Controlling Pd(iv) reductive elimination pathways enables Pd(ii)-catalysed enantioselective C(sp3)−H fluorination

• Published in: Nature chemistry Vol. 10; no. 7; pp. 755 - 762
• Main Authors: Park, Hojoon, Verma, Pritha, Hong, Kai, Yu, Jin-Quan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2018; Springer Nature; Nature Publishing Group
• Subjects: 639/638/403/933; 639/638/77/883; Analytical Chemistry; Biochemistry; Bonding; Chemistry; Chemistry and Materials Science; Chemistry, Multidisciplinary; Chemistry/Food Science; Enantiomers; Fluorination; Inorganic Chemistry; Insertion; Organic Chemistry; Physical Chemistry; Physical Sciences; Science & Technology; Stereochemistry; PD-IV; FUNCTIONALIZATION; ACTIVATION; C-H FLUORINATION; COMPLEXES; CHEMISTRY; ALPHA-AMINO-ACIDS; BOND; FLUORIDE; TRIFLUOROMETHYLATION
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/s41557-018-0048-1

The development of a Pd( ii )-catalysed enantioselective fluorination of C( sp 3 )−H bonds would offer a new approach to making chiral organofluorines. However, such a strategy is particularly challenging because of the difficulty in differentiating prochiral C( sp 3 )−H bonds through Pd( ii )-insertion, as well as the sluggish reductive elimination involving Pd−F bonds. Here, we report the development of a Pd( ii )-catalysed enantioselective C( sp 3 )−H fluorination using a chiral transient directing group strategy. In this work, a bulky, amino amide transient directing group was developed to control the stereochemistry of the C−H insertion step and selectively promote the C( sp 3 )−F reductive elimination pathway from the Pd( iv )–F intermediate. Stereochemical analysis revealed that while the desired C( sp 3 )−F formation proceeds via an inner-sphere pathway with retention of configuration, the undesired C( sp 3 )−O formation occurs through an S N 2-type mechanism. Elucidation of the dual mechanism allows us to rationalize the profound ligand effect on controlling reductive elimination selectivity from high-valent Pd species. Metal-catalysed enantioselective fluorination of C( sp 3 )–H bonds is an attractive method for preparing chiral organofluorines, but the challenge of achieving both enantioselectivity and reductive elimination selectivity remains unsolved. Now, it has been demonstrated that a chiral amino amide transient directing group can serve as a ligand for a palladium catalyst that promotes both enantioselective C( sp 3 )–H insertion and C( sp 3 )–F-selective reductive elimination.