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.

Parametrization of Non-covalent Interactions for Transition State Interrogation Applied to Asymmetric Catalysis

“…Hence, the second case study for the application of these π-parameters is the enantiodivergent fluorination of allylic alcohols previously reported by our teams (Figure 3A), in which an achiral arylboronic acid (BA) in combination with a chiral phosphoric acid catalyst (PA) facilitate the enantioselective reaction. 17 In this process, the allylic alcohol and the BA condense to form a mixed boronic ester, 17b which is proposed to coordinate via H-bonding with the chiral phosphate anion (Figure 3A). From this complex, the enantioselective, electrophilic fluorination occurs.…”

“…Thus, this reaction is highly sensitive to NCIs involved in enantioselectivity controlling events. Despite extensive mechanistic studies that provide support for the general reaction mechanism, 17b a clear representation of the likely NCIs responsible for enantioselectivity has not been elucidated. In this context, previous attempts to correlate all measured enantioselectivities through multilinear regression analysis were unsuccessful.…”

“…On this basis, it was hypothesized that a T-shaped π-interaction may be occurring between the BA and the PA in the TS. 17b Therefore, to define parameters, T-shaped complexes were calculated in a similar manner as previously described, using a perpendicular orientation of the probe, benzene, and the BA’s meta-positions (Figure 1B). T E π and T D π for the T-shaped dimers were calculated for a set of eighteen BAs, including weighting these parameters for differentially substituted arenes ( T E π w and T D π w ).…”

Development and Analysis of a Pd(0)-Catalyzed Enantioselective 1,1-Diarylation of Acrylates Enabled by Chiral Anion Phase Transfer

“…However, the use of arylboronic acids in place of B 2 pin 2 was projected to involve several additional complications, including solubility issues as well as the potential for direct interactions with the chiral anion. 6 …”

“…Nonetheless, both electron-rich and -poor aryldiazonium salts are well-tolerated under the optimized reaction conditions with electron-withdrawing substituents ( 3u and 3v ) leading to slightly lower enantioselectivities. As boronic acids are known to interact directly with phosphates, 6 it was hypothesized that compatibility between these two components may be an issue for the boronic acid scope. This was not foreseen as a detriment since the boronic acid could easily be exchanged with the corresponding diazonium salt.…”