Synthesis of (−)-Pseudotabersonine, (−)-Pseudovincadifformine, and (+)-Coronaridine Enabled by Photoredox Catalysis in Flow

Beatty, Joel W.; Stephenson, Corey R. J.

doi:10.1021/ja506170g

Cited by 156 publications

(78 citation statements)

References 49 publications

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“…We have subsequently leveraged this knowledge by productively employing α-amino radical cations and iminium intermediates in methodology, 13 total synthesis, 14 and the synthesis of pharmaceuticals. 15,16 …”

Section: Initial Methodology and Applications To Total Synthesismentioning

confidence: 99%

Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer

2016

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ConspectusHarnessing visible light as the driving force for chemical transformations generally offers a more environmentally friendly alternative compared with classical synthetic methodology. The transition metal-based photocatalysts commonly employed in photoredox catalysis absorb efficiently in the visible spectrum, unlike most organic substrates, allowing for orthogonal excitation. The subsequent excited states are both more reducing and more oxidizing than the ground state catalyst and are competitive with some of the more powerful single-electron oxidants or reductants available to organic chemists yet are simply accessed via irradiation. The benefits of this strategy have proven particularly useful in radical chemistry, a field that traditionally employs rather toxic and hazardous reagents to generate the desired intermediates.In this Account, we discuss our efforts to leverage visible light photoredox catalysis in radical-based bond-forming and bond-cleaving events for which few, if any, environmentally benign alternatives exist. Mechanistic investigations have driven our contributions in this field, for both facilitating desired transformations and offering new, unexpected opportunities. In fact, our total synthesis of (+)-gliocladin C was only possible upon elucidating the propensity for various trialkylamine additives to elicit a dual behavior as both a reductive quencher and a H-atom donor. Importantly, while natural product synthesis was central to our initial motivations to explore these photochemical processes, we have since demonstrated applicability within other subfields of chemistry, and our evaluation of flow technologies demonstrates the potential to translate these results from the bench to pilot scale.Our forays into photoredox catalysis began with fundamental methodology, providing a tin-free reductive dehalogenation that exchanged the gamut of hazardous reagents previously employed for such a transformation for visible light-mediated, ambient temperature conditions. Evolving from this work, a new avenue toward atom transfer radical addition (ATRA) chemistry was developed, enabling dual functionalization of both double and triple bonds. Importantly, we have also expanded our portfolio to target clinically relevant scaffolds. Photoredox catalysis proved effective in generating high value fluorinated alkyl radicals through the use of abundantly available starting materials, providing access to libraries of trifluoromethylated (hetero)arenes as well as intriguing gem-difluoro benzyl motifs via a novel photochemical radical Smiles rearrangement. Finally, we discuss a photochemical strategy toward sustainable lignin processing through selective C–O bond cleavage methodology. The collection of these efforts is meant to highlight the potential for visible light-mediated radical chemistry to impact a variety of industrial sectors.

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Section: Initial Methodology and Applications To Total Synthesismentioning

confidence: 99%

Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer

2016

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“…Our initial strategy for the synthesis of 1-aminoNBs [18] (see Figure 1A)was informed by our prior efforts leveraging photoredox catalysis for amine oxidation. [19][20][21][22] While the majority of amine oxidation methods lead to a-amino radicals through heterolytic decomposition of amine radical cation intermediates, [10,23] our initial approach operated through strain-driven homolytic decomposition of oxidized aminocyclopropanes,g enerating ac arbon-centered radical that proceeds to the norbornane core via serialized radical cyclizations.Unfortunately,this strategy only proved effective for N,N-dialkylaminocyclopropane starting materials,prohibiting our planned applications of C1-NH 2 1-aminoNBs. Circumventing this limitation would require another means of accessing open-shell character at nitrogen (see Figure 1B).…”

Section: Introductionmentioning

confidence: 99%

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

et al. 2019

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This report details the development of a masked N‐centered radical strategy that harvests the energy of light to drive the conversion of cyclopropylimines to 1‐aminonorbornanes. This process employs the N‐centered radical character of a photoexcited imine to facilitate the homolytic fragmentation of the cyclopropane ring and the subsequent radical cyclization sequence that forms two new C−C bonds en route to the norbornane core. Achieving bond‐forming reactivity as a function of the N‐centered radical character of an excited state Schiff base is unique, requiring only violet light in this instance. This methodology operates in continuous flow, enhancing the potential to translate beyond the academic sector. The operational simplicity of this photochemical process and the structural novelty of the (hetero)aryl‐fused 1‐aminonorbornane products are anticipated to provide a valuable addition to discovery efforts in pharmaceutical and agrochemical industries.

