Asymmetric phosphoric acid–catalyzed four-component Ugi reaction

Zhang, Jian; Yu, Peiyuan; Li, Shaoyu; Sun, Haofan; Xiang, Shao‐Hua; Wang, Jun; Houk, K. N.; Tan, Bin

doi:10.1126/science.aas8707

Cited by 181 publications

(94 citation statements)

References 65 publications

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“…1a, Eq 1). On the other hand, while the activation of stable imines by chiral Brønsted acid catalysts has been extensively investigated in a variety of enantioselective Mannich reactions [25][26][27][28][29][30][31][32][33][34][35][36] , this electrophile-based activating protocol has not been applied to aminomethylation reactions with the in situ-generated formaldimines, probably owing to their generally unstable nature and the lack of steric environment on the carbon atom for efficient stereocontrols (Fig. 1a, Eq 2).…”

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confidence: 99%

Enantioselective three-component aminomethylation of α-diazo ketones with alcohols and 1,3,5-triazines

et al. 2020

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Enantioselective α-aminomethylation of carbonyl compounds constitutes a powerful protocol for introducing aminomethyl groups to simple organic molecules. However, current strategies rely on nucleophile-based enantioselective activation with inherently activated substrates only, and enantioselective protocol based on the activation of in situ-generated unstable formaldimines remains elusive, probably owing to their unstable nature and the lack of steric environment for efficient stereocontrols. Here, based on a rhodium/chiral phosphoric acid cooperative catalysis, we achieved an enantioselective three-component reaction of α-diazo ketones with alcohols and 1,3,5-triazines. A dual hydrogen bonding between the chiral phosphoric acid catalyst and two distinct active intermediates was proposed to be crucial for the efficient electrophile-based enantiocontrol. A series of chiral β-amino-α-hydroxy ketones including those derived from simple aliphatic alcohols, allylic alcohol, propargyl alcohol, complicated natural alcohols and water could all be prepared in high efficiency and enantioselectivity.

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confidence: 99%

Enantioselective three-component aminomethylation of α-diazo ketones with alcohols and 1,3,5-triazines

et al. 2020

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“…For instance, with 10 variations of each reagent, up to 10,000 unique multicomponent products are possible. The Ugi reaction is particularly attractive as a one-pot, single-step, room-temperature reaction 26 that has known catalysts 27,28 , solid supports [29][30][31] , accelerated conditions 32,33 , and multi-step extensions 34 . Ugi reactions have been previously used as secret molecular encryption keys 17 , and to create sequence-defined macromolecules 35 .…”

Section: Resultsmentioning

confidence: 99%

Multicomponent molecular memory

et al. 2020

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Multicomponent reactions enable the synthesis of large molecular libraries from relatively few inputs. This scalability has led to the broad adoption of these reactions by the pharmaceutical industry. Here, we employ the four-component Ugi reaction to demonstrate that multicomponent reactions can provide a basis for large-scale molecular data storage. Using this combinatorial chemistry we encode more than 1.8 million bits of art historical images, including a Cubist drawing by Picasso. Digital data is written using robotically synthesized libraries of Ugi products, and the files are read back using mass spectrometry. We combine sparse mixture mapping with supervised learning to achieve bit error rates as low as 0.11% for single reads, without library purification. In addition to improved scaling of non-biological molecular data storage, these demonstrations offer an information-centric perspective on the high-throughput synthesis and screening of small-molecule libraries.

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“…Since (2R)-isomer is the neuronally active enantiomer in these analogs (see Figure 1), our future studies will straightforwardly focus on the enantioselective synthesis of the only (2R)-isomer. Asymmetric Ugi reaction recently developed [26] is of interest for selective preparation of (2R)-6 (see Schemes 1 and 5) [6,8]. Studies are in progress to develop asymmetric Ugi/Diels-Alder reaction, and the results will be reported in due course.…”

Section: Resultsmentioning

confidence: 99%

Menthyl esterification allows chiral resolution for synthesis of artificial glutamate analogs

Morokuma¹,

Tsukamoto²,

Miyako³

et al. 2020

Preprint

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Herein we report enantiospecific synthesis of two artificial glutamate analogs designed based on IKM–159, an antagonist selective to AMPA-type ionotropic glutamate receptor. The synthesis features chiral resolution of the carboxylic acid intermediate by esterification with L–menthol, followed by configurational analysis by NMR, conformational calculation, and X–ray crystallography. Mice in vivo assay showed that (2R)–MC–27 with six-membered oxacycle is neuroactive, whereas the (2S)–counterpart is inactive. It was also found that the TKM–38 with eight-membered azacycle is neuronally inactive to suggest the possibility that the analog with a smaller five-membered azacycle may act as a potent agent.

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Asymmetric phosphoric acid–catalyzed four-component Ugi reaction

Cited by 181 publications

References 65 publications

Enantioselective three-component aminomethylation of α-diazo ketones with alcohols and 1,3,5-triazines

Enantioselective three-component aminomethylation of α-diazo ketones with alcohols and 1,3,5-triazines

Multicomponent molecular memory

Menthyl esterification allows chiral resolution for synthesis of artificial glutamate analogs

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