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.
In a screening of ligands, ionic liquids and reaction conditions in the Rh-catalyzed hydrogenation of enamides, a novel multi-phase reaction system consisting of an ionic liquid (IL) and water (wet ILs) was found to give the most promising results. In many cases such IL/water combinations were superior compared to conventional organic solvents and biphasic ILs/organic co-solvents media with respect to catalytic performance as well as to catalyst separation and recycling. So far, the best results were obtained with Rh-ferrocenyl-diphosphine catalysts ( > 99% ee).Generally, somewhat lower ees were observed at higher pressure. However, this effect was less pronounced with wet ILs than with conventional solvents. It is shown that IL/water combination allow repeated catalyst recycling without significant loss of activity and that industrially relevant turnover numbers of > 10,000 can be obtained.
Smith's procedure of preparing fragment C15
-
21 (5) from
common precursor 3 was optimized. The ease of plant operations made this six-step route successful for the production of
several kilograms of this fragment with high purity.
Artemisinin and its derivatives, such as artemether, are highly
sensitive compounds, which require careful optimized production processes for their manufacture. Due to robustness issues,
the manufacturing procedure of the reduction of artemisinin
with potassium borohydride to dihydroartemisinin was reinvestigated. The most important factor for obtaining optimal
yields is to ensure low levels of contamination of potassium
hydroxide in potassium borohydride. Application of a lower
reaction temperature, fast addition rate of potassium borohydride, and careful control of the pH during the quench with
acid are further important parameters in guaranteeing a robust
process. In the redesign of the conversion of dihydroartemisinin
to artemether, the yield was increased, and dichloromethane
was replaced by the ecologically friendlier methyl acetate. A
robust manufacturing process for artemether is now at hand,
allowing the production of this important medicine reliably and
in good quality and yield.
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