A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide

Mulzer, Johann; Karig, Gunter; Pojarliev, Peter

doi:10.1016/s0040-4039(00)01318-6

Cited by 33 publications

(16 citation statements)

References 6 publications

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“…Yamaguchi macrolactonization16 furnished lactone 40 which was first deprotected at 7‐O to give 41 and after removal of the 3‐TBS group, epothilone B ( 1 ) which was identical in all pertinent analytical data with the natural compound described. In effect we have thus achieved a truly stereocontrolled synthesis of 1 , in addition to the one reported earlier 3m…”

Section: Resultsmentioning

confidence: 65%

The 12,13-Diol Cyclization Approach for a Truly Stereocontrolled Total Synthesis of Epothilone B and the Synthesis of a Conformationally Restrained Analogue

et al. 2001

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A highly convergent and stereocontrolled synthesis of epothilone B (1) has been developed. The epoxide moiety in 1 was generated by regioselective mesylation and base treatment of the 12,13-diol 30 which was formed by a chelate Cram controlled Grignard addition of 14 and methyl ketone 13. Both fragments were synthesized from the chiral carbon pool precursors (S)-citronellol and (S)-lactic acid, respectively. A highly diastereoselective aldol addition of epoxy-aldehyde 7 and the known Southern hemisphere ketone 8 delivered the full carbon skeleton, containing all the stereogenic centers of 1. Functional group manipulation, macrolactonization and removal of two protecting groups then yielded 1. The spatial closeness of the C4-beta-methyl and C6-methyl group in the crystal structure of 1 inspired us to connect them through a methylene bridge to give a cyclohexanone derivative. Thus, the Northern hemisphere aldehyde 7 was added to the enolate of the cyclohexanone 47. Further manipulations and macrolactonization delivered the conformationally restrained epothilone derivative 42.

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Section: Resultsmentioning

confidence: 65%

The 12,13-Diol Cyclization Approach for a Truly Stereocontrolled Total Synthesis of Epothilone B and the Synthesis of a Conformationally Restrained Analogue

et al. 2001

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“…The crude mixture was purified by flash column chromatography (hex/EE, 1:2) to provide triol 67 (110 mg, 75 % over 4 steps) as a colorless oil, whose spectroscopic data and optical rotation were congruent with those described previously. [5] ( 3S,6R,7S,8S)-3,7-Bis(tert-butyldimethylsilyloxy)-11-{(4R,5R)-5-[(S,E)-2-(tert-butyldimethylsilyloxy)-3-methyl-4-(2-methylthiazol-4-yl)but-3-enyl]-2,2,4-trimethyl-1,3-dioxolan-4-yl}-1-hydroxy-4,4,6,8 041 mmol) was dissolved in THF/tBuOH (1:1, 4 mL) at 0°C and was treated with OsO 4 (10 mg/mL in tBuOH, 50 µL, 0.05 equiv.) and NMO (0.21 mL, 0.042 mmol, 0.2  in H 2 O).…”

Section: ((S)-5-{(4r5r)-5-[3-(benzyloxy)propyl]-224-trimethyl-13-mentioning

confidence: 99%

“…We report contributions to both variations and furthermore, the synthesis of a 12,13-diol derivative 7 will be described in detail. [5] For a stereocontrolled synthesis of the (12Z) double bond in a "northern fragment" such as 3 a surprisingly wide variety of approaches have been reported among which Danishefsky's B-alkyl Miyaura-Suzuki coupling [6] has found particularly widespread application, notwithstanding the low overall yield of 33 %. [7] Alternatively, Wittig [8] or Still-Gennari [9] carbonyl olefinations, organometallic additions to alkynols, [10] allylstannane-carbonyl addition, [11] allylic rearrangement [12] or the functionalization of nerol [3d] have also been used to solve the problem.…”

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confidence: 99%

“…For the conversion into 5, the aldehyde 8 was methylenated and globally deprotected to give the triol 67, whose conversion into the aldehyde 5, and finally into 1 has been described before. [5] For the synthesis of 7, the aldol addition to the aldehyde 8 was performed with ketones 4 (Scheme 12) and 9 (Scheme 13). With the enolate of the ketone 4, the aldehyde 8 gave the aldol adducts 68a and 68b in a ratio of 6:1 and 83 % combined yield.…”

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New Solutions to the C‐12,13 Stereoproblem of Epothilones B and D; Synthesis of a 12,13‐Diol‐Acetonide Epothilone B Analog

