{"id":27784,"date":"2024-10-29T14:53:59","date_gmt":"2024-10-29T14:53:59","guid":{"rendered":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=27784"},"modified":"2025-08-21T14:03:30","modified_gmt":"2025-08-21T13:03:30","slug":"mechanism-of-the-masamune-bergman-reaction-part-4-why-was-the-dft-energy-barrier-too-high-for-the-calicheamicin-reaction","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=27784","title":{"rendered":"Mechanism of the Masamune-Bergman reaction. Part 4. Why was the DFT energy barrier too high for the Calicheamicin reaction?"},"content":{"rendered":"
\n

Michael in a comment here<\/a> on the mechanism of the Masamune-Bergman reaction notes that when it occurs as part of the Calicheamicin (an antibody-drug conjugate or ADC) version of this mechanism, a pre-step is first necessary. As discussed in this review article,[1]<\/a><\/span> the trisulfide linkage is reduced and the resulting thiolate undergoes a facile 1,4-addition to the adjacent enone.<\/p>\n

\"\"<\/a><\/p>\n

DFT calculations on the new form (FAIR Data DOI:[2]<\/a><\/span>, [2]<\/a><\/span> show that the free energy barrier is reduced from 38.6 kcal\/mol to 26.2 kcal\/mol.<\/p>\n

\"\"<\/p>\n

\"\"<\/a><\/p>\n

This is now a reasonable value for a thermal reaction, being a 12.4 kcal\/mol reduction from the unactivated species. We can conclude that Michael’s suggestion was spot on, and suggests in turn that a DFT-biradicaloid calculation is in fact a reasonable procedure for modelling this type of system.<\/p>\n

References<\/h2>\n
  1. V. Kostova, P. D\u00e9sos, J. Starck, and A. Kotschy, \"The Chemistry Behind ADCs\", Pharmaceuticals<\/i>, vol. 14, pp. 442, 2021. https:\/\/doi.org\/10.3390\/ph14050442<\/a>\n\n<\/li>\n
  2. H. Rzepa, \"Mechanism of the Masamune-Bergman reaction. Part 4. Why is the DFT energy barrier too high?\", 2024. https:\/\/doi.org\/10.14469\/hpc\/14632<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    Michael in a comment here on the mechanism of the Masamune-Bergman reaction notes that when it occurs as part of the Calicheamicin (an antibody-drug conjugate or ADC) version of this mechanism, a pre-step is first necessary. As discussed in this review article, the trisulfide linkage is reduced and the resulting thiolate undergoes a facile 1,4-addition […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":false,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"activitypub_content_warning":"","activitypub_content_visibility":"","activitypub_max_image_attachments":5,"activitypub_interaction_policy_quote":"anyone","activitypub_status":"","footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[4],"tags":[],"ppma_author":[2661],"class_list":["post-27784","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry"],"yoast_head":"\nMechanism of the Masamune-Bergman reaction. Part 4. Why was the DFT energy barrier too high for the Calicheamicin reaction? - Henry Rzepa's Blog<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=27784\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Mechanism of the Masamune-Bergman reaction. Part 4. Why was the DFT energy barrier too high for the Calicheamicin reaction? - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"Michael in a comment here on the mechanism of the Masamune-Bergman reaction notes that when it occurs as part of the Calicheamicin (an antibody-drug conjugate or ADC) version of this mechanism, a pre-step is first necessary. 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