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.

Figure 1

(A) Conceptual description of chiral anion phase transfer catalysis. (B) Previously described enantioselective fluorination of allylic alcohols combining a chiral phosphoric acid phase transfer catalyst and a p-tolylboronic acid directing group. (C) Enantioselectivity values obtained with different aryl BAs with (S)-TRIP.

Figure 2

(A) Proposed catalytic cycle for chiral PA catalyzed enantioselective fluorination of allylic alcohols. (B) Control experiments supporting p-tolylboronic acid’s role as a directing group. All reactions were conducted on 0.1 mmol scale with respect to allylic alcohol 1.

Figure 3

(A) Effect of boronic acid structure on enantioselectivity. All reactions were conducted on 0.05 mmol scale with respect to allylic alcohol 1. (B) Visualization of enantioselectivity range of 2 attainable by variation of boronic acid structure.

Figure 4

(A) Enantioselectivity data obtained by variation of PA and BA substitution pattern. All reactions were conducted using 0.050 mmol 1, 0.065 mmol 3, 0.065 mmol Selectfluor, 0.200 mmol Na₂HPO₄, 0.005 mmol 4, and 40 mg MS 4Å in toluene (0.1 M). (B) Graphical representation of BA structure–selectivity trends as a function of catalyst structure.

Figure 5

Relationship between product and catalyst enantioselectivities for various BA-catalyst combinations: (A) 3b and 4b, (B) 3b and 4a, (C) 3b and 4e, (D) 3o and 4b. All reactions were conducted on 0.05 mmol scale with respect to allylic alcohol 1.

Figure 6

(A) Correlation between enantioselectivity of 2 (ΔΔG^‡) and σ_para using catalyst 4e with various boronic acids. All reactions were conducted on 0.05 mmol scale with respect to allylic alcohol 1. (B) Reaction time course data for formation of 2 using 3n and 4e and (C) 3b and 4e. All reactions were conducted on 0.1 mmol scale with respect to allylic alcohol 1.

Figure 7

(A) Comparison of enantioselectivities of 2 and 2-d₂ for various BA and PA combinations. All reactions were conducted on 0.05 mmol scale with respect to allylic alcohol 1. (B) Plausible mechanistic rationale for variable dependence of enantioselectivity on isotopic substitution.

Figure 8

(A) Comparison of enantioselectivity of 2 obtained using hyrid BA 3w versus versus 3o and 3m as a function of catalyst structure. (B) Effect of variation of alkyl vs alkoxy substituents for various 3,5-disubstituted hybrid phenylboronic acid derivatives. All reactions were conducted on 0.05 mmol scale with respect to allylic alcohol 1. (C) Left: Qualitative depiction of lone pair-π interaction as a stabilizing element for the structure of Z-DNA.^, Right: Qualitative description of potential lone pair-π interaction between BA and PA.

Figure 9

(A) Graphical representation of catalyst structure-selectivity trends as a function of BA structure. (B) Enantioselectivity of 2 using catalysts bearing 2,4,6-trisubstituted aryl substituents with various BAs. (C–F) Mathematical correlation of normalized catalyst and BA molecular descriptors to enantioselectivity (ΔΔG^‡) for 2- and 4-substituted aryl BAs (C), all 3,5-disubstituted aryl BAs (D), 3,5-disubstituted aryl BAs with symmetrical substitution or a methoxy substituent (E), and 3-alkoxy-5-methyl substituted aryl BAs (F). All reactions were conducted on 0.05 mmol scales with respect to allylic alcohol 1.

Scheme 1

Inversion of Enantioselectivity of 2 Using Catalyst 4i Changing Only BA Structure^{a a}Reactions were conducted on 0.05 mmol scale with respect to allylic alcohol 1.