A Domino 10-Step Total Synthesis of FR252921 and Its Analogues, Complex Macrocyclic Immunosuppressants

Chen, Yong; Coussanes, Guilhem; Souris, Caroline; Aillard, Paul; Kaldre, Dainis; Runggatscher, Kathrin; Kubicek, Stefan; Mauro, Giovanni Di; Maryasin, Boris; Maulide, Nuno

doi:10.1021/jacs.9b07185

Cited by 21 publications

(20 citation statements)

References 40 publications

(34 reference statements)

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“…Then, the reaction was concentrated to half the original volume on the rotary evaporator, then precipitated with cold methanol. The precipitate was then redissolved in 0.1 mL of ether, and reprecipitated with cold methanol, then dried under high vacuum to afford 4.2 mg (42% yield) of poly (11). The NMR and IR spectrum of this polymer are similar to those recently reported by the Bielawski lab.…”

Section: Poly(2)supporting

confidence: 71%

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Dewar Heterocycles as Versatile Monomers for Ring-Opening Metathesis Polymerization

Nistanaki

Nelson

2020

ACS Macro Lett.

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We report the utility of readily available heterocycles as precursors to unique ring-opening metathesis polymerization (ROMP) monomers. Photochemical valence isomerization reactions of pyridones, dihydropyridines, and pyrones dearomatize the parent heterocycles to their highly strained Dewar isomers, which readily engage in controlled ROMP reactions using Grubbs catalysts. This strategy is used to access novel polymer backbones that contain strained β-lactam and azetidine cores, which can be further derivatized using postpolymerization chemistries. We demonstrate this through the synthesis of water-soluble β-amino acid polymers and soluble poly(acetylene) derivatives. Aromatic compounds make up a vast portion of our feedstock chemicals given their wide abundance in nature and ease of accessibility. However, due to the inherent stability imparted by these molecules' resonance energy, their reactivity is often poor. 1-2 To this end, dearomative functionalization has attracted the attention of the synthetic chemistry community as a potent strategy for accessing complex three-dimensional functionality from readily available "flat" compounds that are typically thought to be too inert to undergo productive chemical transformations. 2-4 Aromatic heterocycles have long been known to undergo photochemical valence isomerization reactions to generate their dearomatized Dewar isomers (Scheme 1). 5-6 These bicyclic photoproducts are often quite reactive given the strained nature of their cyclobutene substructures. Hence, the valence isomerization of these compounds effectively unveils new reactive functional group handles, providing an attractive platform for generating densely functionalized building blocks for organic synthesis. Some Dewar heterocyclic compounds have been used in the context of total synthesis, by our laboratory and others. 7-11 However, their utility as substrates for polymerization reactions is highly underexplored. We reasoned that various heterocycles such as pyridones, pyridines, and pyrones could be converted to their high-energy Dewar isomers by light irradiation, thereby introducing a strained cyclobutene moiety as a reactive handle for ring-opening metathesis polymerization (ROMP). Moreover, we recognized that the resulting polymers would have significant structural novelty in their backbone, and potential for unique physical properties given their structural rigidity, chirality, and capacity to undergo post-polymerization modification. Scheme 1. Examples of Dewar heterocycles accessed via photochemical valence isomerization reactions.

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Section: Poly(2)supporting

confidence: 71%

“…Poly (11). In a nitrogen glovebox, monomer 11 (6.0 mg, 26 µmol) was added to a 4 mL dram vial equipped with a magnetic stir bar and dissolved in 0.6 mL dry DCM.…”

Section: Poly(2)mentioning

confidence: 99%

Dewar Heterocycles as Versatile Monomers for Ring-Opening Metathesis Polymerization

Nistanaki

Nelson

2020

ACS Macro Lett.

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“…2 For example, very recently, Chen et al developed the domino 10-step total synthesis of FR252921 (complex macrocyclic immunosuppressants), and based on this domino synthesis, 14 biologically active compounds were synthesized. 3 This is a good example of the preparation of very complex multi-step compounds that are very difficult or impossible to prepare through step-by-step and conventional methods.…”

Section: Introductionmentioning

confidence: 99%

Ni/Pd-catalyzed Suzuki–Miyaura cross-coupling of alcohols and aldehydes and C–N cross-coupling of nitro and aminesviadomino redox reactions: base-free, hydride acceptor-free

Kazemnejadi

Ahmed²,

Mahmoudi

2020

RSC Adv.

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“…Among these trifluoromethylated substituted compounds, 4‐trifluoromethylated 1,3‐butadienes are useful building blocks in organic chemistry. [ 18‐29 ] However, C vinyl ‐CF 3 compounds do not occur naturally. Therefore, considerable effort to develop new methods for these compounds has become very urgent.…”

Section: Background and Originality Contentmentioning

confidence: 99%

Synthesis of 4‐Trifluoromethylated 1,3‐Butadienes via Palladium Catalyzed Heck Reaction

Meng

Chang

et al. 2021

Chin. J. Chem.

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Main observation and conclusion 1,3‐Butadiene plays a key role in modern synthetic chemistry and biochemistry because it is a key intermediate in the synthesis of many drugs. A new and effective method for the synthesis of 4‐trifluoromethylated 1,3‐butadiene through the fluorinated Heck reaction catalyzed by Pd(0) is described. Without additives, 1‐chloro‐3,3,3‐trifluoropropene (an inexpensive CF3 structural unit that is harmless to ozone) reacts with enamide to synthesize 4‐trifluoromethylated 1,3‐butadienes with good yield, high regioselectivity and chemical selectivity, and strong tolerance of substrate functional groups such as alkynes, aldehyde, and ester groups.

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A Domino 10-Step Total Synthesis of FR252921 and Its Analogues, Complex Macrocyclic Immunosuppressants

Cited by 21 publications

References 40 publications

Dewar Heterocycles as Versatile Monomers for Ring-Opening Metathesis Polymerization

Dewar Heterocycles as Versatile Monomers for Ring-Opening Metathesis Polymerization

Ni/Pd-catalyzed Suzuki–Miyaura cross-coupling of alcohols and aldehydes and C–N cross-coupling of nitro and aminesviadomino redox reactions: base-free, hydride acceptor-free

Synthesis of 4‐Trifluoromethylated 1,3‐Butadienes via Palladium Catalyzed Heck Reaction

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