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Applications of 19F NMR to Pharmaceutical Structure Elucidation Problems - Why Fluorine is Your Best Friend for Structure Elucidation

Date: 
Thursday, November 1, 2018 - 18:30 to 19:30
Speaker: 
Dr. David Russell
Affiliation: 
Genentech, San Francisco, CA
Event Category: 
ODG - Organic Discussion Group
Location: 
Chemistry D300

Abstract:

The presence of fluorine in an active pharmaceutical ingredient (API) can impart important pharmacological attributes with regards to metabolism, stability, and selectivity. As such, nearly one-third of newly approved small molecule drugs contain at least one fluorine atom and the trend towards including more than one fluorine moiety per molecule is growing.

For pharmaceutical applications, the presence of a “new” NMR active nuclide with high receptivity and 100% natural abundance opens up many interesting avenues for obtaining structural data.  The significant chemical shift window and large coupling constants associated with 19F NMR requires very careful consideration of excitation, decoupling, and magnetization transfer schemes, however.  As an example, are HF coupling pathways better elucidated using an HF-COSY approach, or does an indirect method like HETCOR provide more reliable data?  Which nucleus should be used for the direct-observe dimension?  In a similar vein, given that long-range FC coupling constants are significant over multiple bonds, what approaches work best to help simplify the wealth of information available using long-range experiments?  And how can HF-HOESY data be scaled to return reliable internuclear distances?

Results from our investigations using a three-channel HFX system will be presented.