The First Broad Examination of Michael Reactions in the Presence of a Diverse Array of Acidic Spectator Functional Groups: Enantioselective Synthesis

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During synthetic route planning acidic functional groups are purposely circumvented by using protection/deprotection protocols; but these protocols do more to increase waste and lower overall yield than any other general ailment of synthesis. Here we suggest that this general problem can be reduced by showing that many common acidic functional groups (pKa= 0 to 14) can be spectators that require no protection during enantioselective Michael reactions. Our preliminary results go beyond high stereochemical achievement, for example several of the demonstrated reactions do not have racemic equivalents, e.g. when a carboxylic acid spectator group is present. Because of the advantages afforded by removing the need for acid based protecting groups, we are now able to suggest the shortest enantioselective syntheses known to date for Pristiq, a Pfizer drug for depression, and an important natural product, Mevalonic acid. From a global perspective, we hope that this research will inspire a push within the synthetic community to broaden synthetic route planning to include more unprotected acidic moieties to allow for more step-efficient synthesis. Here we show that this is possible.