{"id":12276,"date":"2014-04-13T17:12:43","date_gmt":"2014-04-13T16:12:43","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=12276"},"modified":"2014-04-13T17:12:43","modified_gmt":"2014-04-13T16:12:43","slug":"artemisinin-are-stereo-electronics-at-the-core-of-its-reactivity","status":"publish","type":"post","link":"https:\/\/www.rzepa.net\/blog\/?p=12276","title":{"rendered":"Artemisinin: are stereo-electronics at the core of its (re)activity?"},"content":{"rendered":"
\n

Around 100 tons of the potent antimalarial artemisinin is produced annually; a remarkable quantity given its very unusual and fragile looking molecular structure (below). When I looked at this, I was immediately struck by a thought: surely this is a classic molecule for analyzing stereoelectronic effects (anomeric and gauche). Here this aspect is explored.<\/p>\n

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

I start by listing the bonds around which interesting things might happen:<\/p>\n

    \n
  1. C3-C4 has the gauche motif of a 1,2-diol<\/li>\n
  2. Carbons 7 and 4 are anomeric centres, with the focus on bonds 1-7\/7-6 and 6-4\/4-5<\/li>\n
  3. Bond 1-2 has the potential for a so-called \u03b1-effect, where the lone pairs on adjacent hetero-atoms are buttressed.<\/li>\n<\/ol>\n

    The crystal structure is shown below, annotated with pertinent bond lengths (trivial atom numbering). The dihedral 2-3-4-6 and 2-3-4-6 are respectively -51 and 72\u00b0 (hence a double gauche at the 3-4 bond).<\/p>\n

    \"Click

    Click for 3D<\/p><\/div>\n

    First, an exploration of what might be happening around C4. The following is a search of the Cambridge crystal structure database, plotted for the two C-O bond lengths common to C4.<\/p>\n

    \"artemisinin1\"<\/a> \"artemisinin\"<\/a> Here, DIST1 is C4-O6 and DIST2 is C4-O5. Notice the very pronounced asymmetry; at the red hotspot above, the most frequent occurrence is ~1.39 and 1.46\u00c5 respectively; artemisinin is more or less at that hotspot. This can be quantified by the NBO E(2) energies for the interaction of an oxygen lone pair antiperiplanar to the C-O \u03c3* bond;<\/p>\n

      \n
    1. Lp(O6)-\u03c3*(C4-O5) = 21.2 kcal\/mol which helps to account for the short C4-O6 and the long C4-O5 bonds.<\/li>\n
    2. whereas the reverse donation of Lp(O5)-\u03c3*(C4-O6) is merely 4.8 kcal\/mol (normally the two donations are more or less equal, and hence so at the two C-O bond lengths).<\/li>\n
    3. At the second anomeric centre of C7, Lp(O1)-\u03c3*(C7-O6) = 19.9 kcal\/mol<\/li>\n
    4. whereas the reverse donation of Lp(O6)-\u03c3*(C7-O1) is 5.7 kcal\/mol, again highly asymmetric, as are the C-O bond lengths (1.413\/1.441\u00c5).<\/li>\n
    5. Next, the gauche effect at C3-C4. The C4-H to C3-O2 donation is 6.4 kcal\/mol, again contributing to the longer C-O length of 1.447\u00c5.<\/li>\n<\/ol>\n

      Where such stereoelectronic interactions are asymmetric, one might expect enhanced reactivity. A good example of this are two stereoisomeric of a 7-ring herbicide[1]<\/a><\/span> where one anomer with equal anomeric C-O lengths is a stable soil-persistent species, whereas the other with asymmetric lengths has a very short soil residency due to rapid hydrolysis. It might be tempting to speculate that some aspect of the activity of artemisinin may be due to such stereoelectronic asymmetries.<\/p>\n

      Finally, because it is virtually free to do so in a computational sense, I show the computed VCD spectrum[2]<\/a><\/span> (covering the possibility that it is measured at some point). The calculated[3]<\/a><\/span> optical rotation ([\u03b1]589<\/sub> is +93\u00b0 (obs ~+76\u00b0). Whilst the absolute configuration is not in any doubt, it is always nice to have further confirmations.<\/p>\n

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

      References<\/h2>\n
      1. P. Camilleri, D. Munro, K. Weaver, D.J. Williams, H.S. Rzepa, and A.M.Z. Slawin, \"Isoxazolinyldioxepins. Part 1. Structure\u2013reactivity studies of the hydrolysis of oxazolinyldioxepin derivatives\", J. Chem. Soc., Perkin Trans. 2<\/i>, pp. 1929-1933, 1989. https:\/\/doi.org\/10.1039\/p29890001929<\/a>\n\n<\/li>\n
      2. H.S. Rzepa, \"Gaussian Job Archive for C15H22O5\", 2014. https:\/\/doi.org\/10.6084\/m9.figshare.997360<\/a>\n\n<\/li>\n
      3. H.S. Rzepa, \"Gaussian Job Archive for C15H22O5\", 2014. https:\/\/doi.org\/10.6084\/m9.figshare.997463<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

        Around 100 tons of the potent antimalarial artemisinin is produced annually; a remarkable quantity given its very unusual and fragile looking molecular structure (below). When I looked at this, I was immediately struck by a thought: surely this is a classic molecule for analyzing stereoelectronic effects (anomeric and gauche). Here this aspect is explored. I […]<\/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,"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":[1754,6],"tags":[1188,59,1189],"class_list":["post-12276","post","type-post","status-publish","format-standard","hentry","category-crystal_structure_mining","category-interesting-chemistry","tag-c7-lp","tag-cambridge","tag-stereo-electronics"],"jetpack_publicize_connections":[],"jetpack_featured_media_url":"","jetpack_sharing_enabled":true,"jetpack_shortlink":"https:\/\/wp.me\/p1gPyz-3c0","jetpack_likes_enabled":true,"_links":{"self":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/12276","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=12276"}],"version-history":[{"count":0,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=\/wp\/v2\/posts\/12276\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=12276"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=12276"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.rzepa.net\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=12276"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}