We have developed an enantioselective, copper(I)-catalyzed addition of terminal alkynes to isochroman ketals to set diaryl, tetrasubstituted stereocenters. The success of this reaction relies on identification of a Cu/PyBox catalyst capable of distinguishing the faces of the diaryl-substituted oxocarbenium ion. This challenging transformation enables efficient conversion of readily available, racemic ketals to high-value, enantioenriched isochroman products with fully substituted stereogenic centers. High yields and enantiomeric excesses are observed for various isochroman ketals and an array of alkynes.

Infection by herpes simplex virus 1 (HSV-1) impacts nearly all steps of host cell gene expression. The regulatory mechanisms by which this occurs, and the interplay between host and viral factors, have yet to be fully elucidated. We investigated how the occupancy of RNA polymerase II (Pol II) on the host genome changes during HSV-1 infection and is impacted by the viral immediate early protein ICP4. Pol II ChIP-seq experiments revealed ICP4-dependent decreases and increases in Pol II levels across the bodies of hundreds of genes. Our data suggest ICP4 represses host transcription by inhibiting recruitment of Pol II and activates host genes by promoting release of Pol II from promoter proximal pausing into productive elongation. Consistent with this, ICP4 was required for the decrease in levels of the pausing factor NELF-A on several HSV-1 activated genes after infection. In the absence of infection, exogenous expression of ICP4 activated, but did not repress, transcription of some genes in a chromatin-dependent context. Our data support the model that ICP4 decreases promoter proximal pausing on host genes activated by infection, and ICP4 is necessary, but not sufficient, to repress transcription of host genes during viral infection.

Infection by Herpes simplex virus 1 (HSV-1) impacts nearly all steps of gene expression in the host cell. The regulatory mechanisms by which this occurs, and the interplay between host and viral factors, have yet to be fully elucidated. Here we investigated how the occupancy of RNA polymerase II (Pol II) on the host genome changes during HSV-1 infection and is impacted by the viral immediate early protein ICP4. Pol II ChIP-seq experiments revealed a reduction of Pol II occupancy across the bodies of hundreds of host genes that was dependent upon ICP4. Concomitantly, Pol II levels increased across the bodies of several hundred genes, the majority of which also depended on ICP4 for activation. Our data suggest ICP4 regulates repression of Pol II at host genes by inhibiting recruitment of Pol II, while it regulates activation by promoting release of Pol II from promoter proximal pausing into productive elongation. Consistent with this, relative levels of the pausing factors NELF-A and Spt5 were reduced on an HSV-1 activated gene in an ICP4 dependent manner. Exogenous expression of ICP4 revealed that ICP4 can activate, but not repress, transcription of some genes in the absence of infection in a manner that correlates with the chromatin state of the gene. Together our data support the model that ICP4 decreases promoter proximal pausing on host genes activated by infection, and ICP4 is necessary, but not sufficient, to repress transcription from host genes during viral infection.

An enantioselective,copper(I)-catalyzed addition of terminal alkynes to isochroman ketals to set diaryl, tetrasubstituted stereocenters has been developed. The success of this reaction relies on identification of aCu/PyBoxcatalyst capable of distinguishing the faces of the diaryl-substituted oxocarbenium ion. This challenging transformation enables efficient conversion of readily available,racemic ketals into high-value enantioenriched isochroman products with fully substituted stereogenic centers.High yields and enantiomeric excesses are observed for various isochroman ketals and an arrayo f alkynes.Scheme 1. Enantioselective additions to oxocarbeniumions.

No abstract