Totalsynthese von (—)‐Epothilon A

Balog, Aaron; Meng, Dongfang; Kamenecka, Ted; Bertinato, Peter; Su, Dai‐Shi; Sorensen, Erik J.; Danishefsky, Samuel J.

doi:10.1002/ange.19961082318

Cited by 94 publications

(53 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Esterification of 5 with 3 to form 1 followed by cyclization via a rutheniumcatalyzed olefin metathesis reaction and subsequent deprotection provided epothilone C, which has been reported to undergo epoxidation to afford epothilone A (16). These internal efforts showed the technical feasibility of driving structure-activity studies of epothilones using total synthesis as was shown previously by successful total synthesis publications from several laboratories (14,16,18).…”

Section: Focusturns To Epothilonessupporting

confidence: 54%

Discovery of Ixabepilone

Hunt

2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

The discovery of the antineoplastic agent paclitaxel and its unique activity as a microtubule-stabilizing agent resulted in dramatic improvements in the treatment of breast, ovarian, and non-small cell lung cancers. Despite the potent antitumor activity of taxanes such as paclitaxel, efficacy of these agents has been limited by development of taxane-resistant tumors in patients. This review describes, with some historical context, our successful efforts to discover a next-generation microtubule-stabilizing agent for the treatment of cancer. In collaboration with the Gesellschaft für Biotechnologische Forschung, we evaluated the epothilones, originally isolated from the myxobacterium Sorangium cellulosum, as potential anticancer agents. Experiments performed at Bristol-Myers Squibb confirmed the ability of these agents to induce tubulin polymerization, cell cycle arrest, and apoptosis. Epothilones A and B showed potent cytotoxic activity toward paclitaxel-sensitive and paclitaxel-resistant cells expressing P-glycoprotein or mutant tubulin. Because the parent epothilones were subject to inactivation via esterase cleavage, we used semisynthetic approaches to prepare analogues without this liability. BMS-247550 (ixabepilone), the lactam analogue of epothilone B, showed increased metabolic stability, potent tubulin polymerization activity, and retained activity against paclitaxel-resistant lines. Based on its shown efficacy in clinical trials, ixabepilone was approved by the Food and Drug Administration in 2007 for treatment of drug-resistant/refractory metastatic or locally advanced breast cancer. [Mol Cancer Ther 2009;8(2):275 -81]

show abstract

Section: Focusturns To Epothilonessupporting

confidence: 54%

Discovery of Ixabepilone

Hunt

2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…The crude product was purified by flash chromatography (pentane/Et 2 O 4:1) to yield oxazolidinone 14 (969 mg, 65 % over two steps) as a colorless oil. [a] 20 D À 31.5 (c 1.68, CHCl 3 ); IR (film): n Ä max 2934,1779,1699,1457,1357,1278,1209,1160,100,914,734 4,152.6,138.4,137.0,129.1,128.6,126.8,114.7,82.1,63.5,35.5,35.4,33.4,28.5,28.3,23.8,22.3;MS (PCI,CH 4 ): m/z (%): 316.1 (100) [MH] , 300.1 (7), 272.1 (19) 2976, 2935, 1774, 1698, 1457, 1353, 1277, 1242, 1099, 991, 915, 734, 3,152.3,138.4,136.9,129.1,128.6,126.8,114.7,81.9,63.6,37.6,35.5,33.7,33.0,28.4,26.5,22.2,17.4;MS (PCI,CH 4 (S)-2-Methyl-6-heptenal (3): Dess ± Martin periodinane [15] (1.27 g, 2.99 mmol, 1.3 equiv) ...…”

Section: Methodsmentioning

confidence: 99%

“…The mixture was stirred for 90 min. The reaction was quenched with saturated aqueous NH 4 Cl solution (30 mL). The organic layer was separated and the aqueous layer was extracted with CH 2 Cl 2 (3 Â 50 mL).…”

Section: Methodsmentioning

confidence: 99%

“…Owing to the impressive biological profile of those compounds, several groups engaged in synthetic-organic and natural product chemistry focused their efforts on developing strategies for the total synthesis of epothilones and their synthetic analogues. Several total syntheses of epothilone A [4] and epothilone B [5] as well as various partial syntheses have already been achieved. [6] In this paper, we report on the details of an improved total synthesis of (À)-epothilone A based on our previously communicated olefin metathesis approach, [6a] with a metathesis reaction as the ring-closing step.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Total Synthesis of (−)-Epothilone A

et al. 1999

View full text Add to dashboard Cite

The total synthesis of (À)-epothilone A by a convergent route is reported. The synthesis of the required key intermediates has been improved with respect to stereoselectivity and availability. The access to ethyl ketone 2 has been significantly improved by employment of chiral acetate equivalents, which provided higher optical and chemical yields. Key intermediate 3 was obtained by oxazolidinone auxiliary techniques and stereoselectively coupled with 2 by an aldol reaction. After esterification with thiazole fragment 4, (À)-epothilone A was finally constructed by using ring-closing metathesis.

show abstract

“…This effort has yielded several notable developments, as so often happens during the course of natural product synthesis; a classical example of this would be in the total synthesis of the eponymous epothilones of the title, by this same group (15). One of these contributions, used in the current study by Brailsford and Danishefsky (2), was that of the latent thioester, whereby unmasking of an ortho-thiophenolic ester derivative rearranges to produce the thioester that is a required component of NCL.…”

mentioning

confidence: 99%