Self‐Assembly of Disorazole C 1 through a One‐Pot Alkyne Metathesis Homodimerization Strategy

The macrocyclic core of the cytotoxic marine natural product callyspongiolide (1) was forged by ring‐closing alkyne metathesis (RCAM) of an ynoate precursor using a molybdenum alkylidyne complex endowed with triarylsilanolate ligands as the catalyst. This result is remarkable in view of the failed attempts documented in the literature at converting electron deficient alkynes with the aid of more classical catalysts. The subsequent Z‐selective semi‐reduction of the resulting cycloalkyne by hydrogenation over nickel boride required careful optimization in order to minimize overreduction and competing dehalogenation of the compound's alkenyl iodide terminus as needed for final attachment of the side chain of 1 by Sonogashira coupling. The required cyclization precursor itself was prepared via Kocienski olefination.

Section: Introductionmentioning

confidence: 99%

Total Synthesis of Callyspongiolide, Part 2: The Ynoate Metathesis/cis‐Reduction Strategy

Wölfl

Mata

Fürstner

2018

“…Our programd evoted to this potential lead compound was intended to expediteb iological profiling by providing meaningfula mounts of the naturalp roduct itself as well as of pertinent analogues.A tt he same time, the chosen route should capitalize on methodologyc oncurrently developed in this laboratory.B oth objectives might be reached when forging the macrocyclic frame by ring closing alkyne metathesis (RCAM) [7][8][9] followed by semi-reduction of the resultingp roduct (Scheme 1). Ap riori, this tactics can be applied at the E-configured C10ÀC11a lkene or at the Z-configured enoate site.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Molecular Editing of Callyspongiolide, Part 1: The Alkyne Metathesis/trans‐Reduction Strategy

Mata

Wölfl

Fürstner

2018

A path‐scouting investigation into the highly cytotoxic marine macrolide callyspongiolide is reported that capitalizes on the selective formation of the C10−C11 alkene site. While the closure of the macrocycle by ring closing alkyne metathesis (RCAM) with the aid of a molybdenum alkylidyne complex was high yielding, the envisaged semi‐reduction of the cycloalkyne to the corresponding E‐alkene proved challenging. The reasons are likely steric in origin, in that the methyl branches on either side of the alkyne seem to prevent effective coordination of the substrate to the ruthenium catalyst, which must carry a bulky Cp* ligand to ensure high trans‐selectivity. This notion is supported by the preparation of a callyspongiolide analogue, in which the two methyl groups in question are excised; its formation by RCAM followed by trans‐hydrostannation/proto‐destannation was straightforward. In parallel work the formation of the fully functional building block 54 showed that the presence of an unprotected ‐OH group allows even hindered substrates to be processed: the protic group adjacent to the triple bond engages with a chloride ligand on the ruthenium catalyst in hydrogen bonding and hence assists in substrate binding. Moreover, the preparation of an alkynylogous callyspongiolide analogue is described.

“…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

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.