Total Synthesis Of Epothilone Research Articles

Studies toward the Total Synthesis of Epothilone D: Synthesis of the Thiazole-Containing Northern Segment

Epothilone D, a microtubule-stabilizing macrolide, is an attractive synthetic target molecule as a potential anti-cancer drug candidate. As part of our ongoing synthetic studies of this natural product, this paper describes the synthesis of the thiazole-containing northern segment of epothilone D via an E-selective bromomethylenation and a Ni/Cr-mediated cross-coupling reaction.

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.

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–C12 and C13–C21 in the target molecule.

ChemInform Abstract: A Novel Aldol Condensation with 2-Methyl-4-pentenal and Its Application to an Improved Total Synthesis of Epothilone B.

The stabilization of the transition state through a favorable interaction between the double bond of 1 and the carbonyl group of 2 appears to be responsible for the high diastereoface selectivity of the aldol reaction. This key step in the highly concise total synthesis of epothilone B is followed by a Suzuki coupling to introduce the thiazole domain, a Noyori reduction to control the stereochemistry at C3, and a final macrolactonization (see reaction scheme). X=protecting group.

ChemInform Abstract: The Formal Total Synthesis of Epothilone A.

The formal total synthesis of epothilone A is described. The key steps in the synthesis of the northern hemisphere are a Z-selective ten-membered ring-closing metathesis reaction (RCM) and the diastereoselective alkylation at C8. Aldehyde 3 is formed by introduction of the thiazole moiety by a Wittig reaction and subsequent functional group transformation. An efficient route to keto acid 5 is described.

ChemInform Abstract: Enantioselective Total Synthesis of Epothilone A Using Multifunctional Asymmetric Catalyses.

A catalytic version has now been developed for the enantioselective total synthesis of epothilone A (1). The key is the use of multifunctional asymmetric catalyses for a direct aldol reaction and cyanosilylation. This successful approach demonstrated the usefulness of these reactions for the catalytic asymmetric synthesis of complex molecules.

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.

Total Syntheses of Epothilones B and D

A convergent, total synthesis of epothilones B (2) and D (4) is described. The key steps are Normant coupling to establish the desired (Z)-stereochemistry at C12-C13, Wadsworth-Emmons olefination of methyl ketone 28 with the phosphonate ester 8, diastereoselective aldol condensation of aldehyde 5 with the enolate of keto acid derivatives to form the C6-C7 bond, selective deprotection of acid 52, and macrolactonization.

Cover Picture: Multi-Step Application of Immobilized Reagents and Scavengers: A Total Synthesis of Epothilone C (Chem. Eur. J. 10/2004)

Cover Picture: Multi-Step Application of Immobilized Reagents and Scavengers: A Total Synthesis of Epothilone C (Chem. Eur. J. 10/2004)

Multi-step application of immobilized reagents and scavengers: a total synthesis of epothilone C.

The total synthesis of the cytotoxic antitumour natural product epothilone C has provided a stage for the exploitation and further development of immobilized reagent methods. A stereoselective convergent synthetic strategy was applied, incorporating polymer-supported reagents, catalysts, scavengers and catch-and-release techniques to avoid frequent aqueous work-up and chromatographic purification.

Cover Picture: Multi‐Step Application of Immobilized Reagents and Scavengers: A Total Synthesis of Epothilone C (Chem. Eur. J. 10/2004)

The cover picture, created by Doug Scard, offers a look over the tubulin horizon, depicting the bringing together of ingredients, solid‐supported reagents and scavengers to produce the anti‐tumour compound Epothilone C. Rather like a fine wine, the unwanted residues may be removed by filtration. For more information see the article by S. V. Ley et al. on p. 2529 ff.

Asymmetric aldol reactions using catalytic d(+)-proline: a new, economic and practical approach to a commonly employed C1–C6 keto-acid synthon of the epothilones

A new approach to ketoacid 4 , a common C1–C6 fragment used in the total synthesis of epothilones was initiated by direct aldol reaction of acetone with a pivaldehyde-like substance 5 , catalyzed with d-proline, leading to a 2,6-diketoalcohol with better than 99% ee. Further intramolecular closure of the diketone 8 followed by oxidation of the silyl protected hydroxycyclohexenone 14 led to the desired product 4 . None of the steps have been optimized, yet the overall yield for the four-step process is 31%. The use of commercially available d-proline to construct the chiral center of 4 under very mild reaction conditions provided an economical and practical method for its construction.

A Total Synthesis of Epothilones Using Solid-Supported Reagents and Scavengers.

A Total Synthesis of Epothilones Using Solid-Supported Reagents and Scavengers.

A total synthesis of epothilones using solid-supported reagents and scavengers.

A total synthesis of epothilones using solid-supported reagents and scavengers.

Total synthesis of epothilone a through stereospecific epoxidation of the p-methoxybenzyl ether of epothilone C.

The total synthesis of epothilone A is described by the coupling four segments 4-7 a. Three of the segments, 4, 5 and 7 a, have only one chiral center; all other chiral centers were introduced by simple asymmetric catalytic reactions. The key steps are the ring opening of epoxide 5 with acetylide 8 for the construction of the C12-C13 cis double bond and a practical hydrolytic kinetic resolution (HKR) developed by Jacobsen group for the introduction the chiral center at C3. Especially, the stereospecific epoxidation of 3-O-PMB epothilone C 3 b through long-range effect of 3-O-PMB protecting group gave high yields of the C12-C13 alpha-epoxide for the synthesis of target molecule.

Structure-based rationalization of aldolase-catalyzed asymmetric synthesis

This paper describes a structure-based approach to elucidate the stereospecificity, including inversion of enantioselectivity, of the 2-deoxyribose-5-phosphate aldolase-catalyzed asymmetric aldol addition reaction using unnatural substrates designed for the total synthesis of epothilones. In addition, an aldolase variant with Ser-238 being altered for Asp was found to be 2.5 times more effective than the wild type in accepting the unphosphorylated substrate D-glyceraldehyde. A new H-bonding interaction between the Asp-238 carboxylate and the 3-hydroxyl of the substrate was identified and was used to rationalize the rate enhancements.Key words: aldol reaction, 2-deoxyribose-5-phosphate aldolase, mutagenesis, inversion of enantioselectivity.

ChemInform Abstract: Methodology Based on Chiral Silanes in the Synthesis of Polypropionate‐Derived Natural Products — Total Synthesis of Epothilone A.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Catalytic Antibody Route to the Naturally Occurring Epothilones: Total Synthesis of Epothilones A—F.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Total syntheses of epothilones B and D: applications of allylstannanes in organic synthesis

Following exploratory studies which culminated in syntheses of the alcohol 16 , a total synthesis of epothilones B and D is reported in which the trisubstituted 12,13-double-bond is introduced stereoselectively using the tin(IV) bromide-promoted reaction between the allylstannane 22 and the aldehyde 17 . A Barton deoxygenation then gave the C(7)C(15) fragment 25 . After development of the thiazole containing side-chain, an aldol condensation with the ethyl ketone 36 gave the adduct 37 which was taken through to epothilone D 2 and then to epothilone B 1 .

ChemInform Abstract: Total Synthesis of Epothilone B, Epothilone D, and cis‐ and trans‐9,10‐Dehydroepothilone D.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.