Highly Regio- and Enantioselective Vicinal Dihalogenation of Allyl Amides

Soltanzadeh, Bardia; Jaganathan, Arvind; Yi, Yi; Yi, Hajoon; Staples, Richard J.; Borhan, Babak

doi:10.1021/jacs.6b09203

Cited by 49 publications

(33 citation statements)

References 46 publications

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“…In der organischen Synthese ist die Dihalogenierung von Alkenen eine wichtige Methode, insbesondere im Bereich der Synthese halogenierter Naturstoffe . Während diastereoselektive Dihalogenierungen bereits häufig beschrieben wurden, ist die Reagenz‐kontrollierte, enantioselektive Dihalogenierung immer noch sehr herausfordernd und nur an speziellen Alkenen möglich . Ein beispielhafter Fall findet sich in der enantioselektiven Synthese des Napyradiomycin A1 von Snyder, der ein synthetisches Intermediat mit vier Äquivalenten einer chiralen Lewissäure komplexierte, um es im Anschluss enantioselektiv mit Chlor als Reagenz zu chlorieren .…”

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“…Enantioselektive Dichlorierungen, ‐bromierungen und Chlorbromierungen von Allylalkoholen wurden auch von Burns unter Verwendung stöchiometrischer und sub‐stöchiometrischer Mengen chiraler Titankomplexe in Kombination mit elektrophilen Halogenierungsreagenzien durchgeführt . Borhan zeigte zudem enantioselektive Dichlorierungen von Allylaminen mit (DHQD) 2 PHAL als Katalysator in Kombination mit 1,3‐Dichlor‐5,5‐dimethylhydantoin (DCDMH) und einem Überschuss an LiCl . Diese Ergebnisse zeigen den erheblichen Fortschritt im Bereich der asymmetrischen Dihalogenierung von Substraten mit funktionellen Gruppen in Allylposition.…”

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Organokatalytische, enantioselektive Dichlorierung unfunktionalisierter Alkene

et al. 2019

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Der Einsatz einer neuen Klasse unsymmetrischer Chinaalkaloid‐basierter, Phthalazin‐verbrückter Organokatalysatoren ermöglichte die hoch enantioselektive Dichlorierung von unfunktionalisierten Alkenen. In Kombination mit dem elektrophilen Chlorierungsmittel 1,3‐Dichlor‐5,5‐dimethylhydantoin (DCDMH) und Triethylsilylchlorid (TES‐Cl) als nukleophiler Chloridquelle wurden 1‐Aryl‐2‐alkylalkene mit Enantioselektivitäten von bis zu 94:6 er dichloriert. Erste mechanistische Untersuchungen deuten darauf hin, dass kein freies Chlor gebildet wird. Das Ersetzen von Chlorid durch Fluorid ermöglichte die enantioselektive Chlorfluorierung von Alkenen.

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Organokatalytische, enantioselektive Dichlorierung unfunktionalisierter Alkene

et al. 2019

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“…14 Previous to our work, no selective synthetic bromochlorination reaction existed. 6b The advent of our regio- and enantioselective bromochlorination method thus enabled rapid access to this class of molecules.…”

Section: Vicinal Bromochloride Natural Productsmentioning

confidence: 99%

“…5 Owing to these obstacles, only a single report of a catalytic, enantioselective dihalogenation by Nicolaou and co-workers had been disclosed prior to our work. 6 This dichlorination requires use of styrenyl olefins to electronically bias chloride delivery and hence has limited synthetic utility. Cognizant of the value and challenges associated with enantioselective dihalogenation, we endeavored to develop a method capable of accessing dihalide motifs on natural product-relevant scaffolds.…”

Section: Introductionmentioning

confidence: 99%

Catalytic Enantioselective Dihalogenation in Total Synthesis

Landry

Burns

2018

Acc. Chem. Res.

