An Alkyne‐Metathesis‐Based Approach to the Synthesis of the Anti‐Malarial Macrodiolide Samroiyotmycin A

The first total synthesis of a tetracyclic marine pyridinium alkaloid hinged on recent advances in chemoselectivity management: While many classical methods failed to afford the perceptively simple pyridine-containing core of the target, nickel/iridium photoredox dual catalysis allowed the critical CÀ C bond to be formed in good yield. Likewise, ring closing alkyne metathesis (RCAM) worked well in the presence of the unhindered pyridine despite the innately Lewis acidic Mo(+ 6) center of the alkylidyne catalyst. Finally, an iridium catalyzed hydrosilylation was uniquely effective in reducing a tertiary amide without compromising an adjacent pyridine and the lateral double bonds; this transformation is largely without precedent. The second strained macrocycle enveloping the core was closed by intramolecular N-alkylation with formation of the pyridinium unit; the reaction proceeded site-and chemoselectively in the presence of an a priori more basic tertiary amine.

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“…[33][34][35][36] The projected current application provides a stringent test for this notion. [2,37] A scalable route to the required core fragment, though perceptively simple, proved surprisingly difficult to establish for more than one reason (Scheme 3). Specifically, direct cross coupling of pent-3-ynylzinc (magnesium) reagents 9 with 3,5-dibromopyridine (8) under palladium, nickel, copper, or iron catalysis failed to afford manageable quantities of the desired mono-substitution product 10.…”

Section: Resultsmentioning

confidence: 99%

“…Under this proviso, we opted for ring closing alkyne metathesis (RCAM) followed by semi‐reduction of the triple bond for the formation of the other macrocycle, [27–29] since molybdenum alkylidynes endowed with silanolate ligands are remarkably tolerant towards many different donor sites, [13, 30–32] most notably complexes with a tripodal silanolate ligand framework (“canopy catalysts”) [33–36] . The projected current application provides a stringent test for this notion [2, 37] …”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi‐Tetradehydrohalicyclamine B

Dalling

¹

,

Späth

²

,

Fürstner

³

2022

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The first total synthesis of a tetracyclic marine pyridinium alkaloid hinged on recent advances in chemoselectivity management: While many classical methods failed to afford the perceptively simple pyridine-containing core of the target, nickel/iridium photoredox dual catalysis allowed the critical CÀ C bond to be formed in good yield. Likewise, ring closing alkyne metathesis (RCAM) worked well in the presence of the unhindered pyridine despite the innately Lewis acidic Mo(+ 6) center of the alkylidyne catalyst. Finally, an iridium catalyzed hydrosilylation was uniquely effective in reducing a tertiary amide without compromising an adjacent pyridine and the lateral double bonds; this transformation is largely without precedent. The second strained macrocycle enveloping the core was closed by intramolecular N-alkylation with formation of the pyridinium unit; the reaction proceeded site-and chemoselectively in the presence of an a priori more basic tertiary amine.

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“…Equally useful is controlled head-to-tail cyclodimerization. Recent conquests of disorazole C1 and the antimalarial agent samroiyotmycin A (using the newest canopy catalyst 31 , Scheme ) illustrate this reaction format.…”

Section: New Formatsmentioning

confidence: 99%

“…and the antimalarial agent samroiyotmycin A (using the newest canopy catalyst 31, Scheme 23)185 illustrate this reaction format. RCAM provides selective entry into all diene motifs.…”

mentioning

confidence: 99%

The Ascent of Alkyne Metathesis to Strategy-Level Status

Fürstner

¹

2021

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For numerous enabling features and strategic virtues, contemporary alkyne metathesis is increasingly recognized as a formidable synthetic tool. Central to this development was the remarkable evolution of the catalysts during the past decades. Molybdenum alkylidynes carrying (tripodal) silanolate ligands currently set the standards; their functional group compatibility is exceptional, even though they comprise an early transition metal in its highest oxidation state. Their performance is manifested in case studies in the realm of dynamic covalent chemistry, advanced applications to solid-phase synthesis, a revival of transannular reactions, and the assembly of complex target molecules at sites, which one may not intuitively trace back to an acetylenic ancestor. In parallel with these innovations in material science and organic synthesis, new insights into the mode of action of the most advanced catalysts were gained by computational means and the use of unconventional analytical tools such as 95Mo and 183W NMR spectroscopy. The remaining shortcomings, gaps, and desiderata in the field are also critically assessed.

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An Alkyne‐Metathesis‐Based Approach to the Synthesis of the Anti‐Malarial Macrodiolide Samroiyotmycin A

Cited by 26 publications

References 46 publications

Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi‐Tetradehydrohalicyclamine B

Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi‐Tetradehydrohalicyclamine B

Total Synthesis of the Tetracyclic Pyridinium Alkaloid epi‐Tetradehydrohalicyclamine B

The Ascent of Alkyne Metathesis to Strategy-Level Status

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