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“…Alternatively, binding of secodine (10) to TiDPAS1/2 may 30 provide an enantiomerically enriched cyclization product. However, formation of (-)vincadifformine (11) is not dependent on the presence of a dedicated cyclase enzyme (9).…”

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confidence: 97%

“…B. Biosynthesis of (+)-catharanthine (4). C. Biosynthesis of (-)-vincadifformine (11). D. Biosynthesis of (-)-tabersonine (12).…”

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confidence: 99%

“…1C, green box). We hypothesize that with excess NADPH, TiDPAS1/2 over-reduces precondylocarpine acetate (7) to form secodine (10), which, in the absence of a dedicated cyclase enzyme, cyclizes spontaneously via a Diels-Alder mechanism to form vincadifformine (11). Biomimetic syntheses have shown that a (±)-vincadifformine analog 25 readily forms from secodine (10), potentially due to the propensity of secodine (10) to adopt the conformation required for this Diels-Alder cyclization (7,8).…”

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Biosynthesis of an Anti-Addiction Agent from the Iboga Plant

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Kamileen

Caputi

et al. 2019

Preprint

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Ibogaine and (-)-voacangine are plant derived psychoactives that show promise as effective treatments for opioid addiction. However, these compounds are produced by hard to source plants making these chemicals difficult for broad-scale use. Here we report the complete biosynthesis of (-)-voacangine, and de-esterified voacangine, which is converted to (-)-ibogaine 15 by heating. This discovery will enable production of these compounds by synthetic biology methods. Notably, (-)-ibogaine and (-)-voacangine are of the opposite enantiomeric configuration compared to the other major alkaloids found in this natural product class. Discovery of these biosynthetic enzymes therefore demonstrates how nature generates both enantiomeric series of this medically important alkaloid scaffold using closely related enzymes, 20 including those that catalyze enantioselective formal Diels-Alder reactions.One Sentence Summary: Biosynthesis of iboga alkaloids with anti-addiction promise reveals enantioselectivity of enzymatic Diels-Alder reactions.Main Text: (up to ~2500 words including references, notes and captions) Treatment of opiate addiction remains challenging, with over 45-thousand people in the 25 United States dying in 2017 and a 500% increase in yearly opioid overdose deaths since the year 2000 (1). (-)-Ibogaine (1) (Fig. 1A), a plant-derived iboga-type alkaloid, has anti-addictive properties that were discovered accidentally by Howard Lotsof in 1962 when he noticed that ingesting this compound mitigated heroin cravings and acute opiate withdrawal symptomatology (2, 3). Although the toxicity of (-)-ibogaine (1) has slowed its formal approval for addiction 30 treatment in many countries, increased knowledge of its mode of action, side-effects and the discovery of (-)-ibogaine (1) analogs clearly indicate its potential as an anti-addictive agent (2-4). The plant that synthesizes (-)-ibogaine (1), Tabernanthe iboga (Iboga), is difficult to cultivate, prompting interest in developing biocatalytic methods for (-)-ibogaine (1) production. While the biosynthesis of the (+)-iboga type alkaloid scaffold has been recently elucidated (5), 35 biosynthesis of the antipodal (-)-ibogaine (1) remained uncertain. Here we show that (-)ibogaine (1) biosynthesis uses the same starting substrate as observed in (+)-iboga biosynthesis, but the key cyclization step proceeds via a distinct mechanism to generate the reduced iboga alkaloid (-)-coronaridine (2) (Fig. 1A). We further demonstrate that enzymatically generated (-)coronaridine (2) can be 10-hydroxylated and 10-O-methylated (6) to form (-)-voacangine (3), 40 and treatment of (-)-voacangine (3) with a T. iboga esterase reported here, followed by heating,

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Synthesis of (−)-Pseudotabersonine, (−)-Pseudovincadifformine, and (+)-Coronaridine Enabled by Photoredox Catalysis in Flow

Cited by 156 publications

References 49 publications

Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer

Free Radical Chemistry Enabled by Visible Light-Induced Electron Transfer

Exploiting Imine Photochemistry for Masked N‐Centered Radical Reactivity

Biosynthesis of an Anti-Addiction Agent from the Iboga Plant

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