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.

The synthetic strategy for producing multigram quantities of (+)-discodermolide (1) using a hybridized Novartis−Smith−Paterson synthetic route via common precursor 3 is described. In the first part of this five-part series, we present a multikilogram preparation of α-methyl aldehyde 10 from Roche ester, its syn-aldol reaction with Evans boron enolate, removal of the chiral auxiliary, and the preparation of Weinreb amide 3 (Smith common precursor). The common precursor was produced without any chromatography.

Coupling of C9 - 14 (4) and C15 - 21 (5a) fragments to produce the cis-trisubstituted olefin was achieved using Suzuki-type coupling conditions employed by Marshall (5a/tert-BuLi/B-OMe-9-BBN added to 4/Cs2CO3/Pd(dppf)2). The terminal (Z)-diene moiety was attached to aldehyde 10 by using a sequential Nozaki−Hiyama allylation and Peterson olefination sequence; careful monitoring of the disappearance of both diastereomeric β-hydroxysilanes was found to be essential for achieving a high yield. In the oxidation of alcohols 12 and 16 to 13 and 7, respectively, using iodobenzene diacetate and TEMPO, addition of a trace of water was found to be crucial for complete conversion. The C8 - 9 (Z)-olefin functionality was introduced on to aldehyde 13 using a Still−Gennari HWE reaction. Subsequent carbamate installation at C-19 followed by a reduction/oxidation sequence gave the title fragment C7 - 24 (7) ready to be coupled with the C1 - 6 fragment, which is described in Part 2 of this series.

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.

A series of seven synthetic discodermolide analogues 2-8, which are minor side products generated during the final stages in the synthesis of (+)-discodermolide (1), have been purified and evaluated for in vitro cytotoxicity against A549, P388, MFC-7, NCI/ADR, PANC-1, and VERO cell lines. These synthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 hydroxy through C-17 hydroxy molecular fragment for potency. Specifically, these analogues suggested the relevance of the C-11 hydroxyl group, the C-13 double bond, and the C-16 (S) stereochemistry for the potency of (+)-discodermolide. The preparation, purification, structure elucidation, and biological activity of these new analogues are described.

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. -(MICKEL*, S. J.; NIEDERER, D.; DAEFFLER, R.; OSMANI, A.; KUESTERS, E.; SCHMID, E.; SCHAER, K.; GAMBONI, R.; Org. Process Res. Dev. 8 (2004) 1, 122-130; Chem. Anal. Dev., Pharma Novartis AG, CH-4002 Basel, Switz.; Eng.) -R. Staver 24-191

Kilogram-scale syntheses of fragments C1 - 6 (6) and C9 - 14 (4) of (+)-discodermolide from common precursor 3 are described. Improved procedures for each step of both fragments were developed by minimizing or eliminating the formation of byproducts that were isolated and characterized in Smith's synthesis.

This note discusses an optimisation study of a key reagent-controlled enantioselective boron enolate aldol reaction forming the C6−C7 bond and the C7 hydroxyl-bearing stereocenter in (+)-discodermolide. Conditions were found which increased the yield, decreased the excess of enolate necessary, and increased product stability with respect to the published procedure.