Quasi-biomimetic ring contraction promoted by a cysteine-based nucleophile: Total synthesis of Sch-642305, some analogs and their putative anti-HIV activities

Dermenci, Alpay; Selig, Philipp; Domaoal, Robert A.; Spasov, Krasimir A.; Anderson, Karen S.; Miller, Scott J.

doi:10.1039/c1sc00221j

Cited by 54 publications

(31 citation statements)

References 38 publications

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“…(15) The Rauhut-Currier (RC) reaction is similar to the MBH, proceeding with nucleophile catalysis where the nucleophile can be a cysteine-like thiol. Evidence from bioorganic catalysis (16) and examination of a natural synthetic pathway (17) strongly suggest that the RC is catalyzed by natural enzymes. An MBH enzyme would provide a conceptual “missing link” between small-molecule and protein catalysis.…”

Section: Introductionmentioning

confidence: 99%

Computational Design of Enone-Binding Proteins with Catalytic Activity for the Morita–Baylis–Hillman Reaction

Bjelic¹,

Nivón²,

Çelebi‐Ölçüm

et al. 2013

ACS Chem. Biol.

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The Morita-Baylis-Hillman reaction forms a carbon-carbon bond between the alpha carbon of a conjugated carbonyl compound and a carbon electrophile. The reaction mechanism involves Michael addition of a nucleophile catalyst at the carbonyl beta carbon, followed by bond formation with the electrophile and catalyst disassociation to release the product. We used Rosetta to design 48 proteins containing active sites predicted to carry out this mechanism, of which two show catalytic activity by mass spectrometry (MS). Substrate labeling measured by MS and site-directed mutagenesis experiments show that the designed active-site residues are responsible for activity, although rate acceleration over background is modest. To characterize the designed proteins, we developed a fluorescence-based screen for intermediate formation in cell lysates, carried out microsecond molecular dynamics simulations, and solved X-ray crystal structures. These data indicate a partially formed active site, and suggest several clear avenues for designing more active catalysts.

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Section: Introductionmentioning

confidence: 99%

Computational Design of Enone-Binding Proteins with Catalytic Activity for the Morita–Baylis–Hillman Reaction

Bjelic¹,

Nivón²,

Çelebi‐Ölçüm

et al. 2013

ACS Chem. Biol.

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“…Later, the total synthesis of the natural product Sch‐642305 was accomplished with a key RC reaction by cysteine, 2 , by an intramolecular variant of reaction 30. In a separate study, ortho ‐mercaptobenzoic acid and ortho ‐mercaptophenols were found to efficiently catalyze both the intramolecular RC and MBH processes 31.…”

Section: Introductionmentioning

confidence: 99%

Rhodium(III)‐Catalyzed N‐Nitroso‐Directed CH Addition to Ethyl 2‐Oxoacetate for Cycloaddition/Fragmentation Synthesis of Indazoles

Chen

Song

et al. 2014

Chemistry A European J

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Rh(III) -catalyzed N-nitroso-directed CH addition to ethyl 2-oxoacetate allows subsequent construction of indazoles, a privileged heterocycle scaffold in synthetic chemistry, through the exploitation of reactivity between the directing group and installed group. The formal [2+2] cycloaddition/fragmentation reaction pathway identified herein, a unique reactivity pattern hitherto elusive for the N-nitroso group, emphasizes the importance of forward reactivity analysis in the development of useful CH functionalization-based synthetic tools. The synthetic utility of the protocol is demonstrated with the synthesis of a tricyclic-fused ring system. The diversity of covalent linkages available for the nitroso group should enable the extension of the genre of reactivity reported herein to the synthesis of other types of heterocycles.

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“…Later, the total synthesis of the natural product Sch-642305 was accomplished with a key RC reaction by cysteine, 2, by an intramolecular variant of reaction. [30] In a separate study, ortho-mercaptobenzoic acid and ortho-mercaptophenols were found to efficiently catalyze both the intramolecular RC and MBH processes. [31] Additionally, a combined experimental-theoretical study on the enantioselective intramolecular RC of nitro-olefins with tethered enoates using hydrogen-bonding catalysts has been recently published (see Scheme 5).…”

Section: Introductionmentioning

confidence: 99%

The Roles of Counterion and Water in a Stereoselective Cysteine‐Catalyzed Rauhut–Currier Reaction: A Challenge for Computational Chemistry

Osuna¹,

Dermenci²,

Miller³

et al. 2013

Chemistry A European J

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The stereoselective Rauhut-Currier (RC) reaction catalyzed by a cysteine derivative has been explored computationally with DFT (M06-2X) theory. Both methanethiol and a chiral cysteine derivative were studied as nucleophiles. The complete reaction pathway involves rate-determining elimination of the thiol catalyst from the Michael addition product. The stereoselective Rauhut-Currier reaction, catalyzed by a cysteine derivative as nucleophile, has also been studied in detail. This reaction was experimentally found to be extremely sensitive to the reaction conditions, such as the number of water equivalents and the effect of potassium counterion. The E1cB process for catalyst elimination has been explored computationally for the 8 possible stereoisomers. The effect of explicit water solvation and the presence of counterion (either K+ or Na+) has been studied for the lowest energy enantiomer pair (1S, 2R, 3S)/(1R, 2S, 3R).

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Quasi-biomimetic ring contraction promoted by a cysteine-based nucleophile: Total synthesis of Sch-642305, some analogs and their putative anti-HIV activities

Cited by 54 publications

References 38 publications

Computational Design of Enone-Binding Proteins with Catalytic Activity for the Morita–Baylis–Hillman Reaction

Computational Design of Enone-Binding Proteins with Catalytic Activity for the Morita–Baylis–Hillman Reaction

Rhodium(III)‐Catalyzed N‐Nitroso‐Directed CH Addition to Ethyl 2‐Oxoacetate for Cycloaddition/Fragmentation Synthesis of Indazoles

The Roles of Counterion and Water in a Stereoselective Cysteine‐Catalyzed Rauhut–Currier Reaction: A Challenge for Computational Chemistry

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