One-Pot Selective Homodimerization/Hydrogenation Strategy for Sequential Dicarba Bridge Formation

Burnley, James; Jackson, W. R.; Robinson, Andrea J.

doi:10.1021/acs.joc.5b01312

Cited by 12 publications

(3 citation statements)

References 39 publications

(35 reference statements)

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“…Ring closing alkyne metathesis (RCAM) followed by regioselective trans -hydrometalation , of the ensuing alkyne might allow this challenge to be met, even though this tactic has not yet been applied within a similarly challenging chemical environment. Although RCAM had previously excelled with complex peptidic substrates, , it was by no means clear at the outset of this investigation whether trans -hydrometalation qualifies in the present context: this transformation gains high regioselectivity only if a protic substituent on the substrate steers the incoming [Cp*Ru–Cl] catalyst via hydrogen bonding to the chloride ligand and, in doing so, imposes directionality on the transition state (Scheme ). , While the C7–OMe ether of 1 can obviously be traced back to a propargylic −OH group which then provides the necessary handle, we felt unable to assess with any level of certainty whether or not the protic amide linkages in transannular proximity in a substrate of type B interfere with or potentially even disrupt this crucial preorganization .…”

Section: Results and Discussionmentioning

confidence: 92%

A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues

et al. 2017

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The highly cytotoxic cyclodepsipeptides of the nannocystin family are known to bind to the eukaryotic translation elongation factor 1α (EF-1α). Analysis of the docking pose, as proposed by a previous in silico study, suggested that the trisubstituted alkene moiety and the neighboring methyl ether form a domain that might be closely correlated with biological activity. This hypothesis sponsored a synthetic campaign which was designed to be "motif-oriented": specifically, a sequence of ring closing alkyne metathesis (RCAM) followed by hydroxy-directed trans-hydrostannation of the resulting cycloalkyne was conceived, which allowed this potentially anchoring substructure to be systematically addressed at a late stage. This inherently flexible approach opened access to nannocystin Ax (1) itself as well as to 10 non-natural analogues. While the biological data confirmed the remarkable potency of this class of compounds and showed that the domain in question is indeed an innate part of the pharmacophore, the specific structure/activity relationships can only partly be reconciled with the original in silico docking study; therefore, we conclude that this model needs to be carefully revisited.

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Section: Results and Discussionmentioning

confidence: 92%

A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues

et al. 2017

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“…As an emerging dynamicc ovalent reactiont of orm the robust and linear acetylene linkages, alkyne metathesis has been applied to the synthesis of various smallm olecules and materials, including naturalp roducts, [1][2][3][4][5][6][7][8][9][10][11] polymers, [12][13][14][15][16] and shape-persistent macrocycles. [17][18][19] Numerous molybdenum(VI) and tungsten(VI)a lkylidyne complexes have been developed.…”

Section: Introductionmentioning

confidence: 99%

Highly Active Multidentate Ligand‐Based Alkyne Metathesis Catalysts

Yang

Zhu

et al. 2016

Chemistry A European J

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Alkyne metathesis catalysts composed of molybdenum(VI) propylidyne and multidentate tris(2-hydroxylbenzyl)methane ligands have been developed, which exhibit excellent stability (remains active in solution for months at room temperature), high activity, and broad functional-group tolerance. The homodimerization and cyclooligomerization of monopropynyl or dipropynyl substrates, including challenging heterocycle substrates (e.g., pyridine), proceed efficiently at 40-55 °C in a closed system. The ligand structure and catalytic activity relationship has been investigated, which shows that the ortho groups of the multidentate phenol ligands are critical to the stability and activity of such a catalyst system.

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“…Both monocycles can be converted into the bicyclic product 16 by means of the second metathesis reaction. This result is remarkable since previous attempts of orthogonal macrocycle formation within peptides failed 44 , but were successful only for the assembly of simple building blocks 47 . In an even more demanding set-up, the simultaneous closure of both macrocycles in a one-pot reaction was tested (instead of the previous sequential synthesis).…”

Section: Resultsmentioning

confidence: 95%

Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides

et al. 2016

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Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries. We also demonstrate that the formed alkyne macrocycle can be functionalized subsequently. The orthogonal RCM/RCAM system was successfully used to evolve a monocyclic peptide inhibitor of the small GTPase Rab8 into a bicyclic ligand. This modified peptide shows the highest affinity for an activated Rab GTPase that has been reported so far. The RCM/RCAM-based formation of bicyclic peptides provides novel opportunities for the design of bioactive scaffolds suitable for the modulation of challenging protein targets.

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One-Pot Selective Homodimerization/Hydrogenation Strategy for Sequential Dicarba Bridge Formation

Cited by 12 publications

References 39 publications

A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues

A “Motif-Oriented” Total Synthesis of Nannocystin Ax. Preparation and Biological Assessment of Analogues

Highly Active Multidentate Ligand‐Based Alkyne Metathesis Catalysts

Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides

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