Dedicated to Professor E. J. Corey on the occasion of his 80th birthday Enantioselective CÀH activation has been a longstanding challenge in catalysis and organic chemistry. The insertion of metal-bound carbenes or nitrenes into CÀH bonds has been employed to develop highly enantioselective carbon-carbon and carbon-nitrogen bond-forming reactions.[1] The enantioselective lithiation of C(sp 3 ) À H bonds adjacent to the nitrogen atom in N-tert-butyloxycarbonylpyrrolidine using secBuLi/(À)sparteine has provided a broadly useful method for the differentiation of prochiral C(sp 3 )ÀH bonds.[2] Investigations into the biomimetic oxidation of CÀH bonds using chiral metal-porphyrin complexes [3] and other synthetic catalysts [4] continue to provide inspiration for the development of methods for the asymmetric oxidation of C À H bonds. Remarkable progress in understanding the fundamental mechanisms of CÀH activation by means of metal insertion [5] has spurred the development of metal-catalyzed carboncarbon and carbon-heteroatom bond-forming reactions in organic molecules containing functional groups.[6] Such reactions will impact synthetic and medicinal chemistry in the context of retrosynthetic analysis [7] by providing unprecedented and more efficient strategic disconnections.[8] A major hurdle remaining in Pd II -catalyzed CÀH activation reactions, however, is the need for an external ligand that coordinates to the Pd II species and controls the chemo-, regio-, and stereoselectivity of its insertion into C À H bonds. With this in mind, we embarked on the development of a Pd II -catalyzed enantioselective CÀH activation/CÀC coupling reaction, a process previously unknown owing to the difficulty in differentiating prochiral CÀH bonds through metal insertions.

This critical review discusses historical and contemporary research in the field of transition metal-catalyzed carbon-hydrogen (C-H) bond activation through the lens of stereoselectivity. Research concerning both diastereoselectivity and enantioselectivity in C-H activation processes is examined, and the application of concepts in this area for the development of novel carbon-carbon and carbon-heteroatom bond-forming reactions is described. Throughout this review, an emphasis is placed on reactions that are (or may soon become) relevant in the realm of organic synthesis (221 references).

The Mizoroki-Heck reaction, which couples aryl halides with olefins, has been widely used to stitch together the carbogenic cores of numerous complex organic molecules. Given that the positionselective introduction of a halide onto an arene is not always straightforward, direct olefination of aryl C-H bonds would obviate the inefficiencies associated with generating halide precursors or their equivalents; however, methods for carrying out such a reaction have suffered from narrow substrate scope and low positional selectivity. Here we report an operationally simple, atom-economical, carboxylate-directed Pd(II)-catalyzed C-H olefination reaction with phenylacetic acid and 3-phenylpropionic acid substrates, using oxygen at atmospheric pressure as the oxidant. The positional selectivity can be tuned by introducing amino acid derivatives as ligands. We demonstrate the versatility of the method through direct elaboration of commercial drug scaffolds and efficient synthesis of 2-tetralone and naphthoic acid natural product cores.

Pd(II)-catalyzed meta-olefination of highly electron deficient arenes is achieved through the use of a rationally designed mutually repulsive ligand. The combination of directed and non-directed C-H functionalization of arenes provides a versatile route for the synthesis of highly sought-after 1,2,4-trisubstituted arenes.Since the discovery of the Pd-catalyzed olefination of benzene by Fujiwara, substantial progress has been made to improve the efficiency and practicality of this reaction. 1 To date, reactivity is still limited to electron rich arenes, 1-4 except for a single example using chlorobenzene, a moderately electron deficient arene. 1c Furthermore, olefination of monosubstituted arenes gives an approximately even mixture of ortho-, meta-and para-olefinated products, 1c limiting possible synthetic applications. The ortho-olefination of benzoic acids and anilides via directed C-H activation reported by Miura and de Vries, respectively, represents an important approach to control the regioselectivity of this reaction. 5,6 Herein, we report the first example of a meta-selective olefination process of highly electron deficient arenes. This reaction is promoted by a novel mutually repulsive 2,6-dialkylpyridine ligand, yu200@scripps.edu. Supporting Information Available: Experimental procedure and characterization of all new compounds (PDF). This material is available free of charge via the Internet at

