N-Methylation of Self-Immolative Thiocarbamates Provides Insights into the Mechanism of Carbonyl Sulfide Release.

Hydrogen sulfide (H2S) is an important biomolecule, and self-immolative thiocarbamates have shown great promise as triggerable H2S donors with suitable analogous control compounds; however, thiocarbamates with electron-deficient payloads are less efficient H2S donors. We report here the synthesis and study of a series of N-methylated esterase-triggered thiocarbamates that block the postulated unproductive deprotonation-based pathway for these compounds. The relative reaction profiles for H2S release across a series of electron-rich and electron-poor N-Me aniline payloads are examined experimentally and computationally. We show that thiocarbamate N-methylation does block some side reactivity and increases the H2S release profiles for electron-poor donors. Additionally, we show that isothiocyanate release is not a competitive pathway, and rather that the reduced efficiency of electron-poor donors is likely due to other side reactions.

Citation

Carolyn M Levinn, Jenna L Mancuso, Rachel E Lutz, Haley M Smith, Christopher H Hendon, Michael D Pluth. N-Methylation of Self-Immolative Thiocarbamates Provides Insights into the Mechanism of Carbonyl Sulfide Release. The Journal of organic chemistry. 2021 Apr 16;86(8):5443-5451

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PMID: 33818104

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