURAL PRODUCT SYNTHESIS FROM DEEP SEA SPONGE TO PILOT PLANT. THE LARGE SCALE TOTAL SYNTHESIS OF THE MARINE NATURAL PRODUCT (+)-DISCODERMOLIDE... 

Owing to its exceptional pharmacological potential and scarcity of natural material [0.002% (w/w) from frozen marine sponge], discodermolide have stimulated intensive synthetic efforts [188], The total synthesis of both the unnatural [189] and natural antipodes [190] [(-)- and (+)-104, respectively] by Schreiber and co-workers allowed to establish the correct absolute configuration. 

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