The era of organocatalysis ushered a host of small, organic molecules as efficient catalysts for chemical transformation. These were cheap, efficient, and less toxic to the environment than the organometallic counterparts. Of primary importance for tuning selectivity and reactivity is the use of non-bonding interactions, e.g. hydrogen bonding, to control selectivity and assist in electrophilic activation. Over the past decade, there has been growing interest in the use of isothiourea-based organocatalysts, specifically tetramisoles (TM) and the benzotetramisoles (BTM). These groups of catalysts take advantage of a different type of non-bonding interaction. The acylated isothiourea catalyst shows a distinct preference for the conformation in which the S atom and the C=O O atom are <i>syn</i> to one another, and located at a distance significantly below the sum of their van der Waal’s radii. The energetic penalty to perturbing this conformation is 4-6 kcal/mol, and affords rigidity that effectively “locks” the acylated catalyst, greatly simplifying stereocontrol. In collaboration with the Andrew Smith group (St. Andrews), we have studied these catalysts computationally in a number of organic transformations, including [2,3]-sigmatropic rearrangements and benzothiazole & benzoxazole annulations. Our results highlight how S–O interactions are central to stereocontrol and catalysis in all of these reactions.

Non-bonding S–O interactions: A new element of stereocontrol and catalysis?

253rd National Meeting (2017)

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