189453-35-8

Usage

Uses

Used in Pharmaceutical Industry:
(4S,7R,8S,9S,13Z,16S)-4,8-Bis-[tert-butyl(dimethyl)silyl]oxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-1,3-thiazol-4-yl)ethenyl]oxocyclohexadec-13-ene-2,6-dione is used as an intermediate in the synthesis of Epothilones. Epothilones are polyketide natural products that inhibit cancer cells by a mechanism similar to paclitaxel and are effective against paclitaxel-resistant tumors. Epothilone D is in phase I clinical testing in patients with advanced solid tumors. Epothilone D is a cytotoxic macrolide that stabilizes malignant cells' microtubules and arrests mitosis, a characteristic it shares with other epothilones. They bind to the same hepatic sites as does paclitaxel (Taxol) in a 1:1 stoichiometric ratio of α,β-tubulin heterodimers.
Chemical Properties:
The compound is described as a white foam, indicating its physical state and appearance.

InChI:InChI=1/C39H69NO5SSi2/c1-26-19-18-20-27(2)35(45-48(16,17)38(9,10)11)29(4)36(42)39(12,13)33(44-47(14,15)37(6,7)8)24-34(41)43-32(22-21-26)28(3)23-31-25-46-30(5)40-31/h21,23,25,27,29,32-33,35H,18-20,22,24H2,1-17H3/b26-21-,28-23+/t27-,29+,32-,33-,35?/m0/s1

Upstream product

• 190369-96-1 (12Z,16E)-(3S,6R,7S,8S,15S)-3,7-Bis-(tert-butyl-dimethyl-silanyloxy)-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-thiazol-4-yl)-5-oxo-heptadeca-12,16-dienoic acid 
• 193146-26-8 (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis{[tert-butyl(dimethyl)silyl]oxy}-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl-1,3-thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid 
• 69739-34-0 t-butyldimethylsiyl triflate 
• 189453-10-9 epothilone D 
• 204195-20-0 (Z)-(4S,7R,8S,9S,16S)-4,8-Bis-(tert-butyl-dimethyl-silanyloxy)-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-oxacyclohexadec-13-ene-2,6-dione 
• 189453-43-8 (Z)-(4S,6R,7R,8S,9S,16S)-8-(tert-Butyl-dimethyl-silanyloxy)-4-hydroxy-5,5,7,9,13-pentamethyl-16-[(E)-1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl]-6-triphenylsilanyloxy-oxacyclohexadec-13-en-2-one 
• 736141-33-6 (S)-3-tert-butyl-dimethyl-silanyloxy-2,2-dimethyl-5-phenylselanyl-cyclopentanone 
• 1352079-84-5 (S)-4-((tert-butyldimethylsilyl)oxy)-5,5-dimethylcyclopent-1-en-1-yl trifluoromethanesulfonate 
• 1352079-85-6 (S)-tert-butyl((3-ethyl-2,2-dimethylcyclopent-3-en-1-yl)oxy)dimethylsilane 
• 187283-45-0 (S)-3-((tert-butyldimethylsilyl)oxy)-4,4-dimethyl-5-oxoheptanoic acid 
• 3883-58-7 2,2-dimethylcyclopentane-1,3-dione 
• 76439-01-5 (S)-3-hydroxy-2,2-dimethylcyclopentan-1-one 
• 1415813-42-1 (3S,6R,7S,8S,12Z,15S,16E)-3-((tert-butyldimethylsilyl)oxy)-15-((fluorosulfonothioyl)oxy)-4,4,6,7,8,12,16-heptamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid 
• 1415813-34-1 (2S,6Z,9S,10E)-9-((3-fluoro-1,1,3,3-tetraisopropyldisiloxanyl)oxy)-2,6,10-trimethyl-11-(2-methylthiazol-4-yl)undeca-6,10-dienal 

Downstream Products

• 152044-54-7 epothilone B 
• 219989-84-1 ixabepilone 
• 247230-49-5 (1S,3S,7S,10R,11S,12S,16S)-7,11-dihydroxy-8,8,10,12,16-pentamethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxabicyclo[14.1.0]heptadecane-5,9-dione 
• 189453-10-9 epothilone D 

Relevant academic research and scientific papers

The Total Synthesis of Epothilone D as a Yardstick for Probing New Methodologies

Here, a concise and highly convergent synthesis of epothilone D was investigated, relying on fragments of equal complexity that could be prepared in gram scale quantities. The strategy to construct the fragments includes the use of a previously reported enantiospecific zinc-catalyzed cross-coupling of an α-hydroxy ester triflate with a Grignard reagent, the application of a hydroboration/boron–magnesium exchange sequence for the rapid construction of the Z-substituted trisubstituted double bond present in the natural product, and a Noyori-type hydrogenation to install the β-hydroxy ester moiety of the southern part. The key to success is the diastereoselective head-to-tail macrolactonization by an intramolecular addition of the corresponding ω-alkynyl-substituted carboxylic acids to construct a new stereocenter in the macrocyclic core structure in one single step.

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.

