On the Chlorenium Source in the Asymmetric Chlorolactonization Reaction

Yousefi, Roozbeh; Whitehead, Daniel C.; Mueller, J.; Staples, Richard J.; Borhan, Babak

doi:10.1021/ol102850m

Cited by 106 publications

(62 citation statements)

References 26 publications

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“…Because of the irreversibility of chlorenium transfer as found by Denmark et al and our own group, 10b,13 the first step in paths A and B (Figure 1) is committed (see Supporting Information, section C for further discussion). These two possible paths begin with electrophilic halenium delivery to form a bridged halonium ( I ) or an open β -halo-carbenium ion ( II ), 14 depending on the donor/acceptor nature of substituents attached to the olefin.…”

Section: Resultsmentioning

confidence: 74%

“…To address these issues, we have recently described the halenium affinity scale (HalA), a quantitative ranking of the strengths of interactions of alkenic and heteroatomic Lewis bases with halenium ions. 10a Comparing the HalA(Cl) value for an activated olefin (∼165 kcal/mol) with that of a common Cl + donor such as the monochloro dimethyl hydantoin anion (173.6 kcal/mol), one would predict that simple chlorenium transfer to the alkene would be untenably endothermic (see Supporting Information, section B for further discussion on HalA). Minimization of substrate 1a with a free chlorenium cation results in a simple chloromethyl-substituted benzylic carbenium ion (Figure 3a); the Cl–C–C bond angle and calculated rotation barrier indicate no chlorine bridging in this intermediate, as expected from prior studies.…”

Section: Resultsmentioning

confidence: 99%

“…Our recent mechanistic work, 10 stemming from our ongoing interest in developing asymmetric halofunctionalization reactions, 11 reaffirms the incompleteness of the elementary textbook picture, calling for inclusion of a concerted Ad E 3-type path (formally Ad E 2 for these halocyclizations, where the nucleophile is intramolecular; see Figure 1, path C) 12 in which electrophilic attack on the olefin is activated by the nucleophilic partner's simultaneous electron donation. The present study explores how two species, alkenes and nucleophiles, which otherwise might be expected to electronically repel each other, interact to enable the attack of an approaching electrophile.…”

Section: Introductionmentioning

confidence: 90%

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Nucleophile-Assisted Alkene Activation: Olefins Alone Are Often Incompetent

et al. 2016

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Emerging work on organocatalytic enantioselective halocyclizations naturally draws on conditions where both new bonds must be formed under delicate control, the reaction regime where the concerted nature of the AdE3 mechanism is of greatest importance. Without assistance, many simple alkene substrates react slowly or not at all with conventional halenium donors under synthetically relevant reaction conditions. As demonstrated earlier by Shilov, Cambie, Williams, Fahey, and others, alkenes can undergo a concerted AdE3-type reaction via nucleophile participation, which sets the configuration of the newly created stereocenters at both ends in one step. Herein, we explore the modulation of alkene reactivity and halocyclization rates by nucleophile proximity and basicity, through detailed analyses of starting material spectroscopy, addition stereopreferences, isotope effects, and nucleophile–alkene interactions, all obtained in a context directly relevant to synthesis reaction conditions. The findings build on the prior work by highlighting the reactivity spectrum of halocyclizations from stepwise to concerted, and suggest strategies for design of new reactions. Alkene reactivity is seen to span the range from the often overgeneralized “sophomore textbook” image of stepwise electrophilic attack on the alkene and subsequent nucleophilic bond formation, to the nucleophile-assisted alkene activation (NAAA) cases where electron donation from the nucleophilic addition partner activates the alkene for electrophilic attack. By highlighting the factors that control reactivity across this range, this study suggests opportunities to explain and control stereo-, regio-, and organocatalytic chemistry in this important class of alkene additions.

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Section: Resultsmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 90%

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Nucleophile-Assisted Alkene Activation: Olefins Alone Are Often Incompetent

et al. 2016

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“…Further studies using a series of modified, N-chlorinated hydantoins (both chiral and achiral) supported the hypothesis of participation of complex between the chlorenium source and (DHQD) 2 PHAL in the enantiodetermining step. 20 …”

Section: Introductionmentioning

confidence: 99%

Toward Catalytic, Enantioselective Chlorolactonization of 1,2-Disubstituted Styrenyl Carboxylic Acids

et al. 2016

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An investigation into the use of Lewis base catalysis for the enantioselective chlorolactonization of 1,2-disubstituted alkenoic acids is described. Two mechanistically distinct reaction pathways for catalytic chlorolactonization have been identified. Mechanistic investigation revealed that tertiary amines predominately operate as Brønsted rather than Lewis bases. Two potential modes of activation have been identified that involve donation of electron density of the carboxylate to the C=C bond as well hydrogen bonding to the chlorinating agent. Sulfur- and selenium-based additives operate under Lewis base catalysis; however, due to the instability of the intermediate benzylic chloriranium ion, chlorolactonization suffers from low chemo-, diastereo-, and enantioselectivities. Independent generation of the benzylic chloriranium ion shows that it is in equilibrium with an open cation, which leads to low specificities in the nucleophilic capture of the intermediate.

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“…Subsequent mechanistic studies, probing the role of the chlorenium source, indicate the N1 chlorine of the dichlorodhydantoin serves as an inductive activator, and the N3 chlorine is delivered to the substrate. [49] Jacobsen and co-worker used an anion-binding H-bonding catalysis strategy to achieve enantioselective iodolactonization. [50] Tertiary aminourea complex 81 combined with an I + source gave five-and six-membered iodolactones with high levels of enantioselectivity.…”

Section: Wwwchemeurjorgmentioning

confidence: 99%