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.
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
Modern drug discovery is contingent on identifying lead compounds and rapidly synthesizing analogues. The use of a common pharmacophore to direct multiple and divergent C-H functionalizations of lead compounds is a particularly attractive approach. Herein, we demonstrate the viability of late-stage diversification through the divergent C-H functionalization of sulfonamides, an important class of pharmacophores found in nearly 200 drugs currently on the market, including the non-steroidal anti-inflammatory blockbuster drug celecoxib. We developed a set of six categorically different sulfonamide C-H functionalization reactions (olefination, arylation, alkylation, halogenation, carboxylation, and carbonylation), each representing a distinct handle for further diversification to reach a large number of analogues. We then performed late-stage, site-selective diversification of a sulfonamide drug candidate containing multiple potentially reactive C-H bonds to synthesize directly novel celecoxib analogues as potential cyclooxygenase-II (COX-2)-specific inhibitors. Together with other recently developed practical directing groups, such as CONHOMe and CONHC(6)F(5), sulfonamide directing groups demonstrate that the auxiliary approach established in asymmetric catalysis can be equally effective in developing broadly useful C-H activation reactions.
Pd(II)-catalyzed ortho-hydroxylation of variously substituted benzoic acids under 1 atm of O(2) or air is achieved under nonacidic conditions. Extensive labeling studies support a direct oxygenation of aryl C-H bonds with molecular oxygen.
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...
Detection of chromosome copy number variation (CNV) plays an important role in the diagnosis of patients with unexplained clinical symptoms and for the identification of chromosome disease syndromes in the established fetus. In current clinical practice, karyotyping, in conjunction with array-based methods, is the gold standard for detection of CNV. To increase accessibility and reduce patient costs for diagnostic CNV tests, we speculated that next-generation sequencing methods could provide a similar degree of sensitivity and specificity as commercial arrays. CNV in patient samples was assessed on a medium-density single nucleotide polymorphism array and by low-coverage massively parallel CNV sequencing (CNV-seq), with mate pair sequencing used to confirm selected CNV deletion breakpoints. A total of 10 ng of input DNA was sufficient for accurate CNV-seq diagnosis, although 50 ng was optimal. Validation studies of samples with small CNVs showed that CNV-seq was specific and reproducible, suggesting that CNV-seq may have a potential genome resolution of approximately 0.1 Mb. In a blinded study of 72 samples with known gross and submicroscopic CNVs originally detected by single nucleotide polymorphism array, there was high diagnostic concordance with CNV-seq. We conclude that CNV-seq is a viable alternative to arrays for the diagnosis of chromosome disease syndromes.
The first Pd(II)-catalyzed alkylation of aryl C-H bonds is achieved without using a co-oxidant. The alkylation reaction was followed thereafter by an intramolecular lactonization to give broadly useful γ-and ™-benzolactones.Pd(0)-initiated arylation of C-H bonds with aryl halides is among the earliest examples in Pd-catalyzed C-H activation/arylation chemistry. [1][2][3][4][5][6][7] A single pioneering example of Pd(0)-catalyzed alkylation of aryl C-H bonds using a tethered alkyl chloride was also developed by Buchwald for highly efficient syntheses of oxindoles. 8 In these reactions, no external oxidant other than the aryl halides or alkyl halides themselves are needed, affording this C-H functionalization process a practical advantage. Recently, Pd(II)-catalyzed arylation using Ar 2 IX as the stoichiometric oxidant through a Pd(II)/Pd(IV) catalytic cycle has undergone major advances. 9,10 Especially noteworthy is the broad range of arylation reactions using ArI/AgOAc. 11 To our knowledge, Pd-catalyzed intermolecular alkylation of C-H bonds with alkyl halides 12,13 remains an unsolved problem, except for a single example of methylation of acetanilide via Pd(II)/Pd(IV) catalysis reported by Tremont (Scheme 1). 14 However, in this case, the side reaction of AgOAc with methyl iodide prevented efficient catalysis with this protocol. Herein we report a sequential monoselective alkylation/ lactonization reaction of benzoic acids with 1,2-dichcloroethane, dichloromethane and dibromomethane. Alkylation with 1-chloropentane was also found to proceed, albeit in lower yield. For the first time, Pd-catalyzed alkylation of C-H bonds in the absence of Ag(I) oxidant is made possible. Preliminary mechanistic investigations have also been carried out to shed light into the nature of the catalytic cycle. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptWe recently established that the κ 2 -coordination of a cation with a carboxylate group forces Pd(II) to chelate in the proximity of the ortho-C-H bonds (for benzoic acid and phenyl acetic acid substrates) and β-C-H bonds (for aliphatic acids), a geometry that is essential for facile C-H cleavage. 15 The broad utility of carboxylate groups prompted us to develop a potentially useful catalytic system for alkylation of C-H bonds for these substrates.In Tremont's Pd(II)/Pd(IV) catalytic cycle for methylation with MeI and arylation with ArI, the Pd-I species formed in each cycle needs to be converted to Pd(OAc) 2 by AgOAc.Knowing that Pd-Cl or Pd-Br species would be generated when alkyl chlorides or bromides were used as the alkylating reagents, we began our screening efforts using 1,2-dichloroethane as the alkylating reagent with the aim of discovering conditions that would promote displacement of chloride from the Pd-Cl species by a benzoate anion to close the catalytic cycle (Table 1). We were pleased to find that the presence of K 2 HPO 4 alone is sufficient for the catalytic alkylation to proceed (Table 1, entry 1). As anticipated, the initially f...
The lipid A moiety of lipopolysaccharides (LPS) initiates innate immune responses by interacting with Toll-like receptor 4 (TLR4) which results in the production of a wide range of cytokines. Derivatives of lipid A show potential for use as immuno-modulators for the treatment of a wide range of diseases and as adjuvants for vaccinations. Development to these ends requires a detailed knowledge of patterns of cytokines induced by a wide range of derivatives. This information is difficult to obtain by using isolated compounds due to structural heterogeneity and possible contaminations with other inflammatory components. To address this problem, we have developed a synthetic approach that provides easy access to a wide range of lipid As by employing a common disaccharide building block functionalized with a versatile set of protecting groups. The strategy was employed for the preparation of lipid As derived from E. coli and S. typhimurium. Mouse macrophages were exposed to the synthetic compounds and E. coli 055:B5 LPS and the resulting supernatants examined for tumor necrosis factor alpha (TNF-α), interferon beta (IFN-β), interleukin 6 (IL-6), interferon-inducible protein 10 (IP-10), RANTES, and IL-1β It was found that for each compound, the potencies (EC 50 values) for the various cytokines differed by as much as 100-fold. These differences did not follow a bias towards a MyD88-or TRIF-dependent response. Instead, it was established that the observed differences in potencies of secreted TNF-α and IL-1β were due to differences in the processing of respective pro-proteins. Examination of the efficacies (maximum responses) of the various cytokines showed that each synthetic compound and E. coli 055:B5 LPS induced similar efficacies for the production of IFN-β, and IP-10. However, lipid As 1-4 gave lower efficacies for the production of RANTES and IL-6 compared to LPS. Collectively, the presented results demonstrate that cytokine secretion induced by LPS and lipid A is complex, which can be exploited for the development of immuno-modulating therapies.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.