Discodermolide (original) (raw)
Related papers
Conception, Synthesis, and Biological Evaluation of Original Discodermolide Analogues
Chemistry - A European Journal, 2011
Due to its intriguing biological activity profile and potential chemotherapeutic application discodermolide (DDM) proved to be an attractive target. Therefore, notable efforts have been carried out directed toward its total synthesis as well as toward the production and evaluation of synthetic analogues. Recently, we achieved the total synthesis of DDM. At the present, guided by the knowledge gained during our DDM total synthesis and by the requirement of keeping the bioactive "U" shape conformation, we report the convergent preparation of five original analogues. Three types of changes were realized through modification of the terminal (Z)-diene moiety, of the methyl group in the C14 position, and the lactone region. All analogues were active in the nanomolar range and two of them turned out to be equipotent to DDM.
Total Synthesis of Discodermolide: Optimization of the Effective Synthetic Route
Chemistry - A European Journal, 2008
Elsa de Lemos, [a] François-Hugues Porée, [a] Arnaud Bourin, [a] Julien Barbion, [a] Evangelos Agouridas, [a] Marie-Isabelle Lannou, [a] Alain Commerçon, [b] Jean-François Betzer,* [a] Ange Pancrazi,* [a] Janick Ardisson* [a]
α-Oxygenated Crotyltitanium and Dyotropic Rearrangement in the Total Synthesis of Discodermolide
Angewandte Chemie International Edition, 2007
Discodermolide is a polyketide natural product that was first isolated in 1990 from extracts of the rare Caribbean marine sponge Discodermia dissoluta by Gunasekera et al. [1] This compound has been shown to inhibit the proliferation of cells by arresting the G 2 /M phase of the cell cycle. [2] Discodermolide belongs to the class of antimitotic agents known to act by microtubule stabilization, whose members used clinically include taxol and taxotere. This product is more potent in stabilizing microtubules, more water-soluble than taxoid compounds, and exhibits synergy with taxol. [3] The marine sponge cannot provide the quantities of discodermolide needed for drug development. Therefore, efficient and highly convergent syntheses are needed, and studies in the area are increasing. [4] Herein, we report a new total synthesis of discodermolide that relies on three particular points: elaboration of syn-anti stereotriads linked to a Z-O-enecarbamate group, direct transformation of this core into the terminal Z diene, and stereocontrolled generation of the trisubstituted Z double bond by dyotropic rearrangement. Our convergent synthetic strategy, which is outlined in Scheme 1, relies on the preparation of the three subunits C1-C7 (2), C8-C14 (3), and C15-C24 (4). [4h] Each subunit, or its precursors, possesses a syn-anti methyl-hydroxy-methyl triad (in C2-C4, C12-C10, and C18-C20, respectively, for fragments 2, 3, and 4) with adjacent unsaturation (Scheme 2). Therefore, we developed a convenient and scalable elaboration of this core motif. A crotyltitanation reaction, developed by Hoppe [5] and widely used in total synthesis by us, [6] was selected. The enantioenriched (R)-a-(N,N-diisopropylcarbamoyloxy)crotyltitanium (5) was readily prepared in situ from crotyl diisopropylcarbamate, an equimolar mixture of nBuLi/ (À)-sparteine, and tetra(isopropoxy)titanium. [7] Matched reactions between a-(S)-methyl aldehydes 6 a-c and R-Scheme 1. Retrosynthetic analysis of discodermolide (1). Scheme 2. Preparation of the syn-anti methyl-hydroxy-methyl triad cores and subsequent use of the Z-O-enecarbamate function.
Towards the synthesis of (+)-discodermolide
Tetrahedron Letters, 2001
An approach to the asymmetric synthesis of fragments corresponding to C1 C7 and C15 C24 of (+)-discodermolide is reported. Key elements of the successful strategy include elaboration of two advanced fragments from a common precursor. : S 0 0 4 0 -4 0 3 9 ( 0 1 ) 0 0 7 9 9 -7
The Journal of Organic Chemistry, 2005
A novel total synthesis of the complex polyketide (+)-discodermolide, a promising anticancer agent of sponge origin, has been completed in 7.8% overall yield over 24 linear steps, with 35 steps altogether. This second-generation approach was designed to rely solely on substrate control for introduction of the required stereochemistry, eliminating the use of all chiral reagents or auxiliaries. The common 1,2-anti-2,3-syn stereotriad found in each of three subunits, aldehyde 9 (C 1-C 5), ester 40 (C 9-C 16), and aldehyde 13 (C 17-C 24), was established via a boron-mediated aldol reaction of ethyl ketone 15 and formaldehyde, followed by hydroxyl-directed reduction to give 1,3-diol 14. Alternatively, a surrogate aldehyde 22 was employed for formaldehyde in this aldol reaction, leading to the-hydroxy aldehyde 20 as a common building block, corresponding to the discodermolide stereotriad. Key fragment unions were achieved by a lithium-mediated anti aldol reaction of ester 40 and aldehyde 13 under Felkin-Anh control to provide (16S,17S)-adduct 51 and a boron-mediated aldol reaction between enone 10 and aldehyde 9, exploiting unprecedented remote 1,6-stereoinduction, to give the (5S)-adduct 57.
