Discodermolide Paterson total synthesis

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. 

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... 

To date, three syntheses of (-)-discodermolide [189,191] and two of the natural antipode [190,192] have been described. In this review we will report only the syntheses of the natural product (+)-discodermolide (104). Very recently an alternative total synthesis of the natural (+)-discodermolide has been reported by Paterson [193],... 

In the effort of total synthesis of discodemolide, the Still-Gennari type HWE reaction was also used by Paterson and Lyothier to form the Cg-C9 olefin. Phosphonate 94 was treated with NaH in THE at 0 °C for 30 min prior to the addition of aldehyde 93. The crude product showed a mixture of (Z)- and ( )-olefins, 95 and 96, in a 5 1 ratio. The desired (Z)-isomer 96 could be isolated by flash chromatography in 73% yield. The (Z)-enone 96 was further treated with K-Selectride at 25 C for 24 h. A single diastereomeric alcohol 97 was formed selectively and isolated in 59% yield. This alcohol processing (7/ )-configuration was leading to 1-epi-discodermolide 98 as final product by four additional reactions. 

Paterson I, Florence GJ, Gerlach K, Scott J. Total synthesis of the antimicrotubule agent (+)-Discodermolide using boron-mediated aldol reactions of chiral ketones. Angew. Chem. Int. Ed. 2000 39 377-380. 

Paterson, I. and Wren, S.P. (1993) Studies towards the total synthesis of the marine-derived immunosuppressant discodermolide asymmetric synthesis of a C1-C8 6-lactone subunit. J. Chem. Soc. Chem. Commun., 1790-1792. 

Paterson, I. and Lyothier, I. (2005) Development of a third-generation total synthesis of (+)-discodermolide an expedient Still-Gennari-type fragment coupling utilizing an advanced 3-ketophosphonate. J. Org. Chem., 70, 5494-5507. 

In 2003, Paterson and co-workers reported a second-generation strategy for the synthesis of discodermolide, which aimed to eliminate the use of all chiral reagents and auxiliaries, and reduce the total number of synthetic steps (Scheme 24) [58, 59], These specific aims were achieved by employing an unprecedented aldol coupling at C5-C6 between C1-C5 aldehyde 118 and the advanced C6-C24 methyl ketone 119 and utilising diol 120 as a common precursor for the synthesis of the three subunits 118, 121 (C9-C16) and 98 (C17-C24). 

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