210690-99-6Relevant academic research and scientific papers
PROCESS FOR THE PREPARATION OF (1S,3S,7S,10R,11S,12S,16R)-7,11-DIHYDROXY-8,8,10,12,16-PENTAMETHYL-3-[(1E)-1-METHYL-2-(2-METHYL-4-THIAZOLYL)ETHENYL]-17-OXA-4-AZABICYCLO[14.1.0]HEPTADECANE-5,9-DIONE AND INTERMEDIATES THEREOF
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, (2015/06/25)
The present invention relates to an improved process for the preparation of (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1-methyl-2-(2- methyl-4-thiazolyl)ethenyl]- 17-oxa-4-azabicyclo[ 14.1.0]heptadecane-5,9-dione represented by the following structural formula I and intermediates thereof. The present invention also provides novel intermediate compounds useful for the preparation of compound of formula I and its intermediates.
Synthesis of epothilone D with the forced application of oxycyclopropane intermediates
Hurski,Kulinkovich
, p. 1653 - 1674 (2012/04/04)
The total synthesis of epothilone D with six-fold application in the intermediate stages of successive cyclopropanation - opening or cleavage of the three-membered ring was performed. These transformations underlie the new stereoselective method developed for coupling fragments C7-C 12 and C13-C21 in the target molecule.
Total synthesis of epothilone D by sixfold ring cleavage of cyclopropanol intermediates
Hurski, Alaksiej L.,Kulinkovich, Oleg G.
scheme or table, p. 3497 - 3500 (2010/09/05)
The ring-opening or ring fragmentation reactions of cyclopropanol intermediates are used in the total synthesis of epothilone D for the creation of trisubstituted double bonds, an ethyl ketone functionality, as well as for the protection of carboxylic and ester groups. Epothilone D is obtained in 1.6% overall yield (24 steps in the longest linear sequence) starting from (R)-methyl 2,3-O-isopropylideneglycerate. The key cyclopropanol intermediates are efficiently obtained by titanium(IV)-catalyzed reactions of readily available esters with Grignard reagents. Crown Copyright
Intermediates for the synthesis of epothilones and methods for their preparation
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Page column 25, (2010/01/30)
The invention relates to a method of synthesis for a compound of formula (I), wherein R is a heterocyclyl moiety and X1, X2, X3and X4are, independently of each other, protecting groups, which is appropriate for the synthesis of epothilone B and desoxyepothione B.
Total Syntheses of Epothilones B and D
Mulzer, Johann,Mantoulidis, Andreas,Oehler, Elisabeth
, p. 7456 - 7467 (2007/10/03)
Total syntheses of the microtubule stabilizing antitumor drugs epothilone B and D are described, starting from optically pure (S)-malic acid and methyl (R)-3-hydroxy-2-methylpropionate. The synthesis is highly convergent by coupling the three fragments C1-C6 (fragment D), C7-C10 (fragment C), and C11-C21 (fragment B). Key steps are two stereoselective Wittig type olefinations to generate the 12,13- and 16,17-double bonds, an enantioselective Mukaiyama aldol addition to synthesize fragment D, and a sulfone anion allyl iodide alkylation to connect fragments B and C. Finally fragment D was attached to the B + C fragment via aldol addition.
Syntheses of (-)-epothilone B
Schinzer, Dieter,Bauer, Armin,Schieber, Jennifer
, p. 2492 - 2500 (2007/10/03)
Two efficient routes for the total synthesis of (-)-epothilone B are reported. One strategy is based on ring-closing metathesis, and a second synthesis on a macrolactonization. The key fragments are available on large scale to provide sufficient material for biological tests. Thiazole fragment 4 was obtained by an improved route starting from (S)-malic acid. The first synthesis is based on our preceding paper. The critical trisubstituted double bond C12-13 in our second approach was constructed by a highly efficient Pd- mediated coupling reaction. Ring closure was achieved by macrolactonization.
New chemical synthesis of the promising cancer chemotherapeutic agent 12,13-desoxyepothilone B: Discovery of a surprising long-range effect on the diastereoselectivity of an aldol condensation
Harris, Christina R.,Kuduk, Scott D.,Balog, Aaron,Savin, Ken,Glunz, Peter W.,Danishefsky, Samuel J.
, p. 7050 - 7062 (2007/10/03)
The epothilones are naturally occurring cytotoxic molecules that possess the remarkable ability to arrest cell division through the stabilization of microtubule assemblies. Our in vivo studies with 12,13-desoxyepothilone B (dEpoB), have established that the desoxy compound is well tolerated and virtually curative against a variety of sensitive and resistant xenograft tumors in animal models. In light of these discoveries, we sought a chemical synthesis of dEpoB that would be able to support a serious and substantial discovery research program directed toward the clinical development of this molecule. The overall strategy for this endeavor assumed the ability to synthesize dEpoB from three constructs which include an achiral β,δ-diketo ester construct A, an (S)-2-methylpentenal moiety B, and the thiazoyl-containing vinyl iodide moiety C. We envisioned that a diastereoselective aldol condensation between an achiral C5-C6 (Z)-metalloenolate derived from construct A and an (S)-2-methylalkanal fragment, B, would generate the desired C6-C7 bond. Second, a B-alkyl Suzuki coupling between the vinyl iodide construct C and an alkyl borane would form the C11-C12 bond. Finally, a late-stage reduction of the C3 ketone to the requisite C3 alcohol with high asymmetric induction would permit us to introduce the β,δ-diketo ester fragment A, into the synthesis as a readily accessible achiral building block. The governing concepts for our new synthesis are described herein.
Synthesis of 16-desmethylepothilone B: Improved methodology for the rapid, highly selective and convergent construction of epothilone B and analogues
Nicolaou,Hepworth, David,Finlay, M. Ray V.,King, N. Paul,Werschkun, Barbara,Bigot, Antony
, p. 519 - 520 (2007/10/03)
During a synthesis of 16-desmethylepothilone B new methods for the convergent and highly stereoselective synthesis of epothilone B and analogues were developed.
Synthesis of epothilones: Stereoselective routes to epothilone B
Schinzer, Dieter,Bauer, Armin,Schieber, Jennifer
, p. 861 - 864 (2007/10/03)
In connection with our studies of the total syntheses of epothilones we report our efforts on the syntheses of epothilone B using a macro-lactonization and a metathesis approach. Key reaction for the solution of the acyclic stereoselection is a stereoselective aldol reaction.
Easy access to the epothilone family - Synthesis of epothilone B
Mulzer, Johann,Mantoulidis, Andreas,Oehler, Elisabeth
, p. 8633 - 8636 (2007/10/03)
An easy access to four out of five naturally occurring epothilones (A- E, 1-5) is reported. Key steps are an enantioselective Mukaiyama type aldol reaction, (E)- and (Z)-selective olefinations, and a sulfone alkylation.
