Enantioselective Brønsted Acid-Catalyzed <i>N</i>-Acyliminium Cyclization Cascades

Muratore, Michael E.; Holloway, Chloe A.; Pilling, Adam W.; Storer, Richard; Trevitt, Graham; Dixon, Darren J.

doi:10.1021/ja9024885

Cited by 385 publications

(184 citation statements)

References 38 publications

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“…Both protein-binding frequencies and selectivities are increased among compounds having: (i) increased content of sp 3 -hybridized atoms relative to commercial compounds, and (ii) intermediate frequency of stereogenic elements relative to commercial (low frequency) and natural (high frequency) compounds. Encouragingly, these favorable structural features are increasingly accessible using modern advances in the methods of organic synthesis (21)(22)(23)(24)(25)(26) and commonly targeted by academic organic chemists as judged by the compounds used in this study that were contributed by 6. Analysis of binding promiscuity among hit compounds.…”

Section: Discussionmentioning

confidence: 99%

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

Clemons

Bodycombe²,

Carrinski³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

323

333

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Using a diverse collection of small molecules generated from a variety of sources, we measured protein-binding activities of each individual compound against each of 100 diverse (sequence-unrelated) proteins using small-molecule microarrays. We also analyzed structural features, including complexity, of the small molecules. We found that compounds from different sources (commercial, academic, natural) have different protein-binding behaviors and that these behaviors correlate with general trends in stereochemical and shape descriptors for these compound collections. Increasing the content of sp 3 -hybridized and stereogenic atoms relative to compounds from commercial sources, which comprise the majority of current screening collections, improved binding selectivity and frequency. The results suggest structural features that synthetic chemists can target when synthesizing screening collections for biological discovery. Because binding proteins selectively can be a key feature of high-value probes and drugs, synthesizing compounds having features identified in this study may result in improved performance of screening collections. S mall-molecule probe-and drug-discovery activities in academia and the pharmaceutical industry often begin with highthroughput screening. Many thousands of small molecules are tested with the expectation that each has potential as a discovery lead. Thus, assembling or synthesizing compound collections for small-molecule screening represents an important step in discovery success, particularly when selecting among compounds from a variety of synthetic and natural sources. Unbiased methods to evaluate the assay performance of compounds from different sources, and to relate performance to chemical structure (defined by computed structural properties) (1, 2), can provide guidance to one element of more valuable small-molecule screening collections.Comparative analyses between compounds often involve cheminformatic analysis of compound structures (3-5) or retrospective analysis of compound performance by mining the literature (6-8) or historical data (9, 10). For example, intermediate molecular complexity has been suggested as theoretically preferable for drug leads (11), and this relationship is supported by evidence mined from historical data (9). In this study, we performed unbiased comparisons of compounds from natural and synthetic sources by first identifying compounds with unknown activities and then exposing them to a common assay platform. We identified a compound collection comprising three subsets: (i) 6,152 compounds from commercial sources that are representative of many common screening collections (commercial compounds; CC); (ii) 6,623 compounds assembled from the academic synthetic chemistry community using, e.g., diversity-oriented synthesis (diverse compounds; DC); and (iii) 2,477 naturally occurring compounds (natural products; NP). We then (i) analyzed distributions of stereochemical and shape complexity for each set;(ii) measured protein-binding activities of each membe...

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Section: Discussionmentioning

confidence: 99%

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

Clemons

Bodycombe²,

Carrinski³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

323

333

View full text Add to dashboard Cite

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“…This observation is clearly in contradiction with previously reported works in which amine catalysts were compatible with gold catalysts. [40][41][42][43][44] Indeed, in our case, it seems that the acid prevents the deactivation of the gold catalyst, by interacting with the amine organocatalyst. The amount of p-TsOH should be at least the same as the one of diphenylprolinol silyl ether V so that the reaction can occur (entry 2, Table 8).…”

Section: Nitroenynesmentioning

confidence: 94%

“…[40] Dixon also documented an Au(I) and chiral Brønsted acid multicatalyst cascade in the enantioselective cyclization cascade. [41] Gong reported that the gold catalysis and Brønsted acid catalysis are compatible in the gold-catalyzed hydroamination and transfer hydrogenation. [42] However, those works refer to dual or cooperative catalysis.…”

Section: Nitroenynesmentioning

confidence: 99%

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes and Synthetic Applications

et al. 2010

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The purpose of this study is to point out the synthetic utility of a new class of Michael acceptors (nitrodienes and nitroenynes). The highly enantioselective organocatalytic Michael addition of carbonyl compounds to these functionalized nitroolefins has been carried out in the presence of (S)-diphenylprolinol silyl ether to achieve some interesting building blocks in high selectivities. The adducts thus obtained can be easily converted by taking advantage of the corresponding unsaturated carbon-carbon bond. In presence of the double bond, metathesis or electrophilic activation could be carried out whereas in the presence of the triple bond electrophilic activation could be conducted. We thus focused on a gold-catalyzed cyclization of the bis-homopropargylic alcohol to afford the corresponding substituted tetrahydrofuran. Then, we also demonstrated that organic and gold catalysts were compatible in a one-pot process. Indeed, we developed a one-pot enantioselective organocatalytic Michael addition to a nitroenyne followed by a gold-catalyzed acetalization/cyclization to achieve tetrahydrofuranyl ethers in high diastereoand enantioselectivities with excellent yields.

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“…In the past, organocatalysts exhibiting weak metal-coordination abilities have successfully been combined with transition metal catalysis in elegant reactions. A relatively well-studied system in this direction includes a combined use of a transition metal (such as gold, palladium, iridium, ruthenium) catalyst with chiral amine or phosphoric acid catalysts [7][8][9][10][11][12][13][14] . In contrast, the combined use of N-heterocyclic carbenes(NHCs) as organocatalysts [15][16][17][18] that can likely behave as strong-coordinating ligands [19][20][21][22] with transition metal catalysts remains challenging.…”

mentioning

confidence: 99%

Metal and carbene organocatalytic relay activation of alkynes for stereoselective reactions

et al. 2014

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Transition metal and organic catalysts have established their own domains of excellence. It has been expected that merging the two unique domains should provide complimentary or unprecedented opportunities in converting simple raw materials to functional products. N-heterocyclic carbenes alone are excellent organocatalysts. When used with transition metals such as copper, N-heterocyclic carbenes are routinely practiced as strong-coordinating ligands. Combination of an N-heterocyclic carbene and copper therefore typically leads to deactivation of either or both of the two catalysts. Here we disclose the direct merge of copper as a metal catalyst and N-heterocyclic carbenes as an organocatalyst for relay activation of alkynes. The reaction involves copper-catalysed activation of alkynes to generate ketenimine intermediates that are subsequently activated by an N-heterocyclic carbene organocatalyst for stereoselective reactions. Each of the two catalysts (copper metal catalyst and N-heterocyclic carbene organocatalyst) accomplishes its own missions in the activation steps without quenching each other.

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Enantioselective Brønsted Acid-Catalyzed N-Acyliminium Cyclization Cascades

Cited by 385 publications

References 38 publications

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

Small molecules of different origins have distinct distributions of structural complexity that correlate with protein-binding profiles

Organocatalyzed Conjugate Addition of Carbonyl Compounds to Nitrodienes/Nitroenynes and Synthetic Applications

Metal and carbene organocatalytic relay activation of alkynes for stereoselective reactions

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