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. 2024 Feb 15;4(2):807-815.
doi: 10.1021/jacsau.3c00794. eCollection 2024 Feb 26.

Enantioselective Desymmetrization of Trifluoromethylated Tertiary Benzhydrols via Hydrogen-Acceptor-Free Ir-Catalyzed Dehydrogenative C-H Silylation: Decisive Role of the Trifluoromethyl Group

Yoshihiko Yamamoto  1 , Ryu Tadano  1 , Takeshi Yasui  1
Affiliations

Enantioselective Desymmetrization of Trifluoromethylated Tertiary Benzhydrols via Hydrogen-Acceptor-Free Ir-Catalyzed Dehydrogenative C-H Silylation: Decisive Role of the Trifluoromethyl Group

Yoshihiko Yamamoto et al. JACS Au. .

Abstract

Although the trifluoromethyl (CF3) group is one of the most important fluorinated groups owing to its significant ability to modulate pharmacological properties, constructing trifluoromethylated stereogenic centers in an enantioselective manner has been a formidable challenge. Herein, we report the development of the enantioselective desymmetrization of trifluoromethylated benzhydrols via intramolecular dehydrogenative silylation using Ir catalysts with chiral pyridine-oxazoline (PyOX) ligands. The produced benzoxasilol was transformed into several unsymmetrical benzhydrols via iododesilylation and subsequent transition-metal-catalyzed cross-coupling reactions. Moreover, the same Ir catalyst system was used for the kinetic resolution of unsymmetrical trifluoromethylated benzhydrols.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Background and our reaction design for catalytic desymmetrization of trifluoromethylated benzhydrols. (a) Bioactive compounds with trifluoromethylated tertiary stereogenic carbons and three methods for constructing trifluoromethylated tertiary alcohol motifs. (b) Our Ir-catalyzed enantioselective desymmetrization involving trifluoromethylated benzhydrols. (c) Previous Ir-catalyzed desymmetrization involving tertiary benzhydrol.
Figure 2
Figure 2
Ir-catalyzed intramolecular dehydrogenative silylation of 2a.
Figure 3
Figure 3
Substrate scope of Ir-catalyzed asymmetric dehydrogenative silylation, followed by Tamao oxidation. Yields of isolated products over two steps are indicated along with enantiomeric ratios (er) determined by chiral HPLC analysis (red, nd: not determined). Crude yields of benzoxasilols 3 determined by 19F NMR spectroscopy are indicated in parentheses (blue).
Figure 4
Figure 4
Mechanistic proposal. (a) Plausible catalytic cycle in the presence of NBE. (b) Alternative catalytic cycle in the absence of NBE. (c) Reaction with deuterated substrate 2b-d10.
Figure 5
Figure 5
Computational studies. (a) DFT analysis of the C–H activation step. (b) NCI analyses of TS-1R and TS-1S.
Figure 6
Figure 6
Control experiments. (a) Reaction of 2a under Hartwig and Shi’s conditions. (b) Reaction of 2a under our conditions using a sealed tube. (c) Reactions of nonfluorinated benzhydrol derivatives. (d) Change in Gibbs energies for the transformations of 2 into 3 and H2.
Figure 7
Figure 7
Synthetic applications. (a) Halodesilylation of 3a. (b) Transition-metal-catalyzed transformations of iodide 6a into chiral trifluoromethylated benzhydrol derivatives. (c) Preparation of tosylate 13 and its crystal structure. (d) Kinetic resolution of unsymmetrical benzhydrol derivatives. Relative rate krel was determined using the equation: krel = ln[1 – c(1 + eep)]/ ln[1 – c(1–eep)] (c: conversion based on product yields, eep: product enantiomeric excess).
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