Scope and Mechanism of Direct Indole and Pyrrole Couplings Adjacent to Carbonyl Compounds:  Total Synthesis of Acremoauxin A and Oxazinin 3

Richter, Jeremy M.; Whitefield, Brandon W.; Maimone, Thomas J.; Lin, David W.; Castroviejo, M. Pilar; Baran, Phil S.

doi:10.1021/ja074392m

Cited by 182 publications

(107 citation statements)

References 105 publications

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“…10a Treatment of ketone, ester, or amide enolates with indole anion followed by the addition of a single-electron oxidant (Cu(II) 2-ethylhexanoate is optimal) allows for single-step access to a number of interesting heterocyclic structures that would be difficult to synthesize by other means. 18 This powerful reaction allowed for exceedingly concise syntheses of the hapalindole, fischerindole and welwitindolinone natural products. 6,10,11 Ambiguine H ( 5a ), the simplest ambiguine natural product, was targeted for total synthesis and a retrosynthetic blueprint was developed (Figure 3).…”

Section: Resultsmentioning

confidence: 99%

Scalable total syntheses of (−)-hapalindole U and (+)-ambiguine H

2015

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The Stigonemataceae family of cyanobacteria produces a class of biogenetically related indole natural products that include hapalindoles and ambiguines. In this full account, a practical route to the tetracyclic hapalindole family is presented by way of an eight-step, enantiospecific, protecting-group-free total synthesis of (−)-hapalindole U that features an oxidative indole–enolate coupling. With gram-scale access to hapalindole U, the first total synthesis of an ambiguine alkaloid, (+)-ambiguine H, was completed via an isonitrile-assisted prenylation of an indole followed by a photofragmentation cascade.

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Section: Resultsmentioning

confidence: 99%

Scalable total syntheses of (−)-hapalindole U and (+)-ambiguine H

2015

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“…[135] Although oxidative enolate homodimerization is well-precedented, intermolecular dimerizations are considerably more challenging, often requiring prefunctionalization of one species or the use of a large excess of one coupling partner to achieve reasonable yields. [136] An efficient oxidative copper(II)-mediated protocol that promotes the coupling between the unprotected indole and carvone was developed by Baran and Richter. [137] The core structure of a family of natural products including hapalindole, fischerindole, and ambiguine consists of an indole unit coupled to a carvone unit.…”

Section: Angewandte Chemiementioning

confidence: 99%

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

2009

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Achieving high levels of chemoselectivity has been the Achilles' heel of chemical synthesis. The excitement generated by the successful realization of chemoselective strategies underscores the painstaking efforts to define a set of conditions conducive to selection among the available reaction pathways. We discuss in this Review various aspects of chemoselectivity that have been addressed in a range of synthetic methods over the past decade. We have focused on the proposed mechanistic basis of the reactions under consideration in an attempt to categorize them and highlight the key concepts that have been emerging on the basis of these studies. Our overview of recent advances in chemoselective processes suggests that significant progress has been made, but a lot of challenges lie ahead.

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“…6,9 This was accomplished by deprotonating both reacting partners and reacting them in an oxidative fashion using a copper(II) source. This coupling reaction is applicable to a broad range of carbonyl compounds, generating coupling products from ketones ( 20a – 20q , 20s – 20w , 20ab , 20ac ), esters ( 20r ), and amides ( 20x – 20aa ) (Scheme 3).…”

Section: Enolate Couplingmentioning

confidence: 99%

“…Although this reaction contains interesting mechanistic features, an extensive discussion is beyond the scope of this account and has been reported elsewhere. 9 This indole–enolate coupling reaction showcases an example of an innate, double, selective C–H functionalization method: it is ‘innate’ in that indoles react with electrophiles at its nitrogen atom or at C3, and enolates react at its oxygen atom or at its α carbon; it is a double functionalization, since it is replacing two C–H bonds; and finally, it is selective, as the C–C bond formation selectively takes place over C–N or C–O bond formation.…”

Section: Enolate Couplingmentioning

confidence: 99%

Innate and Guided C–H Functionalization Logic

et al. 2011

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Conspectus The combustion of organic matter is perhaps the oldest and most common chemical transformation utilized by mankind. The generation of a C–O bond at the expense of a C–H bond during this process may be considered the most basic form of C–H functionalization. This illustrates the extreme generality of the term ‘C–H functionalization,’ as it can describe the conversion of literally any C–H bond into a C–X bond (X being anything except H). Therefore, it may be of use to distinguish between what, in our view, are two distinct categories of C–H functionalization logic: ‘guided’ and ‘innate.’ Guided C–H functionalizations, as the name implies, are guided by external reagents or directing groups (covalently or fleetingly bound) to install new functional groups at the expense of specifically targeted C–H bonds. Conversely, innate C–H functionalizations may be broadly defined as reactions that exchange C–H bonds for new functional groups based solely on natural reactivity patterns in the absence of other directing forces. Two substrates that illustrate this distinction are dihydrojunenol and isonicotinic acid. The C–H functionalization processes of hydroxylation or arylation, respectively, can take place at multiple locations on each molecule. Innate functionalizations lead to substitution patterns that are dictated by the inherent bias (steric or electronic) of the substrate undergoing C–H cleavage, whereas guided functionalizations lead to substitution patterns that are controlled by external directing forces such as metal complexation or steric bias of the reagent. Although the distinction between guided and innate C–H functionalizations may not always be clear in cases that do not fit neatly into a single category, it is a useful convention to consider when analyzing reactivity patterns and strategies for synthesis. We must emphasize that although a completely rigorous distinction between guided and innate C–H functionalization may not be practical, we have nonetheless found it to be a useful tool at the planning stage of synthesis. In this Account, we trace our own studies in the area of C–H functionalization in synthesis through the lens of ‘guided’ and ‘innate’ descriptors. We show how harnessing innate reactivity can be beneficial for achieving unique bond constructions between heterocycles and carbonyl compounds, enabling rapid and scalable total syntheses. Guided and innate functionalizations were used synergistically to create an entire family of terpenes in a controlled fashion. We continue with a discussion of the synthesis of complex alkaloids with high nitrogen content, which required the invention of a uniquely chemoselective innate C–H functionalization protocol. These findings led us to develop a series of innate C–H functionalization reactions for forging C–C bonds of interest to the largest body of practicing organic chemists: medicinal chemists. Strategic use of C–H functionalization logic can have a dramatically positive effect on the efficiency of synthesis, whether guided or innate.

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Scope and Mechanism of Direct Indole and Pyrrole Couplings Adjacent to Carbonyl Compounds: Total Synthesis of Acremoauxin A and Oxazinin 3

Cited by 182 publications

References 105 publications

Scalable total syntheses of (−)-hapalindole U and (+)-ambiguine H

Scalable total syntheses of (−)-hapalindole U and (+)-ambiguine H

Chemoselectivity and the Curious Reactivity Preferences of Functional Groups

Innate and Guided C–H Functionalization Logic

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