- 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
-
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
-
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.
- Hurski,Kulinkovich
-
p. 1653 - 1674
(2012/04/04)
-
- Total synthesis of epothilone D by sixfold ring cleavage of cyclopropanol intermediates
-
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
- Hurski, Alaksiej L.,Kulinkovich, Oleg G.
-
scheme or table
p. 3497 - 3500
(2010/09/05)
-
- Diastereoselective Titanium Enolate Aldol Reaction for the Total Synthesis of Epothilones
-
(Matrix Presented) The development of a highly diastereoselective addition of the titanium enolate derived from ketone 1 to aldehyde 2 offers an efficient entry to the total synthesis of the epothilone family. The new aldol process is robust and tolerates
- Koch, Guido,Loiseleur, Olivier,Fuentes, Daniel,Jantsch, Andrea,Altmann, Karl-Heinz
-
p. 3811 - 3814
(2007/10/03)
-
- Total synthesis of epothilones B and D
-
(Matrix presented) A highly convergent total synthesis of the natural products epothilone B and D is described. The route is highlighted by efficient generation of a C12-C13 trisubstituted olefin which exploits a sequential Nozaki-Hiyama-Kishi coupling and a stereoselective thionyl chloride rearrangement.
- Taylor, Richard E.,Chen, Yue
-
p. 2221 - 2223
(2007/10/03)
-
- Total Syntheses of Epothilones B and D
-
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.
- Mulzer, Johann,Mantoulidis, Andreas,Oehler, Elisabeth
-
p. 7456 - 7467
(2007/10/03)
-
- Easy access to the epothilone family - Synthesis of epothilone B
-
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.
- Mulzer, Johann,Mantoulidis, Andreas,Oehler, Elisabeth
-
p. 8633 - 8636
(2007/10/03)
-
- Total syntheses of epothilones A and B via a macrolactonization-based strategy
-
The total syntheses of epothilones A (1) and B (2) and several analogues thereof are described. The reported strategy relies on a macrolactonization approach and features selective epoxidation of the macrocycle double bond in precursors 3 and 4 (Scheme 1), respectively, as well as high convergency and flexibility. Building blocks 9-12 and 15 were constructed by asymmetric processes and coupled via Wittig, aldol, and macrolactonization reactions to afford the basic skeleton of epothilones and that of several of their analogues by a relatively short route. The utilization ofintermediate 14, obtained via a stereoselective Wittig reaction and its Enders coupling to SAMP hydrazone 13 (Scheme 8), in combination with a stereoselective aldol reaction with the modified substrate 69 (Scheme 10) improved the stereoselectivity and efficiency of the total synthesis of these new and highly potent microtubule binding antitumor agents.
- Nicolaou,Ninkovic,Sarabia,Vourloumis,He,Vallberg,Finlay,Yang
-
p. 7974 - 7991
(2007/10/03)
-
