title: Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion.
abstract: Enantioselectivity values represent relative rate measurements that are sensitive to the structural features of the substrates and catalysts interacting to produce them. Therefore, well-designed enantioselectivity data sets are information rich and can provide key insights regarding specific molecular interactions. However, if the mechanism for enantioselection varies throughout a data set, these values cannot be easily compared. This premise, which is the crux of free energy relationships, exposes a challenging issue of identifying mechanistic breaks within multivariate correlations. Herein, we describe an approach to addressing this problem in the context of a chiral phosphoric acid catalyzed fluorination of allylic alcohols using aryl boronic acids as transient directing groups. By designing a data set in which both the phosphoric and boronic acid structures were systematically varied, key enantioselectivity outliers were identified and analyzed. A mechanistic study was executed to reveal the structural origins of these outliers, which was consistent with the presence of several mechanistic regimes within the data set. While 2- and 4-substituted aryl boronic acids favored the (R)-enantiomer with most of the studied catalysts, meta-alkoxy substituted aryl boronic acids resulted in the (S)-enantiomer when used in combination with certain (R)-phosphoric acids. We propose that this selectivity reversal is the result of a lone pair-π interaction between the substrate ligated boronic acid and the phosphate. On the basis of this proposal, a catalyst system was identified, capable of producing either enantiomer in high enantioselectivity (77% (R)-2 to 92% (S)-2) using the same chiral catalyst by subtly changing the structure of the achiral boronic acid.
authors.affiliation: Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California , Berkeley, California 94720, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Neel
authors.affiliation: Department of Chemistry, University of Utah , 315 South 1400 East, Salt Lake City, Utah 84112, United States.|Department of Chemistry, Ben-Gurion University of the Negev , Beer Sheva, 84105, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Milo
authors.affiliation: Department of Chemistry, University of Utah , 315 South 1400 East, Salt Lake City, Utah 84112, United States.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Sigman
authors.affiliation: Chemical Sciences Division, Lawrence Berkeley National Laboratory, and Department of Chemistry, University of California , Berkeley, California 94720, United States.
authors.forename: F Dean
authors.initials: FD
authors.lastname: Toste
mesh_terms: D000838:Anions / Q000737:chemistry; D066264:Datasets as Topic; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry; D008958:Models, Molecular; D020005:Propanols / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000838:Anions; D006845:Hydrocarbons, Fluorinated; D020005:Propanols; C006463:allyl alcohol