Large-Scale Synthesis of the Anti-Cancer Marine Natural Product (+)-Discodermolide. Part 5:  Linkage of Fragments C_1-6 and C_7-24 and Finale

Abstract

The finale of the large-scale preparation of 60 g of the highly complex marine natural product, (+)-discodermolide (1), using a hybridized Novartis-Smith-Paterson synthetic route is presented. This contribution, which is the concluding part of a five-part series, highlights a reagent-controlled stereoselective boron enolate aldol reaction between 2 and 3 forming the C7 hydroxyl-bearing stereocenter, selective reduction of 4a to generate the 1,3-anti-diol 5, and a global deprotection and concomitant lactonization leading to (+)-discodermolide (1). A novel procedure for converting the minor epimeric aldol adduct 4b into discodermolide using a five-step sequence is also described. This large-scale synthesis of discodermolide involved 39 steps (26 steps in the longest linear sequence) and several chromatographic purifications and delivered sufficient material for early-stage human clinical trials. IntroductionAfter 36 chemical steps and a gallant effort by many dedicated scientists, we now describe the finale that resulted in the delivery of 60 g of (+)-discodermolide (1), attesting to the power of contemporary organic synthesis in making available sufficient quantities of a highly complex organic molecule, sourced from nature in submilligram quantities, for a thorough evaluation of its therapeutic potential.

A Green Chemistry Approach to Asymmetric Catalysis: Solvent-Free and Highly Concentrated Reactions

“…122 Employing tridentate complexes A•Cl and A•SbF 6 in the HDA with (2Z,4E)-triethylsilyloxy-2,4-hexadiene and two aldehydes (R 1 = Ph, CH 2 OTBS) generated tetrahydropyranones after desilylation ( Figure 21). While the ee's were moderate (80 and 57% ee, respectively) only the endo product was formed, leading to the all-cis stereochemistry of the tetrahydropyranone product (Table 22, entries 1 and 2).…”

“…Given the successful HDA reactions between (2Z,4E)-triethylsilyloxy-2,4-hexadiene and various aldehydes catalyzed by C•SbF 6 (Table 22), the authors examined the ability of C•C1 to promote HDA reactions with other dienes. As shown in Table 23, reaction of (2E)-2-triethylsilyloxy-l,3-pentadiene resulted in formation of the product in 78% yield with 98% ee (entry 1).…”

Trends in Preparative HPLC

“…After the injection is finished, the solutes are eluted with the mobile phase that has a better solubility. An example of this approach has recently been published for the purification of discodermolide [34] ( Figure 21-4). A 38-g sample of crude product (82.4%) was dissolved in 11.2 L of 2-propanol and diluted with 78.4 L of water.…”

Conception, Synthesis, and Biological Evaluation of Original Discodermolide Analogues

“…All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM. Keywords: anticancer agents · cross-coupling · discodermolide · nickel · polyketides ed toward the total synthesis of (+)-DDM [8,9,10] and toward the production of synthetic analogues. [10,11] These studies have helped to define critical requirements for activity.…”