On the Web edited by
William F. Coleman Wellesley College Wellesley, MA 02481
Molecular Models of Warfarin and Related Compounds William F. Coleman Department of Chemistry, Wellesley College, Wellesley, Massachusetts 02481
[email protected] Our featured molecules this month (1) come from the paper by Terence C. Wong, Camille M. Sultana, and David A. Vosburg (2) in which the authors describe a one-step, enantiomerically selective synthesis of warfarin, a widely used anticoagulant marketed under several brand names. The synthesis is interesting in itself, from the point of view of sustainable chemistry and mechanistically; furthermore, warfarin lends itself nicely to casestudy in courses at all levels of the curriculum. In addition to the components of the warfarin synthesis, we also include in the molecule collection several substances that have been proposed as alternatives to warfarin, because warfarin has a number of potential side-effects and taking this drug requires frequent monitoring of blood chemistry to ensure the safest possible usage for a given individual (3). At the introductory level of chemistry, in either high school or college, it is important for students to begin to make the connection between the simple structural elements they are exposed to (e.g., small molecules discussed in terms of VSEPR), and the structures of larger molecules. Using the interactive structures of warfarin and the proposed alternatives, students could measure bond lengths and angles, and begin to understand that the complex, three-dimensional structures are composed of fragments that they recognize. Students at all levels are intrigued by substances that have, or might have, a direct effect of their lives. These featured molecule pharmaceuticals are such species (Figure 1 shows a selection); warfarin and the search for alternative anticoagulants provide an interesting story for students to pursue. Warfarin itself could easily serve as a vehicle to introduce risk-benefit analysis, something that everyone should understand. The complex world of drug approval, in the United States and around the world, could be approached by examining the approval history of warfarin and the various alternatives. One of the featured molecules, ximelagatran, was withdrawn by its manufacturer as it caused unacceptable levels of liver damage. Warfarin is a sufficiently small molecule that computations at Hartree-Fock and DFT levels are possible in a lab period, perhaps while other work is being performed. Students could compute the expected ratio of the keto and ketal forms of warfarin and compare the results to those from the NMR spectra they obtain. A more time-consuming calculation would be to determine the energy barrier to keto-ketal isomerization. Two structures of substituted warfarin species are included in the collection as A and B. Are those structures enantiomers? If so, do they represent the optimized structures at a given level of theory? What criteria does one need to apply to claim that the structures are optimized? In what ways does the structure for rivaroxaban in water differ from that in the gas phase?
_
Figure 1. Some of the anticoagulant compounds added to the JCE Featured Molecules collection. Ball-and-stick models of (top) the keto and ketal form of warfarin; and (bottom) the gas phase of an alternative drug, rivaroxaban, which changes geometry in aqueous solution.
Warfarin might well serve as a model of using a particular molecule to introduce a variety of chemical principles, but it is certainly not the only substance that can be used this way. The added advantage of the societal importance of warfarin, the ease of using it as an introduction to important aspects of public health, and to the business of chemistry, increase its attraction as a pedagogical example (4). Literature Cited 1. Molecular Models of Warfarin and Related Compounds; available at the JCE Digital Library: http://www.jce.divched.org/JCEDLib/Molecules/2010/Feb. 2. Wong, T. C.; Sultana, C. M.; Vosburg, D. A. A Green, Enantioselective Synthesis of Warfarin for the Undergraduate Organic Laboratory. J. Chem. Educ. 2010, 87, DOI: 10.1021/ed800040m. 3. The Thrombophilia Awareness Project at the University of North Carolina-Chapel Hill offers a partial list of potential alternatives to warfarin: http://www.fvleiden.org/ask/02.html (accessed Dec 2009). 4. As an example of the timeliness of the question of warfarin alternatives, an article appeared in the December 10, 2009 issue of The New England Journal of Medicine entitled Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism . New Engl. J. Med. 2009, 361 (24) 2342-2352; http://content.nejm.org/ cgi/content/short/361/24/2342 (accessed Dec 2009).
_
r 2010 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 87 No. 2 February 2010 10.1021/ed8000733 Published on Web 01/12/2010
_
Journal of Chemical Education
229
