Regioselective functionalization of bicyclic piperazinedione bridgehead carbanions

Williams, Robert M.; Dung, Jen Sen; Josey, John A.; Armstrong, Robert W.; Meyers, Harold V.

doi:10.1021/ja00348a042

Cited by 29 publications

(7 citation statements)

References 8 publications

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“…The 5-amine of THF is indeed a poor leaving group, and the carbanion intermediate can be stabilized through conjugation with the pyrimidine ring, but the C5 proton is in a pseudoequatorial position, which would make it less acidic than if it were pseudoaxial, where conjugation between the developing carbanion and C4 carbonyl could occur. That such an equatorial proton could be more acidic than expected has been demonstrated in a study of bridgehead carbanions derived from bicyclic piperazinediones (Williams et al, 1983). However, a possibly more important factor in increasing the acidity of the C5 proton is the unstable Cys 146-C6 conjugate, as discussed in the next two sections.…”

Section: Resultsmentioning

confidence: 81%

Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of Escherichia coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate^,

1997

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Two crystal structures for E. coli thymidylate synthase (TS) bound to the mechanism-based inhibitor 5-fluoro-dUMP (FdUMP) and methylenetetrahydrofolate (CH2THF) have been determined to 2.6 and 2.2 A nominal resolutions, with crystallographic R factors of 0.180 and 0.178, respectively. The inhibitor and cofactor are well ordered in both structures and display covalent links to each other and to Cys 146 in the TS active site. The structures are in general agreement with a previous report for this complex (D. A. Matthews et al. (1990) J. Mol. Biol. 214, 937-948), but differ in two key respects: (i) the methylene bridge linking FdUMP and CH2THF is rotated about 60 degrees to a different position and (ii) the electron density for C6 of FdUMP, which is covalently linked to Cys 146, is more diffuse than for the other atoms in the pyrimidine ring. The ligand arrangement observed in the previous structure led the authors to propose that a large conformational change in ligand geometry must occur in order to facilitate catalysis and yield the correct chirality in the methyl of product dTMP. The new structures suggest a different mechanism for product formation that does not require ligands to greatly alter their conformations during catalysis and which makes use of instability in the nucleotide-Cys 146 thiol adduct to avoid a deep free energy well and assist in proton abstraction from dUMP. All intermediates in the proposed mechanism were modeled and energy minimized in the TS active site, and all can be accommodated in the present structures. The role of ligand-induced conformational change in the TS mechanism and the possibility of Tyr 94 acting as a base during catalysis are also discussed.

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Section: Resultsmentioning

confidence: 81%

Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of Escherichia coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate^,

1997

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“…3 On the other hand, the bridgehead hydrogen atom (H b ) adjacent to the oxygen atom of piperazinedione (2) is abstracted more readily than that of the alternative one (H a ). 4 We have reported that the double bond migration of 3-C-nitrohex-2-enitol 3 occurred more smoothly than that of the corresponding 5a-carba sugar 6. 5 On the basis of these results we achieved an unprecedented example, in which a vinyl ether (glycal) became a major product by oxidative elimination of the seleno group of 7.…”

mentioning

confidence: 89%

Communication: Double Bond Migration of a 1,5-Anhydro-3-C-p-Tolylsulfonyl-D-Hex-2-Enitol Derivative and the Corresponding 5a-Carba-Dl-Sulfonyl Sugar

Sakakibara¹,

Shindo²,

Narumi³

et al. 2000

Journal of Carbohydrate Chemistry

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“…1 We devised an electrophilic glycine species ( 1 ) that was used to address the installation of the branched isoleucine bridge constituting the bicyclo[4.2.2]diazadecane ring system. 2 Conversion of lactone 3 into the bicyclic substrate 4 was followed by regioselective bridgehead carbanion oxidation and double diastereo-differentiating aldol condensation. The overall synthesis constituted just twelve steps from commercially available glycine anhydride.…”

Section: Introductionmentioning

confidence: 99%

Natural Products Synthesis: Enabling Tools To Penetrate Nature’s Secrets of Biogenesis and Biomechanism

Williams

2011

J. Org. Chem.

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Selected examples from our laboratory of how synthetic technology platforms developed for the total synthesis of several disparate families of natural products was harnessed to penetrate biomechanistic and/or biosynthetic queries is discussed. Unexpected discoveries of biomechanistic reactivity and/or penetrating the biogenesis of naturally occurring substances were made possible through access to substances available only through chemical synthesis. Hypothesis-driven total synthesis programs are emerging as very useful conceptual templates for penetrating and exploiting the inherent reactivity of biologically active natural substances. In many instances, new enabling synthetic technologies were required to be developed. The examples demonstrate the often un-tapped richness of complex molecule synthesis to provide powerful tools to understand, manipulate and exploit Nature’s vast and creative palette of secondary metabolites.

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Regioselective functionalization of bicyclic piperazinedione bridgehead carbanions

Cited by 29 publications

References 8 publications

Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of Escherichia coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate^,

Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of Escherichia coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate^,

Communication: Double Bond Migration of a 1,5-Anhydro-3-C-p-Tolylsulfonyl-D-Hex-2-Enitol Derivative and the Corresponding 5a-Carba-Dl-Sulfonyl Sugar

Natural Products Synthesis: Enabling Tools To Penetrate Nature’s Secrets of Biogenesis and Biomechanism

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Regioselective functionalization of bicyclic piperazinedione bridgehead carbanions

Cited by 29 publications

References 8 publications

Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of Escherichia coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate,

Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of Escherichia coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate,

Communication: Double Bond Migration of a 1,5-Anhydro-3-C-p-Tolylsulfonyl-D-Hex-2-Enitol Derivative and the Corresponding 5a-Carba-Dl-Sulfonyl Sugar

Natural Products Synthesis: Enabling Tools To Penetrate Nature’s Secrets of Biogenesis and Biomechanism

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Product

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About

Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of Escherichia coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate^,

Use of Strain in a Stereospecific Catalytic Mechanism: Crystal Structures of Escherichia coli Thymidylate Synthase Bound to FdUMP and Methylenetetrahydrofolate^,