Several recent reports outlined the singular reactivity of acid fluorides as excellent electrophiles in transition‐metal catalysis. These species undergo oxidative addition of the metal into the C−F bond; then, retention or release of the CO moiety can occur and be controlled by tuning the catalytic system and the reaction parameters. Acid fluorides, which can be derived from carboxylic acids, show good stability and high reactivity in a wide range of possible functionalizations with nucleophiles. Their use provides an interesting alternative to that of the parent carboxylic acid derivatives (acid chlorides, esters, amides, acids, or aldehydes).
2019-02- Ruthenium-catalyzed ring-opening reaction of a 3-aza-2-oxabicyclo[2.2.1]hept-5-ene with amines — an unexpected mode of ring-opening
Tait, K.; Koh, S.; Blanchard, N.; Tam, W. Can. J. Chem. 2019, 97, 310-316.
The ruthenium-catalyzed ring-opening reaction of a 3-aza-2-oxabicyclo[2.2.1]hept-5-ene with amines was investigated. In the presence of an amine and a ruthenium catalyst, the N–O bond is cleaved, forming a ring-opened allylic alcohol product. Through a possible ruthenium-catalyzed redox isomerization, the allylic alcohol is transformed into a saturated carbonyl product. This unexpected mode of ruthenium-catalyzed ring-opening reaction of a 3-aza-2-oxabicyclo[2.2.1]hept-5-ene leads to the formation of a cyclopentanone derivative in moderate yields.
2019-03- Ipomoeassin F Binds Sec61α to Inhibit Protein Translocation
Zong, G.; Hu, Z.; O’Keefe, S.; Tranter, D.; Iannotti, M. J.; Baron, L.; Hall, B.; Corfield, K.; Paatero, A. O.; Henderson, M. J.; Roboti, P.; Zhou, J.; Sun, X.; Govindarajan, M.; Rohde, J. M.; Blanchard, N.; Simmonds, R.; Inglese, J.; Du, Y.; Demangel, C.; High, S.; Paavilainen, V. O.; Shi, W. Q. J. Am. Chem. Soc. 2019, 141, 8450-8461
Ipomoeassin F is a potent natural cytotoxin that inhibits growth of many tumor cell lines with single-digit nanomolar potency. However, its biological and pharmacological properties have remained largely unexplored. Building upon our earlier achievements in total synthesis and medicinal chemistry, we used chemical proteomics to identify Sec61α (protein transport protein Sec61 subunit alpha isoform 1), the pore-forming subunit of the Sec61 protein translocon, as a direct binding partner of ipomoeassin F in living cells.
2019-04- Design, synthesis and biological evaluation of antimicrobial diarylimine and –amine compounds targeting the interaction between the bacterial NusB and NusE proteins
Qiu, Y.; Chan, S. T.; Lin, L.; Shek, T. L.; Tsang, T. F.; Barua, N.; Zhang, Y.; Ip, M.; Chan, P. K.-s.; Blanchard, N.; Hanquet, G.; Zuo, Z.; Yang, X.; Ma, C. Eur. J. Med. Chem. 2019, 178, 214-231
Discovery of antimicrobial agents with a novel model of action is in urgent need for the clinical management of multidrug-resistant bacterial infections. Recently, we reported the identification of a first-in-class bacterial ribosomal RNA synthesis inhibitor, which interrupted the interaction between the bacterial transcription factor NusB and NusE. In this study, a series of diaryl derivatives were rationally designed and synthesized based on the previously established pharmacophore model.
2019-05- Recombinant Antibodies against Mycolactone
Naranjo, L.; Ferrara, F.; Blanchard, N.; Demangel, C.; D’Angelo, S.; Erasmus, F. M.; Teixera, A. A.; Bradbury, R. A Toxins 2019, 11, 346.
In the past, it has proved challenging to generate antibodies against mycolactone, the primary lipidic toxin A of Mycobacterium ulcerans causing Buruli ulcer, due to its immunosuppressive properties. Here we show that in vitro display, comprising both phage and yeast display, can be used to select antibodies recognizing mycolactone from a large human naïve phage antibody library.
2019-06- Activating Pyrimidines by Pre-distortion for the General Synthesis of 7-Aza-indazoles from 2-Hydrazonylpyrimidines via Intramolecular Diels–Alder Reactions
Le Fouler, V.; Chen, Y.; Gandon, V.; Bizet, V.; Salome, C.; Fessard, T.; Liu, F.; Houk, K. N.; Blanchard, N. J. Am. Chem. Soc. 2019, 141, 15901-15909
Pyrimidines are almost unreactive partners in Diels–Alder cycloadditions with alkenes and alkynes, and only reactions under drastic conditions have previously been reported. We describe how 2-hydrazonylpyrimidines, easily obtained in two steps from commercially available 2-halopyrimidines, can be exceptionally activated by trifluoroacetylation. This allows a Diels–Alder cycloaddition under very mild reaction conditions, leading to a large diversity of aza-indazoles, a ubiquitous scaffold in medicinal chemistry. Highlighted in: Actualités de l’INC CNRS, 21 octobre 2019 (link).
2019-07- Nusbiarylins, a new class of antimicrobial agents: Rational design of bacterial transcription inhibitors targeting the interaction between the NusB and NusE proteins
Qiu, Y.; Chan, S. T.; Lin, L.; Shek, T. L.; Tsang, T. F.; Zhang, Y.; Ip, M.; Chan, P. K.-s.; Blanchard, N.; Hanquet, G.; Zuo, Z.; Yang, X.; Ma, C., Bioorganic Chemistry 2019, 92, 103203
Discovery of antibiotics of a novel mode of action is highly required in the fierce battlefield with multi-drug resistant bacterial infections. Previously we have validated the protein-protein interaction between bacterial NusB and NusE proteins as an unprecedented antimicrobial target and reported the identification of a first-in-class inhibitor of bacterial ribosomal RNA synthesis with antimicrobial activities. In this paper, derivatives of the hit compound were rationally designed based on the pharmacophore model for chemical synthesis, followed by biological evaluations.
2019-08- Discussion Addendum for: Synthesis of Ynamides by Copper-Mediated Coupling of 1,1-Dibromo-1-alkenes with Nitrogen Nucleophiles. Preparation of 4-Methyl-N-(2-phenylethynyl)-N-(phenylmethyl)benzenesulfonamide
Since the first reports on the synthesis of ynamides using copper catalysis, including our original report on the use of 1,1-dibromo-1-alkenes as practical alkynylating agents, the chemistry of these nitrogen-substituted alkynes has experienced an impressive growth. Ynamides are now readily available building blocks that can be easily prepared on a multi-gram scale thanks to various efficient and reliable procedures.