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CONSPECTUS To date, more than 5,000 biogenic halogenated molecules have been characterized. This number continues to increase as chemists explore chloride- and bromide-rich marine environments in search of novel bioactive natural products. Naturally-occurring organohalogens span nearly all biosynthetic structural classes, exhibit a range of unique biological activities, and have been the subject of numerous investigations. Despite the abundance of and interest in halogenated molecules, enantioselective methods capable of forging carbon-halogen bonds in synthetically-relevant contexts remain scarce. Accordingly, syntheses of organohalogens often rely on multistep functional group interconversions to establish carbon-halogen stereocenters. Our group has developed an enantioselective dihalogenation reaction and utilized it in the only reported examples of catalytic enantioselective halogenation in natural product synthesis. In this Account, we describe our laboratory’s development of a method for catalytic, enantioselective dihalogenation and the application of this method to the synthesis of both mono- and polyhalogenated natural products. In the first part, we describe the initial discovery of a TADDOL-mediated dibromination of cinnamyl alcohols. Extension of this reaction to a second-generation system capable of selective bromochlorination, dichlorination, and dibromination is then detailed. This system is capable of controlling the enantioselectivity of dihalide formation, chemoselectivity for polyolefinic substrates, and regioselectivity in the case of bromochlorination. The ability of this method to exert control over regioselectivity of halide delivery permits selective halogenation of electronically non-biased olefins required for total synthesis. In the second part, we demonstrate how the described dihalogenation has provided efficient access to a host of structurally diverse natural products. The most direct application of this methodology is in the synthesis of naturally-occurring vicinal dihalides. Chiral vicinal bromochlorides represent a class of >175 natural products; syntheses of five members of this class, including its flagship member, (+)-halomon, have been accomplished through use of the catalytic, enantioselective bromochlorination. Likewise, enantioselective dichlorination has provided selective access to two members of the chlorosulfolipids, a class of linear, acyclic polychlorides. Synthesis of chiral monohalides has been achieved through solvolysis of enantioenriched bromochlorides; this approach has resulted in the synthesis of five bromocyclohexane-containing natural products through an enantiospecific bromopolyene cyclization. In reviewing these syntheses, a framework for the synthesis of chiral organohalogens mediated by catalytic, enantioselective dihalogenation has emerged. The development of a selective dihalogenation method has been highly enabling in the synthesis of halogenated natural products. In this Account, we detail all examples of catalytic, enantioselective halogenation in...

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“…Adaptation of these conditions by Borhan and coworkers to the dichlorination of allylic amides 3 afforded a wide variety of E and Z -disubstituted alkenes with excellent yields and selectivities [27]. In contrast to the method of Nicolaou and coworkers, Cinnamyl and 3,3-dialkyl (trisubstituted) alkene substrates afforded dichloride products with lower enantiomeric ratios, suggesting that the electronic bias of chloriranium opening generally favors the carbon proximal to nitrogen, and stabilization of partial positive charge at the distal carbon reduces that selectivity.…”

Section: Introductionmentioning

confidence: 99%

Organoselenium-catalyzed enantioselective syn-dichlorination of unbiased alkenes

et al. 2019

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The enantioselective dichlorination of alkenes is a continuing challenge in organic synthesis owing to the limitations of selective and independent antarafacial delivery of both electrophilic chlorenium and nucleophilic chloride to an olefin. Development of a general method for the enantioselective dichlorination of isolated alkenes would allow access to a wide variety of polyhalogenated natural products. Accordingly, the enantioselective suprafacial dichlorination of alkenes catalyzed by electrophilic organoselenium reagents has been developed to address these limitations. The evaluation of twenty-three diselenides as precatalysts for enantioselective dichlorination is described, with a maximum e.r. of 76:24 Additionally, mechanistic studies suggest an unexpected Dynamic Kinetic Asymmetric Transformation (DyKAT) process may be operative.

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Highly Regio- and Enantioselective Vicinal Dihalogenation of Allyl Amides

Cited by 49 publications

References 46 publications

Organokatalytische, enantioselektive Dichlorierung unfunktionalisierter Alkene

Organokatalytische, enantioselektive Dichlorierung unfunktionalisierter Alkene

Catalytic Enantioselective Dihalogenation in Total Synthesis

Organoselenium-catalyzed enantioselective syn-dichlorination of unbiased alkenes

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