Divergent Pathway for the Solid-Phase Conversion of Aromatic Acetylenes to Carboxylic Acids, α-Ketocarboxylic Acids, and Methyl Ketones

Abstract

An efficient divergent pathway for the selective and quantitative solid-phase conversion of aromatic acetylenes to the corresponding carboxylic acids, alpha-keto-carboxylic acids, and methyl ketones is presented. A range of aromatic trimethylsilyl-protected acetylene building blocks was synthesized in excellent yields using a Sonogashira cross-coupling protocol and used in solid-phase synthesis on PEGA resin. Dependent on the selection of conditions, the same solid-supported alkyne could be quantitatively converted to an aromatic carboxylic acid, an aromatic alpha-ketocarboxylic acid, or an aromatic methyl ketone. The conversion to carboxylic acid involved an OsO4/NaIO4/HMTA-mediated oxidative cleavage of the silyl-deprotected alkyne to provide the aromatic carboxylate in excellent yield. The alpha-ketocarboxylic acids were obtained by direct treatment of the trimethylsilyl-protected alkyne with OsO4/NMO/HMTA, while the ketones were obtained by simple acid-mediated hydration of the alkyne using aqueous TFA. In general, all products were obtained in excellent purities, typically above 90%. In addition, it was shown that the alkyne-containing building blocks could easily be incorporated into resin-bound peptides and after chemoselective conversion of the alkyne the new functional groups could be used for further derivatization into peptidomimetic compounds.

A spontaneous gold(i)-azide alkyne cycloaddition reaction yields gold-peptide bioconjugates which overcome cisplatin resistance in a p53-mutant cancer cell line

“…TMS-deprotection was accomplished by aspiring 376 mg (1.44 mmol, 5 eq) of tetrabutylammonium fluoride (TBAF$3H 2 O) and 59 ml (mmol, 4.5 eq) of acetic acid, dissolved in 1.5 ml THF, into the syringe. 26 After 2.5 h on a laboratory shaker, the resin was washed (5 Â THF, 5 Â H 2 O, 5 Â DMF, 5 Â DCM) and dried in vacuo. The resin (synthesis of: 8a (130 mg, 0.08 mmol), 8b (170 mg, 0.1 mmol) and 8c (150 mg, 0.09 mmol)) was weighed into a fritted 5 ml plastic syringe and swollen in DMF for 20 min.…”

A Blocking Group Scan Using a Spherical Organometallic Complex Identifies an Unprecedented Binding Mode with Potent Activity In Vitro and In Vivo for the Opioid Peptide Dermorphin

“…Native dermorphin 3 was prepared in 47 % overall isolated yield after HPLC purification. Phe 3 and Tyr 5 modified conjugates 4 and 5 were obtained by incorporation of alkyne‐modified phenylalanine derivative 6 and subsequent Pd/Cu catalyzed Sonogashira cross‐coupling with iodoaryl complex 2 . Cleavage with TFA/H 2 O/TIS gave conjugates 4 and 5 in 12 and 10 % isolated yield, respectively.…”

“…Solvents were dried according to standard procedures and stored over molecular sieves (3 Å). Fmoc‐[4‐(TMS−C≡C)Phe]−OH and the SA M2 solid support were prepared according to literature procedures . Preparative HPLC was performed on a customized Varian ProStar 210 HPLC system with PDA detector.…”

Synthesis of bisarylethyne–peptide conjugates

“…16 This provided a mixture of inseparable products that contained non-reduced and fully reduced triple-bonds. 17 Since the reduction could not be avoided when a silane was present, we attempted to drive the reduction of the triple bond to completion by adding more silane, and by using the more reactive TES. We reasoned that although the triple bond forms an attractive rigidifying feature with interesting opto-and electrochemical properties, having the ability to fully reduce the triple bond would not only result in the formation of valuable compounds for control experiments as it produces non-conductive peptides with a higher flexibility in the bridging section, it would also help us to gain insight into the source of reduction, and how to avoid it.…”