Functionalization and Suzuki-Miyaura cross-coupling of potassium organotrifluoroborates

The Suzuki-Miyaura cross-coupling reaction has proven to be one of the most powerful reactions in modern organic synthesis for the formation of carbon-carbon bonds. Recently, the development of new metal/ligand systems has broadened the scope of the reaction. During the past decade, tetracoordinate potassium organotrifluoroborates have emerged as an exceptional alternative to the traditionally used tricoordinate organoboron species for the synthesis of organic molecules. Because of their tetracoordinate nature, potassium organotrifluoroborates do not undergo undesirable side reactions with the commonly employed organic reagents, and therefore the organic substructure of simple organotrifluoroborates can be functionalized to build molecular complexity, while leaving the valuable carbon-boron bond intact for further transformations. We have achieved the Wittig reaction of potassium organotrifluoroborate-containing phosphorus ylides with aldehydes using K2CO3 as a base. The unsaturated potassium organotrifluoroborates were obtained in high yields. In addition, a protocol for a one-pot transformation was developed from the corresponding potassium 4-(chloromethyl)phenyltrifluoroborate.* Ethers are ubiquitous in natural products and compounds of pharmacological interest. Recognizing their importance in synthesis, we developed an efficient method to access ether linkages via the Suzuki-Miyaura cross-coupling of potassium alkoxymethyltrifluoroborates, which were prepared from the SN2 displacement of bromomethyltrifluoroborate with alkoxides. After an extensive optimization process, conditions were found to cross-couple alkoxymethyltrifluoroborates with aryl- and heteroaryl chlorides to afford benzyl ethers. This method provides a unique dissonant disconnection that allows greater flexibility in the design of new and improved synthetic pathways.* Owing to the prevalence of heterobiaryls in natural products and pharmacologically active compounds, we explored the Suzuki-Miyaura cross-coupling of potassium heteroaryltrifluoroborates. Toward this end, over twenty structurally diverse and bench-stable five-membered, six-membered, and benzannulated heteroaryltrifluoroborate derivatives were prepared from commercially available boronic acids in moderate to excellent yields. After a broad screening, unified and general conditions were found to cross-couple near-stoichiometric amounts of heteroaryltrifluoroborates with aryl- and heteroaryl halides. This method represents an efficient and facile installation of heterocycles onto preexisting organic molecules.* *Please refer to dissertation for diagrams

Functionalization and Suzuki-Miyaura cross-coupling of potassium organotrifluoroborates

The Suzuki-Miyaura cross-coupling reaction has proven to be one of the most powerful reactions in modern organic synthesis for the formation of carbon-carbon bonds. Recently, the development of new metal/ligand systems has broadened the scope of the reaction. During the past decade, tetracoordinate potassium organotrifluoroborates have emerged as an exceptional alternative to the traditionally used tricoordinate organoboron species for the synthesis of organic molecules. Because of their tetracoordinate nature, potassium organotrifluoroborates do not undergo undesirable side reactions with the commonly employed organic reagents, and therefore the organic substructure of simple organotrifluoroborates can be functionalized to build molecular complexity, while leaving the valuable carbon-boron bond intact for further transformations. We have achieved the Wittig reaction of potassium organotrifluoroborate-containing phosphorus ylides with aldehydes using K2CO3 as a base. The unsaturated potassium organotrifluoroborates were obtained in high yields. In addition, a protocol for a one-pot transformation was developed from the corresponding potassium 4-(chloromethyl)phenyltrifluoroborate.* Ethers are ubiquitous in natural products and compounds of pharmacological interest. Recognizing their importance in synthesis, we developed an efficient method to access ether linkages via the Suzuki-Miyaura cross-coupling of potassium alkoxymethyltrifluoroborates, which were prepared from the SN2 displacement of bromomethyltrifluoroborate with alkoxides. After an extensive optimization process, conditions were found to cross-couple alkoxymethyltrifluoroborates with aryl- and heteroaryl chlorides to afford benzyl ethers. This method provides a unique dissonant disconnection that allows greater flexibility in the design of new and improved synthetic pathways.* Owing to the prevalence of heterobiaryls in natural products and pharmacologically active compounds, we explored the Suzuki-Miyaura cross-coupling of potassium heteroaryltrifluoroborates. Toward this end, over twenty structurally diverse and bench-stable five-membered, six-membered, and benzannulated heteroaryltrifluoroborate derivatives were prepared from commercially available boronic acids in moderate to excellent yields. After a broad screening, unified and general conditions were found to cross-couple near-stoichiometric amounts of heteroaryltrifluoroborates with aryl- and heteroaryl halides. This method represents an efficient and facile installation of heterocycles onto preexisting organic molecules.* *Please refer to dissertation for diagrams

