Rapid Access to the Heterocyclic Core of the Calyciphylline A and Daphnicyclidin A-Type <i>Daphniphyllum</i> Alkaloids via Tandem Cyclization of a Neutral Aminyl Radical

Ibrahim, Ahmad; Golonka, Alexander N.; López, Alberto M.; Stockdill, Jennifer L.

doi:10.1021/ol4034868

Cited by 60 publications

(27 citation statements)

References 53 publications

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“…17 Findings that enones analogous to substrate 1 cyclized efficiently, while the corresponding allylic alcohol 14 led only to N–Cl reduction (R 2 N–Cl → R 2 N–H) were consistent with our hypothesis but were insufficient to provide insight into 5-exo and 6-exo cyclizations of conformationally unbiased substrates. Thus, we selected representative unactivated and activated olefin substituents to investigate under these conditions.…”

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confidence: 56%

“…We found that unactivated substrates 3a–3b 18 afforded good to excellent yields of cyclized products 4a–4b when treated with azobisisobutyronitrile (AIBN) and the weak H-atom donor ( i Pr) 3 SiH at 100°C in THF. 14,19 Bicyclic amine 4b was formed as a single diastereomer. The relative stereochemistry is consistent with previous stereochemical studies of 5- exo , 5- exo tandem cyclizations.…”

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confidence: 99%

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Synthetic and Computational Study of Tin-Free Reductive Tandem Cyclizations of Neutral Aminyl Radicals

et al. 2018

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5-exo, 5-exo Cyclizations of conformationally unbiased propargylic aminyl radicals proceed with excellent yield, chemoselectiv ity, and diastereoselectivity under tin-free reductive cyclization conditions, regardless of the electronic environments and intermediate radical stabilization resulting from various olefin substituents. These conditions avoid the need for slow addition of initiator and reductant. By contrast, analogous 6-exo, 5-exo cyclizations require substituents capable of intermediate radical stabilization to avoid premature reduction products. These experimental results are corroborated by computations that further establish the reactivity of these aminyl radicals upon exposure to tin-free cyclization conditions.

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confidence: 56%

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confidence: 99%

Synthetic and Computational Study of Tin-Free Reductive Tandem Cyclizations of Neutral Aminyl Radicals

et al. 2018

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“…The structural complexity and observed bioactivities of the Daphniphyllum alkaloids have inspired numerous efforts toward their synthesis. 4,5,6 …”

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confidence: 99%

“…4 This strategy utilized a neutral dialkyl aminyl radical 7 derived from chloroamine 2 to access tricyclic core 3 . 8 This cyclization was the first to employ a neutral aminyl radical in a cyclization with an enone, and represented one of two reported 6- exo cyclizations of aminyl radicals.…”

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Toward the ABCD core of the calyciphylline A-type Daphniphyllum alkaloids: solvent non-innocence in neutral aminyl radical cyclizations

Stockdill

López

Ibrahim

2015

Tetrahedron Letters

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The Daphniphyllum alkaloids remain an attractive target in the synthetic community because of their unique framework and promising biological activities. We have shown that the ABC core of the calyciphylline A-type alkaloids can be rapidly accessed via the tandem cyclization of a neutral aminyl radical with a polarized cyclic olefin. Deuterium labeling experiments and reactions omitting a tin hydride reagent suggest that the solvent is the major source of the terminating hydrogen atom in the cyclization cascade. Incorporation of an internal alkyne in the radical pathway was tolerated in the reaction, and it provided the necessary atoms to enable completion of the D ring of the calyciphylline A-type alkaloids.

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Cyclization Reactions of Nitrogen‐Centered Radicals

McCombie¹,

Quiclet‐Sire²,

Zard³

2021

Organic Reactions

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The cyclization of nitrogen‐centered radicals constitutes a powerful approach for the synthesis of a broad variety of nitrogen heterocycles. As with carbon‐centered radicals, the most common ring‐closure mode is the 5‐ exo cyclization onto an internal unsaturation, and the stereoselectivity is similar. Numerous methods for the generation of almost every type of nitrogen‐centered radical have been described. They involve the direct or indirect rupture of N–Y bonds, with Y = halogen (except fluorine), oxygen, nitrogen, sulfur, and hydrogen. Indirect methods, such as the addition of carbon radicals to imines, azides, and nitriles, have also been devised. The extended choice of methods and precursors, and the general mildness of the experimental conditions and tolerance for numerous functional groups, represent valuable synthetic advantages. Furthermore, the cyclization step can be part of a radical cascade leading to multiple bond formations and the rapid construction of complex molecular frameworks. This chapter describes the types, structures, and reactivity of nitrogen‐centered radicals, and details the mechanistic basis of the methods used to generate them. The methods include stannane‐based processes, oxidations and reductions by single‐electron transfer, thermolysis, electrolysis, photolysis, and photoredox catalysis. The factors that influence the stereoselectivity of the ring‐closures are discussed briefly. Applications to the total synthesis of natural products, as well as functional‐group compatibilities, reaction variants, and comparison to other methods for the synthesis of nitrogen heterocycles by ionic, organometallic, and uncatalyzed ring‐closures onto alkenes are also presented. The tabular surveys are organized according to the type of nitrogen‐centered radical involved in the cyclization step: aminyls, amidyls, carbamyls, iminyls, amidinyls, and other types of nitrogen‐centered radicals.

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Rapid Access to the Heterocyclic Core of the Calyciphylline A and Daphnicyclidin A-Type Daphniphyllum Alkaloids via Tandem Cyclization of a Neutral Aminyl Radical

Cited by 60 publications

References 53 publications

Synthetic and Computational Study of Tin-Free Reductive Tandem Cyclizations of Neutral Aminyl Radicals

Synthetic and Computational Study of Tin-Free Reductive Tandem Cyclizations of Neutral Aminyl Radicals

Toward the ABCD core of the calyciphylline A-type Daphniphyllum alkaloids: solvent non-innocence in neutral aminyl radical cyclizations

Cyclization Reactions of Nitrogen‐Centered Radicals

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