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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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Experiments to elucidate the reaction mechanism and application to indole nucleophiles(a) Proposed reaction mechanism involving a covalently bound catalyst-substrate intermediate that undergoes SN2′ displacement. (b) Addition of an achiral dithiophosphinic acid across an olefin proceeds with syn stereoselectivity. (c) Reaction of a cyclic substrate using deuterated catalyst reveals 1,4-syn-stereoselectivity. (d) The overall mechanistic picture suggested by these experiments involves initial syn-addition of the S-H(D) bond across the olefin, followed by syn-SN2′ displacement. R = SO2(4-CH3O-C6H4). (e) Dithiophosphoric acid-catalyzed hydroarylation of indole derivatives; MS = molecular sieves.
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Figure 2: Experiments to elucidate the reaction mechanism and application to indole nucleophiles(a) Proposed reaction mechanism involving a covalently bound catalyst-substrate intermediate that undergoes SN2′ displacement. (b) Addition of an achiral dithiophosphinic acid across an olefin proceeds with syn stereoselectivity. (c) Reaction of a cyclic substrate using deuterated catalyst reveals 1,4-syn-stereoselectivity. (d) The overall mechanistic picture suggested by these experiments involves initial syn-addition of the S-H(D) bond across the olefin, followed by syn-SN2′ displacement. R = SO2(4-CH3O-C6H4). (e) Dithiophosphoric acid-catalyzed hydroarylation of indole derivatives; MS = molecular sieves.

Mentions: A number of additional experiments were performed in order to further elucidate the mechanism of this transformation (Fig. 2). We began by analyzing aliquots taken during the course of the catalytic reaction of 1 using time-of-flight mass spectrometry (TOF-MS). A new peak that was fully consistent (m/z and isotopic distribution) with proposed intermediate 6 was observed (Fig. 2A, Supporting Figs. 4 and 5). The proposed formation of this intermediate is also supported by the fact that the addition of dithiophosphoric acids across alkenes and dienes is a well-established process20,22,26,27.


Asymmetric additions to dienes catalysed by a dithiophosphoric acid.

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

Experiments to elucidate the reaction mechanism and application to indole nucleophiles(a) Proposed reaction mechanism involving a covalently bound catalyst-substrate intermediate that undergoes SN2′ displacement. (b) Addition of an achiral dithiophosphinic acid across an olefin proceeds with syn stereoselectivity. (c) Reaction of a cyclic substrate using deuterated catalyst reveals 1,4-syn-stereoselectivity. (d) The overall mechanistic picture suggested by these experiments involves initial syn-addition of the S-H(D) bond across the olefin, followed by syn-SN2′ displacement. R = SO2(4-CH3O-C6H4). (e) Dithiophosphoric acid-catalyzed hydroarylation of indole derivatives; MS = molecular sieves.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 2: Experiments to elucidate the reaction mechanism and application to indole nucleophiles(a) Proposed reaction mechanism involving a covalently bound catalyst-substrate intermediate that undergoes SN2′ displacement. (b) Addition of an achiral dithiophosphinic acid across an olefin proceeds with syn stereoselectivity. (c) Reaction of a cyclic substrate using deuterated catalyst reveals 1,4-syn-stereoselectivity. (d) The overall mechanistic picture suggested by these experiments involves initial syn-addition of the S-H(D) bond across the olefin, followed by syn-SN2′ displacement. R = SO2(4-CH3O-C6H4). (e) Dithiophosphoric acid-catalyzed hydroarylation of indole derivatives; MS = molecular sieves.
Mentions: A number of additional experiments were performed in order to further elucidate the mechanism of this transformation (Fig. 2). We began by analyzing aliquots taken during the course of the catalytic reaction of 1 using time-of-flight mass spectrometry (TOF-MS). A new peak that was fully consistent (m/z and isotopic distribution) with proposed intermediate 6 was observed (Fig. 2A, Supporting Figs. 4 and 5). The proposed formation of this intermediate is also supported by the fact that the addition of dithiophosphoric acids across alkenes and dienes is a well-established process20,22,26,27.

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