Gram-scale synthesis and shape evolution of micro-CaCO3.

ChemInform Abstract: Evolution of a Gram-Scale Synthesis of (+)-Discodermolide

References, x Gram-scale synthesis of (+)-discodermolide

An efficient gram-scale synthesis of the active enantiomer BMS-593214 was developed, which required significant optimization of the key Povarov annulation. Importantly, BMS-593214 showed antithrombotic efficacy in a rabbit arterial th...

Org Lett 1:1823–1826; (c) Smith III AB, Kaufman MD, Beauchamp TJ, LaMarche MJ, Arimoto H (2000) Gram-scale synthesis of (+)-discodermolide.

Evolution of a Gram-Scale Synthesis of (+)-Discodermolide ..

Jones, and Kaoru Kobayashi

Contribution from the Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Received May 2, 2000

Abstract:

An efficient, highly convergent, stereocontrolled total synthesis of the potent antimitotic agent (+)-discodermolide (1) has been achieved on gram scale.



Not surprisingly the remarkable biological activity and novel structure, in conjunction with the scarcity of the natural material, has led to considerable interest in discodermolide as a synthetic target.10 To date, six total syntheses of discodermolide, including our first-generation synthesis of the unnatural levorotatory congener, have been reported.2,11 In this, a full paper, we describe the evolution of a synthetic strategy which recently culminated in the preparation of 1 g of the natural congener.11b

Synthetic Plan.


, x Evolution of a gram-scale synthesis …

Org Process Res Dev 8:92–100; (b) Mickel SJ, Sedelmeier GH, Niederer D, Schuerch F, Grimler D, Koch G, Daeffler R, Osmani A, Hirni A, Schaer K, Gamboni R, Bach A, Chaudhary A, Chen A, Chen W, Chen B, Hu B, Jagoe CT, Kim H-Y, Kinder FR, Liu Y, Lu Y, McKenna J, Prasad M, Ramsey TM, Repic O, Rogers L, Shieh W-C, Wang R-M, Waykole L (2004) Large-scale synthesis of the anti-cancer marine natural product (+)-discodermolide.

our large scale synthesis of (+)-discodermolide ..

Org Process Res Dev 8:101–106; (c) Mickel SJ, Sedelmeier GH, Niederer D, Schuerch F, Koch G, Kuesters E, Daeffler R, Osmani A, Seeger-Weibel M, Schmid E, Hirni A, Schaer K, Gamboni R, Bach A, Chen S, Chen W, Geng P, Jagoe CT, Kinder FR, Lee GT, McKenna J, Ramsey TM, Repic O, Rogers L, Shieh W-C, Wang R-M, Waykole L (2004) Large-scale synthesis of the anti-cancer marine natural product (+)-discodermolide.

, K KobayashiEvolution of a gram-scale synthesis …

J Am Chem Soc 122:8654–8664; (e) Smith III AB, Freeze BS, Brouard I, Hirose T (2003) A practical improvement, enhancing the large-scale synthesis of (+)-discodermolide: a third generation approach.

Gram-scale synthesis of (+)-discodermolide.

Org Lett 2:1983; (d) Smith III AB, Beauchamp TJ, LaMarche MJ, Kaufman MD, Qiu YP, Arimoto H, Jones DR, Kobayashi K (2000) Evolution of the gram-scale synthesis of discodermolide.

Gram-scale synthesis of (+)-discodermolide

Importantly, the synthesis is highly efficient, proceeding in 6% overall yield (longest linear sequence, 24 steps), stereocontrolled, and amenable to gram-scale production of this potentially important natural product.

Gram Scale Synthesis of (+)-discodermolide.

(+)-Discodermolide, a polyhydroxylated lactone isolated from the marine sponge Discodermia dissoluta, is a promising antitumor agent that continues to be the subject of intensive chemical, biological, and pharmaceutical research since its discovery two decades ago. Although structurally distinct from taxol, discodermolide shares a common mechanism of action as a potent tubulin polymerizer, resulting in blockage of cells in the G2/M phase of the cell cycle, aberrant microtubule function, and cell death. Following its licensing from Harbor Branch Oceanographic Institution in 1998 by Novartis AG as an antitumor agent, discodermolide was afforded an unprecedented priority status for synthesis on an industrial scale, borrowing and modifying in some cases, academic synthetic schemes to produce quantities sufficient for clinical trial. From a co-discoverer’s viewpoint, the story of discodermolide will be described here, starting with its discovery, its progression through preclinical evaluation, highlights from the synthetic contributions of academia and industry, a brief SAR walk around the molecule, the results of the first clinical trial and the more recent journey from the actual compound, through its various analogs and finally to its evolution to some exciting novel “hybrid” molecules.