Synthesis of the C 1–C 6 subunit of discodermolide from furan
Tetrahedron, 2001
AbstractÐThe synthesis of the C 1 ±C 6 subunit of the potent antitumor agent discodermolide has been performed using 7-oxanorbornene derivatives, derived from furan, as key intermediates to control the stereochemistry of the incoming functional groups. q
Organic Letters, 2002
A convergent and stereoselective assembly of the C1−C14 subunit of marine natural product (+)-discodermolide has been completed. The approach employs chiral allylsilane bond construction methodology to establish four of the eight stereogenic centers. Key fragment coupling is achieved via an efficient stereoselective acetate aldol reaction between C1−C6 and C7−C14 subunits. (+)-Discodermolide 1 is a polypropionate-derived marine metabolite, isolated from the Caribbean deep sea sponge Discodermia dissoluta. 1,2 The structure of discodermolide, determined through a combination of spectroscopic techniques, was shown to possess a tetrasubstituted δ-lactone ring, a side chain containing four double bonds, and a total of 13 stereocenters. The relative stereochemistry was assigned by X-ray crystallography, while the absolute configuration remained unidentified until Schreiber and co-workers 3 synthesized both antipodes. (+)-Discodermolide was initially shown to be a potent immunosuppressive agent, both in vitro and in vivo, and also an antifungal agent. 4 Further biological studies revealed remarkable cytotoxic activity in a variety of human and murine cell lines. This cytotoxicity is due to binding and stabilizing mitotic spindle microtubules causing cell cycle arrest in the M phase. 5 The striking biological profile as well as its structural complexity prompted substantial synthetic effort toward the total synthesis of (+)-discodermolide. 6 To date, six total
Journal of Natural Products, 2002
A series of 12 semisynthetic discodermolide analogues, 2-13, have been prepared using natural (+)discodermolide (1) and evaluated for in vitro cytotoxicity against cultured murine P-388 leukemia and A-549 human adenocarcinoma cells. These semisynthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 through C-19 molecular fragment for potency. Specifically, these analogues suggested the importance of the C-11 and C-17 hydroxyl groups and the C-13 double bond for the potency of discodermolide. The preparation, structure elucidation, and biological activity of these new analogues are described. Earlier, we reported the preparation, structure elucidation, biological activity, and structure-activity relationship of eight acetylated discodermolide analogues. 1-3 Recently, our group reported the isolation, structure determination, and biological activity of five new naturally occurring discodermolide analogues from a sponge sample of Discodermia sp. 4 Herein, we report the preparation, structural elucidation, biological activity, and structure-activity relationship of 12 (2-13) new semisynthetic analogues of natural (+)-discodermolide (1). Discodermolide (1) was first reported in 1990, 5 and since then, studies by our group and others have indicated its immunosuppresive 6-8 and antimitotic properties 9-11 with a mechanism of action similar to that of paclitaxel. 9,10 Discodermolide has been shown to promote the rapid polymerization of purified tubulin and to hyperstabilize the microtubule complex in cultured cells. (+)-Discodermolide inhibits the in vitro growth of several cancer cell lines, including paclitaxel-resistant ovarian and colon cancer cells. 11-13 The Schreiber group has synthesized both antipodes of discodermolide, establishing the absolute configuration, 14 and prepared a number of structural variants. 15 Since then, several other groups have synthesized (+)-discodermolide, 16,17 antipode (-)-discodermolide, 18,19 or various fragments of discodermolide using different synthetic approaches. 20-33 In 2001, the Paterson group 34 synthesized (+)-discodermolide and three epimeric discodermolides.
Total Synthesis of the Marine Natural Product (+)-Discodermolide in Multigram Quantities
ChemInform, 2007
The novel polyketide (+)-discodermolide was isolated in very small quantities from sponge extracts. This compound is one of several microtubule stabilizers showing promise as novel chemotherapeutic agents for the treatment of cancer. The clinical evaluation of this and similar compounds is hampered by lack of material, and at present, the only way to obtain the necessary quantities is total chemical synthesis.