Enantioselective C(sp3)‒H bond activation by chiral transition metal catalysts

Abstract

Organic molecules are rich in carbon-hydrogen bonds; consequently, the transformation of C-H bonds to new functionalities (such as C-C, C-N, and C-O bonds) has garnered much attention by the synthetic chemistry community. The utility of C-H activation in organic synthesis, however, cannot be fully realized until chemists achieve stereocontrol in the modification of C-H bonds. This Review highlights recent efforts to enantioselectively functionalize C(sp³)-H bonds via transition metal catalysis, with an emphasis on key principles for both the development of chiral ligand scaffolds that can accelerate metalation of C(sp³)-H bonds and stereomodels for asymmetric metalation of prochiral C-H bonds by these catalysts.

Fig. 1. Overview of mechanistic differentiation in transition metal-mediated enantioselective C–H functionalization

(A) Biomimetic approaches/metal-oxo H-atom abstraction. (B) Metallonitrene and metallocarbene insertion into C–H bonds. (C) Topic of this review: transition metal-mediated C–H activation. Me = methyl, t-Bu = tert-butyl, *L = chiral ligand, [M] = transition metal, BPin = pinacolatoboron, X = aryl, alkyl, alkynyl, N, O, B.

Fig. 2. Overview of enantioselective C–H activation

(A) Point desymmetrization of C(sp²)–H and C(sp³)–H substrates. (B) Planar and axial desymmetrization of C(sp²)–H substrates. DG = Directing group, [M] = transition metal, L*–L = chiral ligand, M′ = Fe, Ru.

Fig. 3. Discovery of mono-N-protected amino acids

(A) Initial discovery and ligand examples. (B) Coresponding stereomodels. (C) Preliminary results of enantioselective C(sp³)–H activation. n-Bu = n-Butyl, Boc = tert-butyloxycarbonyl, i-Pr = isopropyl, OAc = acetate.

Fig. 4. Strong versus weak directing group

(A) Reaction coordinate comparing strong directing groups, weak directing groups, and weak directing groups with ligand. (B) Typical strong directing groups encountered in the literature.

Fig. 5. Representative examples of enantioselective C(sp³)–H point desymmetrization

(A) Examples and stereomodels of Pd(II)/Pd(0) chemistry. (B) Examples of Pd(0)/Pd(II) chemistry. (C) Examples of Rh(I)/Rh(III) chemistry. n-Pr = n-propyl, EWG = electron-withdrawing group, COD = 1,5-cyclooctadiene, Ar = aryl, OTf = triflate, NHC = N-heterocyclic carbine.

Fig. 6. Desymmetrization of acyclic systems and desymmetrization of geminal-dimethyl amides

(A) Examples and limitations of enantioselective C–H activation of acyclic systems. (B) Inspiration for a novel ligand design. (C) Desymmetrization of geminal dimethyl amide substrates. (D) Proposed stereomodel of APAO ligands. IOAc = iodoacetate, Ph = phenyl, TIPS = triisopropylsilyl, APAO = acetyl-protected, amino oxazoline.

Fig. 7. Overview of methylene C–H activation

(A) Overview of major challenges in methylene C–H activation. (B) Representative C–H activation of methylene C–H bonds α-to heteroatoms (C) Representative examples of benzylic C–H activation. dba = dibenzylideneacetone, MeCN = acetonitrile.

Fig. 8. Unbiased methylene C–H activation

(A) Significant problems of bidentate directing groups. (B) Inspiration for novel bidentate APAQ ligands. (C) APAQ-enabled enantioselective methylene C–H activation. (D) Proposed stereomodel for APAQ-enabled enantioselective methylene C–H activation. TFA = trifluoroacetic acid, APAQ = acetyl-protected amino quinoline.

Fig. 9. Kinetic resolution C–H activation

(A) Overview of kinetic resolution and parallel kinetic resolution. (B) Initial report on MPAA-enabled C(sp²)–H kinetic resolution. (C) Early examples of C(sp³)–H kinetic resolution. PG = protecting group, Cy = cyclohexyl,