An essential component to a proficient understanding of Organic Chemistry is the ability to justify and predict the stereochemical outcome of chemical reactions. It is therefore imperative for educators to develop highly instructive inquiry-based lab experiments to help students learn how to predict and evaluate the stereochemistry of organic chemistry transformations. An exemplary experiment addressing this topic is the reduction of benzoin with NaBH4, resulting in the formation of a meso vicinal diol. The students conducting this experiment are introduced to the Felkin-Anh model for nucleophilic addition to the carbonyl group, which predicts the formation of the meso product in part by assigning small, medium, and large sizes to the H, OH, and Ph groups located on the alpha carbon. Furthermore, the students learn through 1HNMR analysis of the diol product's acetonide derivative that the reaction proceeds at nearly 100% (de)diastereoselectivity. More importantly, in an elegant follow up experiment, the students are then instructed to evaluate the diastereoselectivity of the reaction upon altering the size of the medium group on the alpha carbon via acylation reactions. Previously, it has been demonstrated that converting the ‘medium’ sized hydroxyl group to a benzoyl moiety abolished the diastereoselectivity, in fact slightly favoring the non-meso product in a 6:5 ratio. We wondered whether further modifications of the hydroxyl group, by introduction of bulkier three-dimensional substituents on the oxygen, would result in significantly increased reversal of diastereoselectivity in favor of the non-meso reduction product, thereby making the experiment more effective. This strategy has proven fruitful in pushing the diastereoselectivity of the reduction reaction further in favor of the non-meso product. In our own work, introduction of the bulky tert-butyldimethylsilanyl (TBDMS) group, the bulkier triisopropylsilanyl (TIPS) group, and the yet bulkier tert-butyldimethylsilanyl (TBDPS) group has forced the reduction reaction in favor non-meso product at increasingly high ratios. We believe that this dramatic shift in diastereoselectivity from completely favoring one diastereomer to then producing the opposite diastereomer as the major product is highly instructive to students, and provides a good inquiry-based teaching laboratory.

Using bulky groups to favor the typically unfavored diastereomer in benzoin reduction: An inquiry-based teaching laboratory

256th National Meeting (2018)

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