Epothilone D and its 9-Methyl analogues: Combinatorial syntheses, conformation, and biological activities

Epothilone D (Epo D) and its 9-Methyl conformational analogues were synthesized through a highly efficient combinatorial approach. The fragment E was synthesized in 11 total steps with 6 longest linear steps, and each aldehyde B was prepared via a 3-step sequence. Starting from the common precursor E and a suitable aldehydes B, each target molecule were obtained in only 4 steps. The 9-(S)-epo D and 9-(R)-epo D demonstrated significant difference in inhibition activities against cancer cell lines and in conformational analysis.

An efficient total synthesis of (-)-epothilone B

An efficient total synthesis of (-)-epothilone B has been achieved in ca. 8% yield over 11 steps from 9 (or 10 steps from 7/8), which features a bissiloxane-tethered ring closing metathesis reaction to approach the trisubstituted (Z) double bond and forms a new basis for further development of an industrial process for epothilone B and ixabepilone.

Total synthesis of epothilones using functionalised allylstannanes for remote stereocontrol

Two syntheses of the C(7)-C(16)-fragment 41 of epothilone D 2 were developed that were based on tin(iv) bromide mediated reactions of 5,6-difunctionalised hex-2-enylstannanes with aldehydes. In the first synthesis, (5S)-6-tert-butyldimethylsilyloxy-5-hydroxy-2-methylhex-2-enyl(tributyl) stannane 20 was reacted with (E)-but-2-enal to give (2S,7R,4Z,8E)-1-tert- butyldimethylsilyloxy-5-methyldeca-4,8-diene-2,7-diol 26 containing ca. 20% of its (7S)-epimer. Following desilylation, the crystalline (2S,7R)-triol 32 was protected as its acetonide 33 and esterified to give the (4-methoxybenzyloxy) acetate 34. An Ireland-Claisen rearrangement of this ester gave methyl (2R,3S,10S,4E,7Z)-3,7-dimethyl-10,11-(dimethylmethylene)dioxy-2-(4- methoxybenzyloxy)undeca-4,7-dienoate 35 that was converted into (2S,9S,6Z)-2,6-dimethyl-9,10-(dimethylmethylene)dioxydec-6-en-1-ol 41 by regioselective alkene manipulation, ester reduction and cleavage of the resulting terminal diol 40 with a reductive work-up. The second synthesis involved the tin(iv) bromide mediated reaction between the stannane 20 and (3S)-4-(4-methoxybenzyloxy)-3-methylbutanal 44 that gave (2S,7S,9S,4Z)-1-tert- butyldimethylsilyloxy-5,9-dimethyl-10-(4-methoxybenzyloxy)dec-4-ene-2,7-diol 45 containing ca. 20% of its (7R)-epimer. After desilylation and protection of the vicinal diol as its acetonide 46, a Barton-McCombie reductive removal of the remaining hydroxyl group gave the (2S,9S,6Z)-2,6-dimethyl-9,10- (dimethylmethylene)dioxydec-6-en-1-ol 41 after oxidative removal of the PMB-ether. The first of these syntheses uses just one chiral starting material, but the second is shorter and more convergent. It was therefore modified by the use of (5S)-6-tert-butyldimethylsilyloxy-5-(2-trimethylsilylethoxy)methoxy-2- methylhex-2-enyl(tributyl)stannane 49 that reacted with (3S)-4-(4- methoxybenzyloxy)-3-methylbutanal 44 to give a 50:50 mixture of the C(4)-epimers of (2S,9S,6Z)-10-tert-butyldimethylsilyloxy-1-(4-methoxybenzyloxy)-2,6- dimethyl-9-(2-trimethylsilylethoxy)methoxydec-6-en-4-ol 50 with high fidelity for formation of the (Z)-alkene. Following the Barton-McCombie deoxygenation, the product 52 was taken through to (2S,9S,6Z,10E)-2,6,10-trimethyl-11-(2- methyl-1,3-thiazol-4-yl)-9-(2-trimethylsilylethoxy)methoxyundeca-6,10-dienal 59 that corresponded to the fully functionalised C(7)-C(17) fragment of epothilone D 2. A precedented stereoselective aldol condensation followed by O-protection, selective deprotection, oxidation and macrocyclisation then gave the macrolide 71 that was deprotected to complete a synthesis of epothilone D 2. Finally regio- and stereo-selective epoxidation gave epothilone B 1.

Z-SELECTIVE RING-CLOSING METATHESIS REACTIONS

The present invention relates generally to olefin metathesis. In some embodiments, the present invention provides methods for Z-selective ring-closing metathesis.

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.

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

Rapid access to epothilone analogs via semisynthetic degradation and reconstruction of epothilone D

A facile and efficient route to epothilone analogs has been developed from the natural product epothilone D (1). Degradation of 1 via an oxidative cleavage sequence provides acid intermediate 4 rapidly in six steps. From 4, a variety of epothilone analogs have been prepared utilizing ring-closing metathesis to reconstruct the trisubstituted-12,13-double bond. Using this approach, we report a number of epothilone analogs with varying C-15 aromatic side chains and C-14 allylic substitutions and their biological activities.

Synthesis of epothilones, intermediates thereto, analogues and uses thereof

The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof. Also provided are analogues related to epothilone A and B and intermediates useful for preparing same. The present invention further provides novel compositions based on analogues of the epothilones and methods for the treatment of cancer and cancer which has developed a multidrug-resistant phenotype.