{"id":4525,"date":"2011-07-06T15:47:29","date_gmt":"2011-07-06T15:47:29","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=4525"},"modified":"2011-07-07T05:59:56","modified_gmt":"2011-07-07T05:59:56","slug":"scalemic-molecules-a-cheminformatics-challenge","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=4525","title":{"rendered":"Scalemic molecules: a cheminformatics challenge!"},"content":{"rendered":"<div class=\"kcite-section\" kcite-section-id=\"4525\">\n<p>A <strong>scalemic<\/strong> molecule is the term used by <a href=\"http:\/\/www.uottawa.ca\/publications\/interscientia\/inter.4\/eliel\/eliel.html\" target=\"_blank\">Eliel<\/a> to describe any non-racemic chiral compound. Synthetic chemists imply it when they describe a synthetic product with an observable enantiomeric excess or <strong>ee<\/strong> (which can range from close to 0% to almost 100%). There are two cheminformatics questions of interest to me:<\/p>\n<ol>\n<li>How many non-trivial scalemic molecules have been reported in the literature (let&#8217;s assume their <strong>ee<\/strong> is significantly greater than 0%)?\n<ul>\n<li>The distribution function for the <strong>ee<\/strong> of these molecules would be most interesting!<\/li>\n<\/ul>\n<\/li>\n<li>Of those, how many have the absolute configuration of the predominant enantiomer established with high confidence?\n<ul>\n<li>Or, to put this another way, how many may prove to be mis-assigned?<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n<p>Note the careful qualification in the above questions. Thus by non-trivial, I mean compounds whose scalemic attributes persist in solution for a chemically useful duration. That could be taken to mean configurationally stable chiral molecules, rather than those that might be conformationally chiral (an example of a trivial scalemic molecule would be <em>e.g.<\/em> the twist-boat conformation of cyclohexane, which having D<sub>2<\/sub> symmetry is dissymetric, but which would only retain its scalemic property for a trivially short timescale).<\/p>\n<p>What are boundary values? These are some:<\/p>\n<ul>\n<li>As I write this, CAS records 61,257,703 chemical substances.\u00a0Needless to say (unless I missed it), the answer to my first question is not to be found there.<\/li>\n<li>Beilstein (Reaxys) records 1,126,995 compounds as having one or more reported chiroptical properties (which is the most direct way of establishing a molecule is scalemic, although strictly, having say an optical rotation of 0\u00b0 does not necessarily mean the molecule is not scalemic). We have no way of knowing how many molecules are scalemic for which no chiroptical measurement has been made (but one would hope its a small proportion). Perhaps that is a good answer to question <strong>1<\/strong>?\n<ul>\n<li>of which 1,097,094 relate to optical rotatory power, 17,515 to optical rotatory dispersion and 62,248 to electronic circular dichroism.<\/li>\n<li>it is more difficult to answer how many of these\u00a01,126,995 substances have a firmly established absolute configuration. Measuring a chiroptical property <em>per se<\/em> does NOT in itself establish the absolute configuration. Doing so is a fascinating exercise in sequential logical argument, and how one does it has changed quite a lot over time. And what might I mean with <em>high confidence<\/em>? An older assignment (made say &gt; 40 years ago) might be less confident than one established in 2011 (fortunately, we can probably trust the absolute configurations of the amino acids!). A bit of a can of worms, nevertheless. But it interests me because it is a good example of what the <strong>semantic web<\/strong> is supposed to be all about.<\/li>\n<\/ul>\n<\/li>\n<li>The Cambridge crystallographic database reports 560,307 entries, of which 72,340 are in chiral space groups (in which a chiral molecule can crystallise) and exhibit no disorder or other errors. We do not know how many of these are non-trivial, since all manner of small (and low energy) distortions can create a chiral species (in the solid state), but which would not persist \u00a0for a chemically useful duration in solution\u00a0(<em>i.e.<\/em> it might for example immediately racemize and become non-scalemic).<\/li>\n<li>The <a href=\"http:\/\/dx.doi.org\/10.1107\/S0108767383001762\" target=\"_blank\">Flack parameter<\/a> has been used since <a href=\" 10.1002\/chir.20473\" target=\"_blank\">1983<\/a> for enantiomorph estimation (a value of ~\u2264 0.10(10) would be considered meaningful). This could in principle provide an\u00a0answer of known confidence to my question <strong>2<\/strong> above (but would not address the issue of non-triviality).\n<ul>\n<li>The challenge now is to quantify how many compounds have a meaningful reported Flack parameter (presumably a sub-set of 72,340?)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>Let me declare one personal interest. Over the last four years or so, we have been asked to confirm the absolute configuration of around eight scalemic molecules. After a detailed study, we concluded three were mis-assigned. Now this in no way implies anything about what the answer to question <strong>2<\/strong> above might be! But it does make one think!<\/p>\n<!-- kcite active, but no citations found -->\n<\/div> <!