Diastereoselectivity in nucleophilic displacement reactions at phosphorus; isolation and characterization of a pentacoordinated intermediate

Merckling, F. A.; Rüedi, Peter

doi:10.1016/0040-4039(96)00275-4

Cited by 17 publications

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“…Given the increased concentration of the reactive nucleophilic thiolate in 1 relative to that of the corresponding alkoxide in 5 under these conditions, this 27-fold observed difference indicates the rate of thiolate attack on the adjacent phosphodiester bond is a striking 10 7 -fold slower than that of the corresponding alkoxide. Thus, thiolate groups are remarkably reticent nucleophiles when the target is an electrophilic phosphate center. , …”

Section: Resultsmentioning

confidence: 99%

Reactivity of a 2‘-Thio Nucleotide Analog

Dantzman

Kiessling

1996

J. Am. Chem. Soc.

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The chemical reactivity of ribonucleotide analog 2‘-deoxy-2‘-thiouridine 3‘-(p-nitrophenyl phosphate) (1), in which the 2‘ hydroxyl is replaced with a 2‘-thiol group, has been characterized. The major reaction pathway for 1, as monitored by 31P NMR spectroscopy, is transphosphorylation to afford 2‘,3‘-cyclic phosphorothioate 3, followed by hydrolysis of 3 to produce 2‘-deoxy-2‘-thiouridine 2‘-phosphorothioate (4). Thus, the reaction pathway of 1 is similar to that of the hydrolysis of ribonucleotides, yet there are significant differences. The pH−rate profile for transphosphorylation of 1 was determined by monitoring the formation of p-nitrophenol or p-nitrophenolate by UV−visible spectroscopy. Analysis of the profile reveals the attacking nucleophile to be thiolate, and the pK a of the 2‘-thiol was determined to be 8.3 ± 0.1. At pH 7.4, the thiol-containing ribonucleotide analog 1 is hydrolyzed at an observed rate 27-fold slower than its 2‘-hydroxyl counterpart. These results indicate that the rate of thiolate attack on the adjacent phosphodiester bond is 107-fold slower than that of the corresponding alkoxide. Thiolate nucleophiles, therefore, are remarkably reticent toward attack at electrophilic phosphate centers. In addition to providing new information about the reactivity of phosphodiester bonds, our studies highlight the potential of 2‘-thiol-containing nucleotides for the study of an array of RNA processes, especially those in which the 2‘-substituent plays a critical role.

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Section: Resultsmentioning

confidence: 99%

Reactivity of a 2‘-Thio Nucleotide Analog

Dantzman

Kiessling

1996

J. Am. Chem. Soc.

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“…1 3 ) For the most comprehensive, critical review covering the last 4 decades of research on that subject, see 1281. 14) We recently demonstrated [29] that also the bulkiness of otherwise very similar auxiliary bases can be crucial in the stereochemical outcome of nucleophilic catalysed displacements at P. 15) Recently, it could be shown by X-ray analysis [9] that the phosphonylation of a-lytic protease by P-epimeric hexapeptide analogues yields the same covalent adduct. This result indicates inversion of configuration at P for one diastereoisomer and retention for the other one.…”

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confidence: 97%

Stereochemistry of the Inhibition of δ‐Chymotrypsin with Optically Active Bicyclic Organophosphates: ³¹P‐NMR studies

Ganci

Meier

Merckling

et al. 1997

Helvetica Chimica Acta

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The inhibition of S-chymotrypsin with optically active, axially and equatorially substituted frans-3-(2,4-dinitrophenoxy)-2,4-dioxa-325-phosphabicyclo[4.4.O]decan-3-ones ( = hexahydro-4H-1,3,2-benzodioxaphosphorin 3-oxides) was investigated. Their inhibitory power was determined by kinetic measurements, and the stereochemical course of the reaction of stoichiometric amounts of the enzyme and inhibitor was monitored with "P-NMR spectroscopy at pH 7.8. The irreversible inhibitors show significant enantioselectivity (the (S,)-enantiomer reacting faster) and yield diastereoisomeric, covalently phosphorylated derivatives of 6-chymotrypsin.31P-NMR Spectroscopic studies of the inhibition by the axially substituted inhibitor revealed for the racemic (*)-2a first a resonance at -4.4 ppm and later, while inhibition proceeded, a second one at -4.5 ppm. The reaction with optically active (+)-2a showed only one signal at -4.4ppm and its enantiomer (-)-2a only one signal at -4.5 ppm. Using the equatorially substituted racemic epimer (*)-2b, we observed the main resonance at -5.3 ppm and two minor ones at -4.4 and -4.5 ppm. The optically active compound (+)-2b showed two peaks at -4.5 and -5.3 ppm, whereas its antipode (-)-2b revealed two signals at -4.4 and -5.3 ppm.Comparing the 31P chemical shifts of the corresponding covalent phosphoserine derivatives 4a (-5.7 ppm, axial) and 4b (-4.5ppm, equatorial) shows the inhibition with the axial compounds 2a to proceed via neat inversion of the configuration at the P-atom, whereas the equatorial epimers 2b with a higher conformational flexibility seem to follow a different stereochemical pathway which results in both inversion and retention.

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Asymmetric Synthesis ofP‐Chirogenic Phosphorus Compounds

2016

Asymmetric Synthesis in Organophosphorus Chemistry

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Diastereoselectivity in nucleophilic displacement reactions at phosphorus; isolation and characterization of a pentacoordinated intermediate

Cited by 17 publications

References 18 publications

Reactivity of a 2‘-Thio Nucleotide Analog

Reactivity of a 2‘-Thio Nucleotide Analog

Stereochemistry of the Inhibition of δ‐Chymotrypsin with Optically Active Bicyclic Organophosphates: ³¹P‐NMR studies

Asymmetric Synthesis ofP‐Chirogenic Phosphorus Compounds

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Diastereoselectivity in nucleophilic displacement reactions at phosphorus; isolation and characterization of a pentacoordinated intermediate

Cited by 17 publications

References 18 publications

Reactivity of a 2‘-Thio Nucleotide Analog

Reactivity of a 2‘-Thio Nucleotide Analog

Stereochemistry of the Inhibition of δ‐Chymotrypsin with Optically Active Bicyclic Organophosphates: 31P‐NMR studies

Asymmetric Synthesis ofP‐Chirogenic Phosphorus Compounds

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Product

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Stereochemistry of the Inhibition of δ‐Chymotrypsin with Optically Active Bicyclic Organophosphates: ³¹P‐NMR studies