Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp3)−H Activation Strategy

Thesmar, Pierre and Coomar, Seemon and Prescimone, Alessandro and Häussinger, Daniel and Gillingham, Dennis and Baudoin, Olivier. (2020) Divergent Synthesis of Bioactive Dithiodiketopiperazine Natural Products Based on a Double C(sp3)−H Activation Strategy. Chemistry - A European Journal, 26.

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Official URL: https://edoc.unibas.ch/78909/

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This article provides a detailed report of our efforts to synthesize the dithiodiketopiperazine (DTP) natural products (−)‐epicoccin G and (−)‐rostratin A using a double C(sp3)−H activation strategy. The strategy's viability was first established on a model system lacking the C8/C8’ alcohols. Then, an efficient stereoselective route including an organocatalytic epoxidation was secured to access a key bis‐triflate substrate. This bis‐triflate served as the functional handles for the key transformation of the synthesis: a double C(sp3)−H activation. The successful double activation opened access to a common intermediate for both natural products in high overall yield and on a multigram scale. After several unsuccessful attempts, this intermediate was efficiently converted to (−)‐epicoccin G and to the more challenging (−)‐rostratin A via suitable oxidation/reduction and protecting group sequences, and via a final sulfuration that occurred in good yield and high diastereoselectivity. These efforts culminated in the synthesis of (−)‐epicoccin G and (−)‐rostratin A in high overall yields (19.6 % over 14 steps and 12.7 % over 17 steps, respectively), with the latter being obtained on a 500 mg scale. Toxicity assessments of these natural products and several analogues (including the newly synthesized epicoccin K) in the leukemia cell line K562 confirmed the importance of the disulfide bridge for activity and identified dianhydrorostratin A as a 20x more potent analogue.
Faculties and Departments:05 Faculty of Science > Departement Chemie > Chemie > Nuclear Magnetic Resonance (Häussinger)
05 Faculty of Science > Departement Chemie > Chemie > Synthetische Chemie (Baudoin)
UniBasel Contributors:Baudoin, Olivier and Häussinger, Daniel
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Oct 2021 01:30
Deposited On:21 Oct 2020 14:39

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