-- kcite-section 4525 -->","protected":false},"excerpt":{"rendered":"<p>A scalemic molecule is the term used by Eliel to describe any non-racemic chiral compound. Synthetic chemists imply it when they describe a synthetic product with an observable enantiomeric excess or ee (which can range from close to 0% to almost 100%). There are two cheminformatics questions of interest to me: How many non-trivial scalemic [&hellip;]<\/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":false,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[2],"tags":[144,576,399,575,552,574,578,573,218,577],"ppma_author":[2661],"class_list":["post-4525","post","type-post","status-publish","format-standard","hentry","category-chemical-it","tag-cambridge","tag-chemical-substances","tag-chiral","tag-chiroptical","tag-disorder","tag-dissymetric","tag-low-energy","tag-scalemic-molecules","tag-semantic-web","tag-synthetic-product"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.5 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Scalemic molecules: a cheminformatics challenge! - Henry Rzepa&#039;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=4525\" \/>\n<meta property=\"og:locale\" content=\"en_GB\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Scalemic molecules: a cheminformatics challenge! - Henry Rzepa&#039;s Blog\" \/>\n<meta property=\"og:description\" content=\"A scalemic molecule is the term used by Eliel to describe any non-racemic chiral compound. Synthetic chemists imply it when they describe a synthetic product with an observable enantiomeric excess or ee (which can range from close to 0% to almost 100%). 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Synthetic chemists imply it when they describe a synthetic product with an observable enantiomeric excess or ee (which can range from close to 0% to almost 100%). 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Eudesma-1,3-dien-6,13-olide.","author":"Henry Rzepa","date":"December 8, 2011","format":false,"excerpt":"Previously, I had noted that Corey\u00a0reported\u00a0in 1963\/65 the total synthesis of\u00a0the sesquiterpene dihydrocostunolide. Compound 16, known as\u00a0Eudesma-1,3-dien-6,13-olide was represented as shown below in black; the hydrogen shown in red was implicit in Corey's representation, as was its stereochemistry. As of this instant, this compound is just one of 64,688,893 molecules\u2026","rel":"","context":"In &quot;Chemical IT&quot;","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2011\/12\/p34a1.svg","width":350,"height":200},"classes":[]},{"id":363,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=363","url_meta":{"origin":4525,"position":1},"title":"The chirality of  M\u00f6bius annulenes","author":"Henry Rzepa","date":"April 22, 2009","format":false,"excerpt":"Much like climbing Mt. Everest because its there, \u00a0some hypothetical molecules are just too tantalizing for chemists to resist attempting a synthesis. Thus in 1964, Edgar Heilbronner \u00a0speculated on whether a conjugated annulene ring might be twistable into a \u00a0M\u00f6bius strip. It was essentially a fun thing to try to\u2026","rel":"","context":"In &quot;Interesting chemistry&quot;","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"The 16-annulene synthesized by Herges and his team.","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/herges.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":20120,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=20120","url_meta":{"origin":4525,"position":2},"title":"Organocatalytic cyclopropanation of an enal: (computational)  assignment of absolute configurations.","author":"Henry Rzepa","date":"September 1, 2018","format":false,"excerpt":"I am exploring the fascinating diverse facets of a recently published laboratory experiment for undergraduate students. Previously I looked at a possible mechanistic route for the reaction between an enal (a conjugated aldehyde-alkene) and benzyl chloride catalysed by base and a chiral amine, followed by the use of NMR coupling\u2026","rel":"","context":"In &quot;Interesting chemistry&quot;","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":6455,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=6455","url_meta":{"origin":4525,"position":3},"title":"A golden age for (computational) spectroscopy.","author":"Henry Rzepa","date":"April 2, 2012","format":false,"excerpt":"I mentioned in my last post an unjustly neglected paper from that golden age of 1951-1953 by Kirkwood and co. They had shown that Fischer's famous guess for the absolute configurations of organic chiral molecules was correct. The two molecules used to infer this are shown below. Using the theory\u2026","rel":"","context":"In &quot;Chiroptics&quot;","block_context":{"text":"Chiroptics","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2644"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":221,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=221","url_meta":{"origin":4525,"position":4},"title":"How do molecules interact with each other?","author":"Henry Rzepa","date":"April 12, 2009","format":false,"excerpt":"Understanding how molecules interact (bind) with each other when in close proximity is essential in all areas of chemistry. One specific example of this need is for the molecule shown below. This is the so-called Pirkle Reagent and is much used to help resolve the two enantiomers of a racemic\u2026","rel":"","context":"In &quot;Interesting chemistry&quot;","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"The Pirkle reagent","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/pirkle.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":8337,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8337","url_meta":{"origin":4525,"position":5},"title":"A chiral molecular wire.","author":"Henry Rzepa","date":"November 20, 2012","format":false,"excerpt":"More than 60 million molecules are known, and many are fascinating. But beauty is in the eye of the beholder. Thus it was that I came across the attached molecule. It struck me immediately as, well, beautiful! This is one that comes to life in 3D and I strongly urge\u2026","rel":"","context":"In &quot;Interesting chemistry&quot;","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.imperial.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2012\/11\/GOCTOH.jpg?resize=350%2C200","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\/4525","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=4525"}],"version-history":[{"count":0,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/4525\/revisions"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=4525"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=4525"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=4525"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=4525"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}