{"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:\/\/rzepa.net\/blog\/2014\/04\/13\/artemisinin-are-stereo-electronics-at-the-core-of-its-reactivity\/","title":{"rendered":"Artemisinin: are stereo-electronics at the core of its (re)activity?"},"content":{"rendered":"

\n\tAround 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.\n<\/p>\n

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

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

    \n
  1. \n\t\tC3-C4 has the gauche motif of a 1,2-diol\n\t<\/li>\n
  2. \n\t\tCarbons 7 and 4 are anomeric centres, with the focus on bonds 1-7\/7-6 and 6-4\/4-5\n\t<\/li>\n
  3. \n\t\tBond 1-2 has the potential for a so-called α-effect, where the lone pairs on adjacent hetero-atoms are buttressed.\n\t<\/li>\n<\/ol>\n

    \n\tThe 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° (hence a double gauche at the 3-4 bond).\n<\/p>\n

    \"Click
    Click for 3D<\/figcaption><\/figure>\n

    \n\tFirst, 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.\n<\/p>\n

    \n\t\"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 1.46Å 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 σ* bond;\n<\/p>\n

      \n
    1. \n\t\tLp(O6)-σ*(C4-O5) = 21.2 kcal\/mol which helps to account for the short C4-O6 and the long C4-O5 bonds.\n\t<\/li>\n
    2. \n\t\twhereas the reverse donation of Lp(O5)-σ*(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).\n\t<\/li>\n
    3. \n\t\tAt the second anomeric centre of C7, Lp(O1)-σ*(C7-O6) = 19.9 kcal\/mol\n\t<\/li>\n
    4. \n\t\twhereas the reverse donation of Lp(O6)-σ*(C7-O1) is 5.7 kcal\/mol, again highly asymmetric, as are the C-O bond lengths (1.413\/1.441Å).\n\t<\/li>\n
    5. \n\t\tNext, 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 1.447Å.\n\t<\/li>\n<\/ol>\n

      \n\tWhere such stereoelectronic interactions are asymmetric, one might expect enhanced reactivity. A good example of this are two stereoisomeric of a 7-ring herbicide[cite]10.1039\/P29890001929[\/cite] 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.\n<\/p>\n

      \n\tFinally, because it is virtually free to do so in a computational sense, I show the computed VCD spectrum[cite]10.6084\/m9.figshare.997360[\/cite] (covering the possibility that it is measured at some point). The calculated[cite]10.6084\/m9.figshare.997463[\/cite] optical rotation ([α]589<\/sub> is +93° (obs ~+76°). Whilst the absolute configuration is not in any doubt, it is always nice to have further confirmations.\n<\/p>\n

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

      \n

      This post has DOI: 10.14469\/hpc\/12766<\/p>\n

      \n","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":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,11],"tags":[343,351,2316],"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"],"_links":{"self":[{"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/posts\/12276","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/comments?post=12276"}],"version-history":[{"count":0,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/posts\/12276\/revisions"}],"wp:attachment":[{"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/media?parent=12276"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/categories?post=12276"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/rzepa.net\/blog\/wp-json\/wp\/v2\/tags?post=12276"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}