Alkyne metathesis

Fürstner, Alois; Davies, Paul W.

doi:10.1039/b419143a

Cited by 386 publications

(213 citation statements)

References 121 publications

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“…Our previous investigations have shown that ring-closing alkyne metathesis (31)(32)(33)(34) combined with Lindlar hydrogenation is a highly adequate tool for the stereospecific formation of the macrocyclic rings in the parent compounds 1 and 2 (27,28). This strategy, which is exemplarily outlined for 2 in Scheme 2, therefore constitutes a conserved design element en route to all analogues prepared herein.…”

Section: Resultsmentioning

confidence: 99%

Diverted total synthesis: Preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties

Fürstner

Kirk

Fenster

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Two largely catalysis-based and highly convergent total syntheses of latrunculin A (1) and B (2) were diverted to the preparation of a focused library of analogues of these potent actin-binding macrolides that enjoy widespread use in chemical biology. Because the chosen route allows for structural variations of all characteristic parts of the natural leads, it was possible to map the previously largely unknown structure͞activity profile of this class of bioactive natural products. This led to the discovery that the removal of the methyl branches decorating the macrocycle in 2 engenders a significant increase in potency, while streamlining the synthesis to a considerable extent. Moreover, compelling evidence is provided that the conspicuous 2-thiazolidinone ring present in all naturally occurring latrunculins may be an optimal but not an essential structural motif for actin binding because it can be replaced by an oxazolidinone moiety with only slight loss in efficacy. Likewise, the inversion of the absolute configuration of the chiral center at C.16 is well accommodated. From the purely chemical perspective, this investigation attests to the maturity of alkyne metathesis, a method that has received attention as efficient means for the formation of macrocycles only recently.alkyne metathesis ͉ natural products

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Section: Resultsmentioning

confidence: 99%

Diverted total synthesis: Preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties

Fürstner

Kirk

Fenster

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…[25][26][27] In contrast to the more widely practiced ring-closing alkene metathesis (RCM) reaction, [28] RCAM ensures a stereoselective entry into macrocyclic (Z)-alkenes when combined with a Lindlar semireduction of the cycloalkynes primarily formed. The projected RCAM cases B!A and D!C, however, are highly demanding since the catalyst must rigorously distinguish between the triple-and the double bonds of the substrates; whereas the former must be activated, the latter must remain untouched.…”

Section: Resultsmentioning

confidence: 99%

“…As outlined in the Results and Discussion section (Scheme 1), this target constitutes a particularly stringent test for ring-closing alkyne metathesis (RCAM). [25] Not only must the chosen catalyst be able to rigorously distinguish between the p-system of the alkynes on the one hand and the olefins on the other hand, even though the latter are conjugated and hence electronically coupled, but the metathesis event also has to build up considerable strain: note that the resulting product embodies an (E)-configured olefin in addition to the a priori linear acetylene moiety in its bicyclic meta-bridged edifice that incorporates a 16-membered ring. Although model studies on alkyne-selective enyne-yne metathesis reactions provided encouraging preA C H T U N G T R E N N U N G cedence with regard to the chemoselectivity issue, the smallest cycle so far to be successfully forged by this transformation was an 18-membered ring.…”

Section: -Epi-latrunculin Bmentioning

confidence: 99%

Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

Fürstner

Souza

Turet

et al. 2006

Chemistry A European J

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The latrunculins are highly selective actin-binding marine natural products and as such play an important role as probe molecules for chemical biology. A short, concise and largely catalysis-based approach to this family of bioactive macrolides is presented. Specifically, the macrocyclic skeletons of the targets were forged by ring-closing alkyne metathesis (RCAM) or enyne–yne metathesis of suitable diyne or enyne–yne precursors, respectively. This transformation was best achieved with the aid of [(tBu)(Me₂C₆H₃)N]₃Mo (37) as precatalyst activated in situ with CH₂Cl₂, as previously described. This catalyst system is strictly chemoselective for the triple bond and does not affect the olefinic sites of the substrates. Moreover, the molybdenum-based catalyst turned out to be broader in scope than the Schrock alkylidyne complex [(tBuO)₃WCΞCMe₃] (38), which afforded cycloalkyne 35 in good yield but failed in closely related cases. The required metathesis precursors were assembled in a highly convergent fashion from three building blocks derived from acetoacetate, cysteine, and (+)-citronellene. The key fragment coupling can either be performed via a titanium aldol reaction or, preferentially, by a sequence involving a Horner–Wadsworth–Emmons olefination followed by a protonation/cyclization/diastereoselective hydration cascade. Iron-catalyzed C[BOND]C-bond formations were used to prepare the basic building blocks in an efficient manner. This synthesis blueprint gave access to latrunculin B (2), its naturally occurring 16-epimer 3, as well as the even more potent actin binder latrunculin A (1) in excellent overall yields. Because of the sensitivity of the 1,3-diene motif of the latter, however, the judicious choice of protecting groups and the proper phasing of their cleavage was decisive for the success of the total synthesis. Since latrunculin A and B had previously been converted into latrunculin S, C and M, respectively, formal total syntheses of these congeners have also been achieved. Finally, a previously unknown acid-catalyzed degradation pathway of these bioactive natural products is described. The cysteine-derived ketone 18, the tetrahydropyranyl segment 31 serving as the common synthesis platform for the preparation of all naturally occurring latrunculins, as well as the somewhat strained cycloalkyne 35 formed by the RCAM reaction en route to 2 were characterized by X-ray crystallography

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“…Such a reaction allows obtaining at will the Z or E stereochemistry of the double bond by further control of the hydrogenation of the triple bond. In that context, Fürstner has applied his trisamidomolybdenum complex as a catalyst precursor for the synthesis of several natural products and the reader will find most of his results in a recent review [40].…”

Section: Applicationsmentioning

confidence: 99%

Alkyne metathesis catalysts: Scope and future

Mortreux

Coutelier

2006

Journal of Molecular Catalysis A: Chemical

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This paper presents the evolution of alkyne metathesis since the early discoveries, essentially from the catalyst point of view. It is shown that although well defined carbynes may be useful for this reaction, further work has been made, aimed at the synthesis of new catalysts or catalytic systems, based on molybdenum precursors , associated or not with phenolic cocatalysts. The major objectives have been to obtain more functional groups tolerants catalysts, for their application in organic synthesis, including RCM for further stereoselective hydrogenation of the triple bond in the cycle, as well as for polymerization of aromatic diynes. Some insights into the possible mechanisms are given, and data relevant to the metathesis of terminal alkynes, a still challenging reaction where polymerization is occurring via the formation of deprotonated metallacyclobutadiene, are also presented and discussed.2

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Alkyne metathesis

Abstract: This review discusses the emergence of alkyne metathesis as a valuable synthetic tool applicable in the synthesis of complex molecules and polymer science.

Cited by 386 publications

References 121 publications

Diverted total synthesis: Preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties

Diverted total synthesis: Preparation of a focused library of latrunculin analogues and evaluation of their actin-binding properties

Total Syntheses of the Actin‐Binding Macrolides Latrunculin A, B, C, M, S and 16‐epi‐Latrunculin B

Alkyne metathesis catalysts: Scope and future

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