{"id":27729,"date":"2024-09-11T12:22:33","date_gmt":"2024-09-11T11:22:33","guid":{"rendered":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=27729"},"modified":"2025-08-21T14:04:22","modified_gmt":"2025-08-21T13:04:22","slug":"mechanism-of-the-masamune-bergman-reaction-part-3-the-transition-state-for-calicheamicin-models","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=27729","title":{"rendered":"Mechanism of the Masamune-Bergman reaction. Part 3: The transition state for Calicheamicin models."},"content":{"rendered":"
\n

Calicheamicin<\/a> was noted in the previous post as a natural product with antitumour properties and having many weird structural features such as \u00a0an unusual “enedidyne” motif. The representation is shown below.
\n\"\"<\/a><\/p>\n

A partial structure shown below for Calicheamicin replaces the -(CH2<\/sub>)4- substructure with a four carbon chain that includes two sp2<\/sup>centres instead of two sp3<\/sup> centres. The purpose is to find out how these structural modifications to the classic Bergman affect the mechanism.
\n\"\"<\/a><\/p>\n

TS1 is shown below for this model and the computed free energy barrier for this cyclisation is 42.5 kcal\/mol at the u\u03c9B97XD\/Def2-TZVPP level,\u00a0<S2<\/sup>> = 0.345. FAIR Data DOI[1]<\/a><\/span>. This compares with\u00a033.0 kcal\/mol calculated for the -(CH2<\/sub>)4- version, for which <S2<\/sup>> = 0.266. To prepare for modelling the full Calicheamicin<\/a> molecule, the basis set for this model was reduced to Def2-SVPP and at this level \u0394G\u2021<\/sup> was 43.0 kcal\/mol, <S2<\/sup>> = 0.368, the difference being small enough that the reduction in basis set seems unlikely to affect the results. The C-C bond forming lengths are 1.957 (Deft-TZVPP) and 1.989Å (Def2-SVPP).
\n\"\"<\/p>\n

Now for a larger model containing the entire Calicheamicin molecule. Two possibilities were explored; one where the geometry of the system was fully optimised in isolation to yield a conformation for Calicheamicin which folded in upon itself and for which \u0394G\u2021<\/sup> (Def2-SVPP) 40.1 kcal\/mol,\u00a0<S2<\/sup>> 0.368.<\/p>\n

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

\nThe second model used the initial geometry of Calicheamicin as obtained from a crystal structure of the ligand folded into the minor grove of a DNA fragment and which has a much more linear form. The reactant in this mode was +6.1 kcal\/mol higher in energy than the previous and TS1 was 4.6 kcal\/mol higher, leading to \u0394G\u2021<\/sup> 38.6 kcal\/mol, <S2<\/sup>>\u00a00.367.
\n\"\"\n<\/p>\n

\nSo what conclusions can we draw from these extended models of the Bergman cyclisation? The activation free energies for all three models are in the range 42.5 – 38.6 kcal\/mol, which is a great deal higher than a value commensurate with a facile room temperature reaction (~22±3). The observation that Calicheamicin can in fact be characterised as a crystal structure when bound to DNA suggests that the cyclisation barrier cannot be too low, but conversely the range 42.5 – 38.6 kcal\/mol appears too large for Calicheamicin to easily activate into a biradical in order to abstract hydrogen atom and end up causing strand scission. Might the simplistic model of a split UHF wavefunction resulting in values of <S2<\/sup>> 0.37 be the problem? Well, a similar approach was taken to modelling the Stevens rearrangement [2]<\/a><\/span>. Using a plain non-biradical closed shell wavefunction, a barrier of ~48 kcal\/mol was obtained, but this reduced to 14 kcal\/mol when the UHF method was applied (<S2<\/sup>> \u00a00.421), so this model appears to work well in those circumstances. The jury must still be out on whether the Bergman cyclisation mechanism is being correctly modelled here or whether something more complex is going on. <\/p>\n

<\/p>\n

References<\/h2>\n
  1. H. Rzepa, \"Mechanism of the Masamune-Bergman reaction. Calicheamicin\", 2024. https:\/\/doi.org\/10.14469\/hpc\/14583<\/a>\n\n<\/li>\n
  2. H. Rzepa, \"The Stevens rearrangement: how history gives us new insights.\", 2021. https:\/\/doi.org\/10.59350\/4010f-fvr26<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

