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Asymmetric additions to dienes catalysed by a dithiophosphoric acid.

Shapiro ND, Rauniyar V, Hamilton GL, Wu J, Toste FD - Nature (2011)

Bottom Line: Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess.We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism.The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Chemistry, University of California, Berkeley, California 94720, USA [2].

ABSTRACT
Chiral Brønsted acids (proton donors) have been shown to facilitate a broad range of asymmetric chemical transformations under catalytic conditions without requiring additional toxic or expensive metals. Although the catalysts developed thus far are remarkably effective at activating polarized functional groups, it is not clear whether organic Brønsted acids can be used to catalyse highly enantioselective transformations of unactivated carbon-carbon multiple bonds. This deficiency persists despite the fact that racemic acid-catalysed 'Markovnikov' additions to alkenes are well known chemical transformations. Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess. We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism. The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems.

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A possible solution to the mechanistic challenge of asymmetric acid-catalyzed additions to olefins(a) Protonation of an imine with a chiral Brønsted acid (X*–H) leads to a hydrogen bonded intermediate, while protonation of an olefin results in a carbocation that cannot form a hydrogen bond. (b) Proposed mechanism wherein a nucleophilic chiral acid adds to a diene then undergoes enantioselective SN2′ displacement.
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Figure 1: A possible solution to the mechanistic challenge of asymmetric acid-catalyzed additions to olefins(a) Protonation of an imine with a chiral Brønsted acid (X*–H) leads to a hydrogen bonded intermediate, while protonation of an olefin results in a carbocation that cannot form a hydrogen bond. (b) Proposed mechanism wherein a nucleophilic chiral acid adds to a diene then undergoes enantioselective SN2′ displacement.

Mentions: This unfortunate limitation can perhaps be explained by considering the different intermediates generated by protonation of an imine or carbonyl versus an olefin (Fig. 1A). Protonation of an imine or carbonyl generates a species that can hydrogen bond with the conjugate base of the chiral Brønsted acid. This hydrogen bond serves as an anchor to keep the chiral information close to the reactive electrophile and also contributes to the molecular organization that favours one particular diastereomeric transition state. On the other hand, protonation of an olefin leads to a carbocation. Although the conjugate base of the chiral acid can still be held in proximity to the carbocation through electrostatic interactions, the lack of rigidity in this association presumably results in poor discrimination between the enantiotopic faces of the carbocation. In fact, a recent review on chiral Brønsted acid catalysis goes as far as to say that “The key to realizing enantioselective catalysis using a chiral Brønsted acid is the hydrogen bonding interaction between a protonated substrate and the chiral conjugate base”3. Clearly, a conceptually different approach is needed to achieve the desired enantioselective additions to olefins.


Asymmetric additions to dienes catalysed by a dithiophosphoric acid.

Shapiro ND, Rauniyar V, Hamilton GL, Wu J, Toste FD - Nature (2011)

A possible solution to the mechanistic challenge of asymmetric acid-catalyzed additions to olefins(a) Protonation of an imine with a chiral Brønsted acid (X*–H) leads to a hydrogen bonded intermediate, while protonation of an olefin results in a carbocation that cannot form a hydrogen bond. (b) Proposed mechanism wherein a nucleophilic chiral acid adds to a diene then undergoes enantioselective SN2′ displacement.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3104668&req=5

Figure 1: A possible solution to the mechanistic challenge of asymmetric acid-catalyzed additions to olefins(a) Protonation of an imine with a chiral Brønsted acid (X*–H) leads to a hydrogen bonded intermediate, while protonation of an olefin results in a carbocation that cannot form a hydrogen bond. (b) Proposed mechanism wherein a nucleophilic chiral acid adds to a diene then undergoes enantioselective SN2′ displacement.
Mentions: This unfortunate limitation can perhaps be explained by considering the different intermediates generated by protonation of an imine or carbonyl versus an olefin (Fig. 1A). Protonation of an imine or carbonyl generates a species that can hydrogen bond with the conjugate base of the chiral Brønsted acid. This hydrogen bond serves as an anchor to keep the chiral information close to the reactive electrophile and also contributes to the molecular organization that favours one particular diastereomeric transition state. On the other hand, protonation of an olefin leads to a carbocation. Although the conjugate base of the chiral acid can still be held in proximity to the carbocation through electrostatic interactions, the lack of rigidity in this association presumably results in poor discrimination between the enantiotopic faces of the carbocation. In fact, a recent review on chiral Brønsted acid catalysis goes as far as to say that “The key to realizing enantioselective catalysis using a chiral Brønsted acid is the hydrogen bonding interaction between a protonated substrate and the chiral conjugate base”3. Clearly, a conceptually different approach is needed to achieve the desired enantioselective additions to olefins.

Bottom Line: Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess.We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism.The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Chemistry, University of California, Berkeley, California 94720, USA [2].

ABSTRACT
Chiral Brønsted acids (proton donors) have been shown to facilitate a broad range of asymmetric chemical transformations under catalytic conditions without requiring additional toxic or expensive metals. Although the catalysts developed thus far are remarkably effective at activating polarized functional groups, it is not clear whether organic Brønsted acids can be used to catalyse highly enantioselective transformations of unactivated carbon-carbon multiple bonds. This deficiency persists despite the fact that racemic acid-catalysed 'Markovnikov' additions to alkenes are well known chemical transformations. Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess. We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism. The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems.

Show MeSH
Related in: MedlinePlus