et al. 2006

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Keywords: Microtubule stabilizing agent (MSAA) / Antitumor drugs / Ring-closing metathesis / Silicon tether / Epoxide formation / Stereoselective synthesis New approaches are described to the synthesis of epothilone B and a 12,13-diol-acetonide derivative. Specifically the (12Z) double bond is formed quantitatively by a silicon-tethered ring-closing metathesis (RCM) reaction with 85 % selecEpothilone B (1) [1] shows outstanding microtubule binding affinities and cytotoxity against tumor cells and multiple drug resistant tumor cell lines.[2] The role of 1 as a potential paclitaxel successor has initiated intense interest in its synthesis, resulting in numerous total syntheses of 1 and numerous derivatives thereof. [3] A central issue in most syntheses of epothilone B, in particular when aiming for the larger scale, has been the introduction of a 12R,13R-configured trisubstituted epoxide. The standard solution of this problem is the synthesis of the deoxy precursor, epothilone D (2) with a 12,13-(Z) double bond, which is epoxidized to give epothilone B in the last step of the sequence (Scheme 1). Alternatively, the 12,13-epoxide has been introduced with high stereocontrol relatively early, and has then been carried through the sequence to furnish 1 directly. [4] In both variants, the key step is an aldol addition of an enolate 4 or 6 ("southern fragment") to an aldehyde 3 or 5 ("northern fragment"). We report contributions to both variations and furthermore, the synthesis of a 12,13-diol derivative 7 will be described in detail.[5]For a stereocontrolled synthesis of the (12Z) double bond in a "northern fragment" such as 3 a surprisingly wide variety of approaches have been reported among which Danishefsky's B-alkyl Miyaura-Suzuki coupling [6] has found particularly widespread application, notwithstanding the low overall yield of 33 %.[7] Alternatively, Wittig [8] or Still-Gennari [9] carbonyl olefinations, organometallic additions to alkynols, [10] allylstannane-carbonyl addition, [11] allylic rearrangement [12] or the functionalization of nerol [3d] have also been used to solve the problem.[ Our approach was to enforce the (Z) geometry of the 12,13-olefin by incorporating it into a relatively small ring, with a maximum ring size of 8 (Scheme 2). Hence, the lactone 10 could be envisaged as a suitable precursor of 3. Following literature precedence, [13] 10 could be generated through a [3.3]-sigmatropic rearrangement of the ketene acetal 11, which was to be prepared from the carbonate 12 by a Tebbe olefination or from ortho-acetal 13 by a ClaisenJohnson protocol.In fact, the known aldehyde 14 [8,9] was converted into a 60:40 diastereomeric mixture of diols 15 (Scheme 3). Treatment with triphosgene furnished the cyclic carbonate 12, again as a 60:40 mixture of isomers. However, all attempts to convert 12 into 11 with Tebbe's reagent failed. Thus, the 15a/b mixture was heated with triethyl orthoacetate and a catalytic amount of amberlyst 15. Three products were isolated: ortho-acetal 13 (22 %) as a pure dias...

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“…A novel synthesis of epothilone B was described by the same research group, via a highly stereoselective aldol and Davis-Evans-Hydroxylation in the synthesis of epothilone B and its novel derivative 173 (scheme 31) [34].…”

Section: Other Workmentioning

confidence: 99%

Synthetic Methodologies for the Preparation of Epothilones and Analogs

Luduvico¹,

Hyaric²,

Almeida³

et al. 2006

MROC

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Epothilones are natural products present in the myxobacterium Sorangium cellulossum strain 90. Due to their antitumoral activity, they are good candidates for the treatment of various forms of cancer, and epothilones B and D and some synthetic analogs are actually under advanced clinical trials. This review describes the synthesis of epothilones A and B and some of their analogs. synthetic methodologies reported in the literature to prepare epothilones A and B and some of their analogs. TOTAL SYNTHESIS OF EPOTHILONES The Danishefsky Group StrategiesThe first total synthesis of both epothilones A and B, including their respective deoxy precursors C and D, were carried out in the working group of S. J. Danishefsky [8-10].The main strategies used for the construction of the macrocycle include a macroaldolization reaction [9][10][11], an olefin metathesis approach [11,12], and a macrolactonization procedure [11]. Three key step reactions were employed: Suzuki-type coupling, aldol reaction and a stereoselective Noyori reduction [12] (Fig. 2). Metathesis (Approach I, Fig. 2) Initially, a strategy in which the C9-C10 bond would be formed during the macrocyclization reaction was chosen. The First Generation Ring-Closing OlefinTwo key intermediates 11 [11,12] and 18 [10,11] were synthesized as shown in scheme 1. Compound 11 was synthesized from β-benzyloxy(isobutyraldehyde) 7: a titanium cyclocondensation, followed by a reduction with lithium aluminum hydride provided glycal 8. Compound 9 was obtained by oxidative solvolytic fragmentation of a cycloproprane intermediate. After reductive deiodination of 9 and triphenylsilylation, cleavage of the pyran ring afforded dithioacetal 10. Protection of alcohol, followed by olefin formation and liberation of the aldehyde function led to intermediate 11. 50

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A novel highly stereoselective total synthesis of epothilone B and of its (12R,13R) acetonide

Cited by 33 publications

References 6 publications

The 12,13-Diol Cyclization Approach for a Truly Stereocontrolled Total Synthesis of Epothilone B and the Synthesis of a Conformationally Restrained Analogue

The 12,13-Diol Cyclization Approach for a Truly Stereocontrolled Total Synthesis of Epothilone B and the Synthesis of a Conformationally Restrained Analogue

New Solutions to the C‐12,13 Stereoproblem of Epothilones B and D; Synthesis of a 12,13‐Diol‐Acetonide Epothilone B Analog

Synthetic Methodologies for the Preparation of Epothilones and Analogs

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