    Calicheamicin was noted in the previous post as a natural product with antitumour properties and having many weird structural features such as \u00a0an unusual “enedidyne” motif. The representation is shown below. A partial structure shown below for Calicheamicin replaces the -(CH2)4- substructure with a four carbon chain that includes two sp2centres instead of two sp3 […]<\/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-27729","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry"],"yoast_head":"\nMechanism of the Masamune-Bergman reaction. Part 3: The transition state for Calicheamicin models. - 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=27729\" \/>\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 3: The transition state for Calicheamicin models. - Henry Rzepa's Blog\" \/>\n<meta property=\"og:description\" content=\"Calicheamicin was noted in the previous post as a natural product with antitumour properties and having many weird structural features such as \u00a0an unusual “enedidyne” motif. The representation is shown below. A partial structure shown below for Calicheamicin replaces the -(CH2)4- substructure with a four carbon chain that includes two sp2centres instead of two sp3 […]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=27729\" \/>\n<meta property=\"og:site_name\" content=\"Henry Rzepa's Blog\" \/>\n<meta property=\"article:published_time\" content=\"2024-09-11T11:22:33+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2025-08-21T13:04:22+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2024\/08\/Calicheamicin.svg\" \/>\n<meta name=\"author\" content=\"Henry Rzepa\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Henry Rzepa\" \/>\n\t<meta name=\"twitter:label2\" content=\"Estimated reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"4 minutes\" \/>\n<!-- \/ Yoast SEO plugin. -->","yoast_head_json":{"title":"Mechanism of the Masamune-Bergman reaction. 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Part 2: a possible 3D Model for Calicheamicin revealing the non-covalent-interactions (NCI) present.","author":"Henry Rzepa","date":"August 26, 2024","format":false,"excerpt":"Calicheamicin is a natural product with antitumour properties discovered in the 1980s, with the structure shown below. As noted elsewhere, this structure has many weird properties, including amongst other features an unusual \"enedidyne\" motif and the presence of an iodo group on an aromatic ring. Its\u00a0isolated 3D structure is quite\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":27784,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=27784","url_meta":{"origin":27729,"position":1},"title":"Mechanism of the Masamune-Bergman reaction. Part 4. Why was the DFT energy barrier too high for the Calicheamicin reaction?","author":"Henry Rzepa","date":"October 29, 2024","format":false,"excerpt":"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\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":27317,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=27317","url_meta":{"origin":27729,"position":2},"title":"Mechanism of the Masamune-Bergman reaction. Part 1.","author":"Henry Rzepa","date":"August 24, 2024","format":false,"excerpt":"The Masamune-Bergman reaction, is an example of \u00a0a highly unusual class of chemical mechanism involving the presumed formation of the biradical species shown as Int1 below by cyclisation of a cycloenediyne reactant.\u00a0Such a species is \u00a0so reactive that it will be quickly trapped, as for example by dihydrobenzene to form\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":26272,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=26272","url_meta":{"origin":27729,"position":3},"title":"Pre-mechanism for the Swern Oxidation: formation of chlorodimethylsulfonium chloride.","author":"Henry Rzepa","date":"August 25, 2023","format":false,"excerpt":"The Swern oxidation is a class of \"activated\" dimethyl sulfoxide (DMSO) reaction in which the active species is a chlorodimethylsulfonium chloride salt. The mechanism of this transformation as shown in e.g. Wikipedia is illustrated below.\u2021 However, an interesting and important aspect of chemistry is not apparent in this schematic mechanism\u2026","rel":"","context":"In "Curly arrows"","block_context":{"text":"Curly arrows","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2327"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":20354,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=20354","url_meta":{"origin":27729,"position":4},"title":"Epoxidation of ethene: a new substituent twist.","author":"Henry Rzepa","date":"December 21, 2018","format":false,"excerpt":"Five years back,\u00a0I speculated about the mechanism of the epoxidation of ethene by a peracid, concluding that kinetic isotope effects provided interesting evidence that this mechanism is highly asynchronous and involves a so-called \"hidden intermediate\". Here I revisit this reaction in which a small change is applied to the atoms\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2018\/12\/imine2.gif?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":6708,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6708","url_meta":{"origin":27729,"position":5},"title":"Reductive ozonolysis: the interesting step.","author":"Henry Rzepa","date":"May 7, 2012","format":false,"excerpt":"The mechanism of the reaction of alkenes known as ozonolysis was first set out in its modern form by Criegee. The crucial steps, (a), (b) and (d), are all pericyclic cycloaddition\/eliminations. The last step (e) is known as reductive ozonolysis, and this step is often treated as an afterthought, part\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/05\/ozonolysis.svg","width":350,"height":200},"classes":[]}],"jetpack_likes_enabled":false,"authors":[{"term_id":2661,"user_id":1,"is_guest":0,"slug":"admin","display_name":"Henry Rzepa","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/27729","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=27729"}],"version-history":[{"count":46,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/27729\/revisions"}],"predecessor-version":[{"id":29604,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/27729\/revisions\/29604"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=27729"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=27729"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=27729"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=27729"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}