Total Synthesis of Iejimalide B

Fürstner, Alois; Nevado, Cristina; Tremblay, Martin; Chevrier, Carine; Teplý, Filip; Aïssa, Christophe; Waser, Mario

doi:10.1002/anie.200601860

Cited by 69 publications

(28 citation statements)

References 68 publications

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“…Since the deconjugation could not be suppressed,65 the outcome was rectified in a separate step by subjecting the mixture to catalytic amounts of DBU in MeCN at elevated temperature 66. 67 In striking contrast to the difficulties with the ester bond formation, the macrocyclization of the resulting diyne 60 proceeded with remarkable ease even at ambient temperature when catalyzed by the molybdenum alkylidyne 61 as the arguably most active and selective catalyst for alkyne metathesis known to date 68.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis, Stereochemical Revision, and Biological Reassessment of Mandelalide A: Chemical Mimicry of Intrafamily Relationships

Willwacher

Heggen

Wirtz

et al. 2015

Chemistry A European J

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Mandelalide A and three congeners had recently been isolated as the supposedly highly cytotoxic principles of an ascidian collected off the South African coastline. Since these compounds are hardly available from the natural source, a concise synthesis route was developed, targeting structure 1 as the purported representation of mandelalide A. The sequence involves an iridium-catalyzed two-directional Krische allylation and a cobalt-catalyzed carbonylative epoxide opening as entry points for the preparation of the major building blocks. The final stages feature the first implementation of terminal acetylene metathesis into natural product total synthesis, which is remarkable in that this class of substrates had been beyond the reach of alkyne metathesis for decades. Synthetic 1, however, proved not to be identical with the natural product. In an attempt to clarify this issue, NMR spectra were simulated for 20 conceivable diastereomers by using DFT followed by DP4 analysis; however, this did not provide a reliable assignment either. The puzzle was ultimately solved by the preparation of three diastereomers, of which compound 6 proved identical with mandelalide A in all analytical and spectroscopic regards. As the entire "northern sector" about the tetrahydrofuran ring in 6 shows the opposite configuration of what had originally been assigned, it is highly likely that the stereostructures of the sister compounds mandelalides B-D must be corrected analogously; we propose that these natural products are accurately represented by structures 68-70. In an attempt to prove this reassignment, an entry into mandelalides C and D was sought by subjecting an advanced intermediate of the synthesis of 6 to a largely unprecedented intramolecular Morita-Baylis-Hillman reaction, which furnished the γ-lactone derivative 74 as a mixture of diastereomers. Whereas (24R)-74 was amenable to a hydroxyl-directed dihydroxylation by using OsO4 /TMEDA as the reagent, the sister compound (24S)-74 did not follow a directed path but simply obeyed Kishi's rule; only this unexpected escape precluded the preparation of mandelalides C and D by this route. A combined spectroscopic and computational (DFT) study showed that the reasons for this strikingly different behavior of the two diastereomers of 74 are rooted in their conformational peculiarities. This aspect apart, our results show that the OsO4 /TMEDA complex reacts preferentially with electron deficient double bonds even if other alkenes are present that are more electron rich and less encumbered. Finally, in a brief biological survey authentic mandelalide A (6) was found to exhibit appreciable cytotoxicity only against one out of three tested human cancer cell lines and all synthetic congeners were hardly active. No significant fungicidal properties were observed.

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Section: Resultsmentioning

confidence: 99%

Total Synthesis, Stereochemical Revision, and Biological Reassessment of Mandelalide A: Chemical Mimicry of Intrafamily Relationships

Willwacher

Heggen

Wirtz

et al. 2015

Chemistry A European J

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“…These unique yet effective conditions have been reported by Fürstner and coworkers and a series of hindered substrates have been successfully cross-coupled. [26] The resulting secondary alcohol 17 was then efficiently acylated with dienoic acid 5 under Yamaguchi esterification [27] conditions to give ester 18 in 86% yield. Pleasingly, the subsequent RCM [28] of olefin 18 proceeded smoothly utilizing the second generation Grubbs catalyst (15 mol%) to give a mixture of E:Z macrocycles in a overall yield of 90%.…”

Section: Communicationmentioning

confidence: 99%

Total Synthesis of the Protected Aglycon of Fidaxomicin (Tiacumicin B, Lipiarmycin A3)