Monoprotected chiral amino acids have recently been established as a class of ligand scaffolds for effecting Pd-catalyzed enantioselective C-H bond activation reactions. However, to elucidate the mechanistic details and controlling factors of these reactions, more comprehensive studies are needed. In this work we report computational investigations into the key mechanistic features of enantioselective C-H bond activation reactions catalyzed by a [chiral (mono-N-protected amino acid)-Pd(II)] complex. Structural analysis points to a C-H insertion intermediate in which the nitrogen atom of the ligand is bound as a neutral σ-donor. The formation of this C-H insertion intermediate could, in principle, proceed via a "direct C-H cleavage" or via "initial N-H bond cleavage followed by C-H cleavage". The computational studies presented herein show that the pathway initiated by N-H bond cleavage is more kinetically favorable. It is shown that the first step of the reaction is the N-H bond cleavage by the coordinated acetate group (OAc). In the next stage, the weakly coordinated OAc(-) (the second acetate group) activates the ortho-C-H bond of the substrate and transfers the H-atom from the C-atom to the bound N-atom of the ligand. As a result, a new Pd-C bond is formed and the carbamate is converted from X-type to L-type ligand. The absolute configuration of the products that are predicted on the basis of the calculated energies of the transition states matches the experimental data. The calculated enantioselectivity is also comparable with the experimental result. On the basis of these data, the origin of the enantioselectivity can be largely attributed to steric repulsions in the transition states.

Pd(II)-catalyzed enantioselective C-H olefination of diphenylacetic acid substrates has been achieved through the use of mono-protected chiral amino acid ligands. The absolute configuration of the resulting olefinated products is consistent with that of a proposed C-H insertion intermediate.Despite substantial progress in developing various Pd-catalyzed C-heteroatom and C-C bond forming reactions via C-H activation,1 achieving enantioselectivity in these reactions through a stereoselective Pd insertion step remains a significant challenge.2 -9 In our ongoing studies to design and evaluate new ligands to effect asymmetric C-H cleavage, two major problems have become apparent. First, the simultaneous binding of both the substrate and the chiral ligand to the Pd(II) center is often difficult to achieve. Second, even if such complexes are assembled, the ligand often strongly inhibits C-H activation, either because it induces an unwanted conformational change or adversely affects the electronic properties of the Pd(II) center.yu200@scripps.edu. Supporting Information Available: X-ray diffraction analysis for 2e, experimental procedure and characterization of all new compounds (PDF). This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public AccessAuthor Manuscript J Am Chem Soc. Author manuscript; available in PMC 2011 January 20. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe have recently found that mono-protected amino acid ligands and 2-benzylpyridine substrates coordinate with Pd(II) in a one-to-one ratio with high fidelity. 3 Importantly, the resulting chiral Pd(II) complexes were found to induce asymmetric C-H cleavage with high enantioselectivity (up to 95% ee). Of critical importance for the viability of this process is the precise match between the binding ability of the pyridine substrate and the chiral ligand. This observation, however, calls into question whether this chiral ligand scaffold is broadly applicable to synthetically useful substrates, including those that contain weakly coordinating functional groups. Herein, we report an enantioselective C-H olefination reaction of α,α-diphenylacetic acids using mono-protected amino acids as chiral ligands. This new development represents an encouraging step towards the realization of synthetically useful Pdcatalyzed enantioselective C-H activation reactions.We previously reported that both inorganic and organic cations dramatically accelerate carboxyl-directed C-H activation reactions.10 Our current hypothesis, based on the structure of a C-H insertion intermediate, 10b is that the σ-chelation of the carbonyl oxygen of the carboxylate salt with Pd(II) is responsible for the facile C-H cleavage promoted by the complexinduced proximity effect. Following this hypothesis, we anticipated that a chiral carbon-Pd intermediate B could be formed in analogy to intermediate A, which is formed following enantioselective C-H activation using a pyridyl directing group. Subsequently, we envisioned t...

Transition-metal-catalyzed, coordination-assisted C(sp 3 )−H functionalization has revolutionized synthetic planning over the past few decades as the use of these directing groups has allowed for increased access to many strategic positions in organic molecules. Nonetheless, several challenges remain preeminent, such as the requirement for high temperatures, the difficulty in removing or converting directing groups, and, although many metals provide some reactivity, the difficulty in employing metals outside of palladium. This review aims to give a comprehensive overview of coordination-assisted, transitionmetal-catalyzed, direct functionalization of nonactivated C(sp 3 )−H bonds by covering the literature since 2004 in order to demonstrate the current state-of-the-art methods as well as the current limitations. For clarity, this review has been divided into nine sections by the transition metal catalyst with subdivisions by the type of bond formation. Synthetic applications and reaction mechanism are discussed where appropriate.

Give Me an Ar, give Me an N! Arylation of the methyl group in a simple derivative of readily available alanine under palladium catalysis was followed by intramolecular amidation at the same position to give chiral α-amino-β-lactams with a wide range of aryl substituents (see scheme; Phth=phthaloyl). The α-amino-β-lactams were obtained in moderate to high yields with good functional-group tolerance and high diastereoselectivity.