From Pd(OAc)2 to Chiral Catalysts: The Discovery and Development of Bifunctional Mono-N-Protected Amino Acid Ligands for Diverse C-H Functionalization Reactions

Abstract

The functionalization of unactivated carbon-hydrogen bonds is a transformative strategy for the rapid construction of molecular complexity given the ubiquitous presence of C-H bonds in organic molecules. It represents a powerful tool for accelerating the synthesis of natural products and bioactive compounds while reducing the environmental and economic costs of synthesis. At the same time, the ubiquity and strength of C-H bonds also present major challenges toward the realization of transformations that are both highly selective and efficient. The development of practical C-H functionalization reactions has thus remained a compelling yet elusive goal in organic chemistry for over a century.Specifically, the capability to form useful new C-C, C-N, C-O, and C-X bonds via direct C-H functionalization would have wide-ranging impacts in organic synthesis. Palladium is especially attractive as a catalyst for such C-H functionalizations because of the diverse reactivity of intermediate palladium-carbon bonds. Early efforts using cyclopalladation with Pd(OAc)₂ and related salts led to the development of many Pd-catalyzed C-H functionalization reactions. However, Pd(OAc)₂ and other simple Pd salts perform only racemic transformations, which prompted a long search for effective chiral catalysts dating back to the 1970s. Pd salts also have low reactivity with synthetically useful substrates. To address these issues, effective and reliable ligands capable of accelerating and improving the selectivity of Pd-catalyzed C-H functionalizations are needed.In this Account, we highlight the discovery and development of bifunctional mono-N-protected amino acid (MPAA) ligands, which make great strides toward addressing these two challenges. MPAAs enable numerous Pd(II)-catalyzed C(sp²)-H and C(sp³)-H functionalization reactions of synthetically relevant substrates under operationally practical conditions with excellent stereoselectivity when applicable. Mechanistic studies indicate that MPAAs operate as unique bifunctional ligands for C-H activation in which both the carboxylate and amide are coordinated to Pd. The N-acyl group plays an active role in the C-H cleavage step, greatly accelerating C-H activation. The rigid MPAA chelation also results in a predictable transfer of chiral information from a single chiral center on the ligand to the substrate and permits the development of a rational stereomodel to predict the stereochemical outcome of enantioselective reactions.We also describe the application of MPAA-enabled C-H functionalization in total synthesis and provide an outlook for future development in this area. We anticipate that MPAAs and related next-generation ligands will continue to stimulate development in the field of Pd-catalyzed C-H functionalization.

Figure 1.

General structures of MPAA ligand, binding mode, and involvement in C–H activation.

Figure 2.

Mechanistic hypotheses for cyclopalladation C–H cleavage.

Figure 3.

Initial mechanistic hypotheses for C–H cleavage with MPAA ligands.

Figure 4.

Monomeric Pd promoted by MPAA binding and internal amidate MPAA mechanism.

Figure 5.

Important structural features of MPAA ligands.

Figure 6.

Stereomodel for bidentate internal amidate MPAA enantioselective C–H activation.

Figure 7.

Stereomodel for enantioselective C–H activation with MPAAs.

Figure 8.

Rationale for the absence of enantioinduction with C₂-symmetric MPAA ligands.

Figure 9.

Potential issues with pseudo C₂-symmetric ligands.

Figure 10.

Next generation ligand design based on MPAA mechanistic understanding.

Scheme 1.

Acetate anion-enabled cyclopalladation of (dimethylamino)methylferrocene.

Scheme 2.

Diastereoselective cyclopalladation controlled by substrate chirality.

Scheme 3.

Asymmetric stoichiometric cyclopalladation with (S)-Ac-Val-OH as a chiral carboxylate.

Scheme 4.

Diastereoselective C(sp³)–H functionalization using a chiral oxazoline auxiliary.

Scheme 5.

Enantioselective C(sp²)–H activation/cross coupling enabled by a MPAA ligand.

Scheme 6.

Enantioselective C(sp³)–H activation/cross coupling enabled by a MPAA ligand.

Scheme 7.

MPAA-enabled C–H olefination and reversal of reactivity in competition experiment.

Scheme 8.

Desymmetrization of diphenylacetic acid substrates.

Scheme 9.

Kinetic resolution of phenylacetic acid substrates by C–H olefination.

Scheme 10.

C(sp²)–H olefination of phenethyl alcohols.

Scheme 11.

ortho-C(sp²)–H olefinations directed by various other directing groups.

Scheme 12.

C(sp²)–H cross-coupling with arylboron reagents.

Scheme 13.

C(sp²)–H cross-coupling with alkylboron reagents.

Scheme 14.

Desymmetrization and kinetic resolution of benzylamines.

Scheme 15.

C(sp²)–H carbonylation of phenethyl alcohols.

Scheme 16.

C–H activation/C–O bond formation.

Scheme 17.

Enantioselective C(sp²)–H iodination.

Scheme 18.

C–H alkylation with epoxides.

Scheme 19.

meta-C–H functionalizations directed by a U-shaped template.

Scheme 20.

meta-C–H functionalizations of amines.

Scheme 21.

meta-C–H functionalizations of indolines.

Scheme 22.

meta-C–H functionalizations using pyridine-based templates.

Scheme 23.

Remote site-selective C–H activation with a bifunctional coordinating template.

Scheme 24.

Enantioselective C(sp³)–H cross-coupling of cyclopropane acid derivatives.

Scheme 25.

C(sp3)–H cross-coupling of cyclobutane carboxylic acid derivatives.

Scheme 26.

C(sp³)–H cross-coupling of free cyclopropane carboxylic acids using MPAA ligands.

Scheme 27.

C(sp³)–H cross-coupling of amine derivatives.

Scheme 28.

Enantioselective C(sp³)–H functionalization of amines.

Scheme 29.

Application of a C–H olefination towards the synthesis of (+)-lithospermic acid.

Scheme 30.

Application of C–H alkylation in the synthesis of (+)-hongoquercin A.

Scheme 31.

Consecutive C–H functionalizations towards synthesis of (−)-incarvitone A.

Scheme 32.

Construction of benzo-fused indoxamycin cores via C–H olefination.

Scheme 33.

C–H amination/indolization in the formal syntheses of herbindole B and cis-trikenterin A.

Scheme 34.

Kinetic resolution of triflamides via C–H olefination for the synthesis of delavatine A.