2014

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Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic that is used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have excellent bactericidal activity against multidrug-resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has been reported to date. The enantioselective synthesis of the central 18-membered macrolactone is reported herein. The key reactions include ring-closing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis involves three medium-sized fragments, thus leading to a flexible yet convergent synthetic route. COMMUNICATION Total Synthesis of the Protected Aglycon of Fidaxomicin (Tiacumicin B, Lipiarmycin A3)Hideki Miyatake-Ondozabal, Elias Kaufmann and Karl Gademann* Dedication ((optional)) Abstract: Fidaxomicin, also known as tiacumicin B or lipiarmycin A3, is a novel macrocyclic antibiotic used in hospitals for the treatment of Clostridium difficile infections. This natural product has also been shown to have an excellent bactericidal activity against multi-drug resistant Mycobacterium tuberculosis. In spite of its attractive biological activity, no total synthesis has ever been reported to date. Herein, we report the enantioselective synthesis of the central 18-membered macrolactone. The noteworthy reactions include ringclosing metathesis between a terminal olefin and a dienoate moiety for macrocyclization, a vinylogous Mukaiyama aldol reaction, and a Stille coupling reaction of sterically demanding substrates. The retrosynthesis comprises of three medium sized fragments leading to a flexible yet convergent synthetic route.

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“…Accordingly, formyl hexatriene 7 was synthesized by subjecting stannane 5 and iodide 6 to modified Liebeskind coupling conditions (Scheme 2). 6,7 The synthesis and purification of stannane 5 was complicated by its propensity to undergo protodestannylation as well as the sensitivity of iodide 4. Therefore, 4 and 5 were carried through to the coupling reaction with minimal purification.…”

Section: Variation Of Lewis Basic Hexatrienesmentioning

confidence: 99%

On the Development of Catalytic Carba-6π Electrocyclizations

et al. 2010

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Hexatriene substrates substituted in the 2-position with carbonyl groups were studied in the context of catalytic 6π electrocyclizations. The nature of the carbonyl group and the substitution pattern on the hexatriene have significant effects on the ability of these substrates to succumb to catalysis. A novel 2-formyl hexatriene dimerization was observed. The first example of a catalytic asymmetric carba-6π electrocyclization is reported along with the discovery of an unusual kinetic resolution via a catalytic photochemical electrocyclic ring-opening.Key words: electrocyclic reactions, catalysis, dimerization, asymmetric catalysis, kinetic resolution.The ability to catalyze pericyclic reactions has greatly increased their synthetic utility and has allowed for the development of asymmetric versions. Among the different types of these reactions, Diels-Alder cycloadditions, Claisen rearrangements, and Nazarov cyclizations have been rendered asymmetric by using a variety of chiral Lewis acids, Brønsted acids and aminocatalysts. 1,2 Our group has contributed to this topic by introducing 2-alkoxy-1,4-pentadien-3-ones as excellent substrates for Nazarov cyclizations, which have yielded the first highly enantioselective examples of these 4π electrocyclizations. 2 More recently, 6π electrocyclizations have come into focus. In 2009, List and Smith independently reported asymmetric catalysis in aza-6π electrocyclizations. 3 Prior to this, we demonstrated that carba-6π electrocyclizations could be catalyzed with Lewis acids (Scheme 1). 4,5 Using esters (e.g., 1) and ketones (e.g., 2) as Lewis bases and Me 2 AlCl as a Lewis acid, we showed that rate accelerations up to 55-fold could be achieved. Our experimental results were accompanied by theoretical calculations on simple aldehydes, such as 3, which indeed showed that placement of a formyl group in the 2-position should result in significant rate accelerations upon binding of a Lewis acid or a proton.It is generally believed that aldehydes are preferred substrates for asymmetric Lewis acid catalyzed reactions, since the geometry of their complexation is well-defined. In addition, unsaturated aldehydes, such as 3, allow for aminocatalysis, which is more problematic with ketones due to their decreased electrophilicity and increased steric hindrance. We have therefore investigated 2-formyl hexatrienes in the context of catalytic 6π electrocyclizations. Herein, we report on our experiences with these substrates and provide an update on our continued studies of catalytic and asymmetric catalytic carba-6π electrocyclizations. In the course of these investigations, we have established that certain substituents on the hexatriene system are required to promote electrocyclizations and prevent side reactions, such as double bond isomerizations or Prins-type cyclizations. Powerful new Lewis acid catalysts have been identified that have led to rate accelerations an order of magnitude higher than previously described. In addition, we have launched preliminary investigations ...

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Total Synthesis of Iejimalide B

Cited by 69 publications

References 68 publications

Total Synthesis, Stereochemical Revision, and Biological Reassessment of Mandelalide A: Chemical Mimicry of Intrafamily Relationships

Total Synthesis, Stereochemical Revision, and Biological Reassessment of Mandelalide A: Chemical Mimicry of Intrafamily Relationships

Total Synthesis of the Protected Aglycon of Fidaxomicin (Tiacumicin B, Lipiarmycin A3)

On the Development of Catalytic Carba-6π Electrocyclizations

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