Discovery of Novel Dual Inhibitors of the Wild-Type and the Most Prevalent Drug-Resistant Mutant, S31N, of the M2 Proton Channel from Influenza A Virus

Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N mutant. However, the S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches, and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol (<b>44</b>) is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections

NMR Chemical Shifts of Trace Impurities: Industrially Preferred Solvents Used in Process and Green Chemistry

The ¹H and ¹³C NMR chemical shifts of 48 industrially preferred solvents in six commonly used deuterated NMR solvents (CDCl₃, acetone-<i>d</i>₆, DMSO-<i>d</i>₆, acetonitrile-<i>d</i>₃, methanol-<i>d</i>₄, and D₂O) are reported. This work supplements the compilation of NMR data published by Gottlieb, Kotlyar, and Nudelman (J. Org. Chem. 1997, 62, 7512) by providing spectral parameters for solvents that were not commonly utilized at the time of their original report. Data are specifically included for solvents, such as 2-Me-THF, <i>n</i>-heptane, and <i>iso</i>-propyl acetate, which are being used more frequently as the chemical industry aims to adopt greener, safer, and more sustainable solvents. These spectral tables simplify the identification of these solvents as impurities in NMR spectra following their use in synthesis and workup protocols

Discovery of Novel Dual Inhibitors of the Wild-Type and the Most Prevalent Drug-Resistant Mutant, S31N, of the M2 Proton Channel from Influenza A Virus

Anti-influenza drugs, amantadine and rimantadine, targeting the M2 channel from influenza A virus are no longer effective because of widespread drug resistance. S31N is the predominant and amantadine-resistant M2 mutant, present in almost all of the circulating influenza A strains as well as in the pandemic 2009 H1N1 and the highly pathogenic H5N1 flu strains. Thus, there is an urgent need to develop second-generation M2 inhibitors targeting the S31N mutant. However, the S31N mutant presents a huge challenge to drug discovery, and it has been considered undruggable for several decades. Using structural information, classical medicinal chemistry approaches, and M2-specific biological testing, we discovered benzyl-substituted amantadine derivatives with activity against both S31N and WT, among which 4-(adamantan-1-ylaminomethyl)-benzene-1,3-diol (44) is the most potent dual inhibitor. These inhibitors demonstrate that S31N is a druggable target and provide a new starting point to design novel M2 inhibitors that address the problem of drug-resistant influenza A infections. [Image: see text

Flipping in the Pore: Discovery of Dual Inhibitors That Bind in Different Orientations to the Wild-Type versus the Amantadine-Resistant S31N Mutant of the Influenza A Virus M2 Proton Channel

[Image: see text] Influenza virus infections lead to numerous deaths and millions of hospitalizations each year. One challenge facing anti-influenza drug development is the heterogeneity of the circulating influenza viruses, which comprise several strains with variable susceptibility to antiviral drugs. For example, the wild-type (WT) influenza A viruses, such as the seasonal H1N1, tend to be sensitive to antiviral drugs, amantadine and rimantadine, while the S31N mutant viruses, such as the pandemic 2009 H1N1 (H1N1pdm09) and seasonal H3N2, are resistant to this class of drugs. Thus, drugs targeting both WT and the S31N mutant are highly desired. We report our design of a novel class of dual inhibitors along with their ion channel blockage and antiviral activities. The potency of the most active compound 11 in inhibiting WT and the S31N mutant influenza viruses is comparable with that of amantadine in inhibiting WT influenza virus. Solution NMR studies and molecular dynamics (MD) simulations of drug-M2 interactions supported our design hypothesis: namely, the dual inhibitor binds in the WT M2 channel with an aromatic group facing down toward the C-terminus, while the same drug binds in the S31N M2 channel with its aromatic group facing up toward the N-terminus. The flip-flop mode of drug binding correlates with the structure–activity relationship (SAR) and has paved the way for the next round of rational design of broad-spectrum antiviral drugs