Organic Synthesis: Synthetic Methods Development, Natural Product and Fluorinated Liquid Crystal Synthesis

Research in the Sampson group is focused in the field of organic synthesis, with an emphasis on the development of new synthetic methods and their subsequent application in the synthesis of targets (including natural product analogs) which might either possess interesting biological activities or exhibit liquid crystalline properties. Several projects involve work in the field of organofluorine chemistry. Examples of ongoing research programs are outlined below.

Stereoselective synthesis of chiral fluorinated liquid crystals (mesogens) and fluorinated bioactive molecules: Fluorine has a number of unique properties (e.g., small size, high electronegativity, strong C-F bond) that make it an attractive substituent for the manipulation of the electronic environment within a molecule, without unduly altering the steric requirements of the compound. We are interested in exploiting these effects in two major areas:

• Its small size and high C-F bond dipole make the incorporation of fluorine into liquid crystalline (mesogenic) compounds very appealing. For example, the presence of fluorine at a stereogenic center in a chiral mesogenic compound can confer useful ferroelectric properties. We are interested in developing chemistry suitable for the enantioselective synthesis of various chiral liquid crystalline compounds that contain fluorine at a stereogenic center. We are also engaged in the synthesis of other novel liquid crystalline targets bearing fluorine within the achiral mesogenic core. For example, we are currently exploring the development of some of the first synthetic approaches to ring fluorinated thiophenes, and are applying this chemistry in the synthesis of novel fluorothiophene-containing liquid crystalline materials. (These studies are being pursued in collaboration with Dr. Alex Seed’s group.)
• The incorporation of fluorine substituents into various classes of biologically important compounds is an established approach for manipulating the activity and/or metabolic stability of these compounds. We have interests in selectively incorporating fluorine substituents into various classes of biologically important compounds (e.g., carbohydrates, nucleosides) with a view to affording analogs which might possess useful medicinal properties. Much of our chemistry in these areas requires the stereoselective synthesis of electron-deficient fluorinated alkenes followed by a detailed exploration of their chemistry.

Development of macrocyclization/transannular ring closure reactions; applications to the synthesis of analogs of the potent anticancer natural product paclitaxel (taxol): A major area of current research involves the development of macrocyclization/transannular (“across-the-ring”) ring closure approaches for the synthesis of medium-sized (i.e., 8-, 9- and 10-membered) carbocyclic ring systems. Such rings are found in many important natural products (e.g., the potent anticancer natural product paclitaxel (taxol)) and they are often among the most synthetically challenging structural features in such compounds. The restricted conformational flexibility associated with an initially formed macrocyclic ring in our systems is exploited to minimize the entropic barrier to transannular ring closure by holding the reactive sites in close proximity, thus facilitating closure of the medium-sized ring. We are currently applying this chemistry in the synthesis of structurally simplified analogs of the potent anticancer natural product paclitaxel (taxol) that may retain the potent antitumor activity of the parent compound.

Selected Publications:

1. Sybo, B., Bradley, P., Grubb, A., Miller, S., Proctor, K. J. W., Clowes, L., Lawrie, M. R., Sampson, P. & Seed, A. J. 1,3,4-Thiadiazole-2-carboxylate esters: New synthetic methodology for the preparation of an elusive family of self-organizing materials. Journal of Materials Chemistry 17, 3406-3411 (2007).

2. Chumachenko, N. & Sampson, P. Synthesis of beta-hydroxy sulfones via opening of hydrophilic epoxides with zinc sulfinates in aqueous media. Tetrahedron 62, 4540-4548 (2006).

3. Novikov, Y. Y. & Sampson, P. 1-bromo-1-lithioethene: A practical reagent in organic synthesis. Journal of Organic Chemistry 70, 10247-10259 (2005).

4. Chumachenko, N., Sampson, P., Hunter, A. D. & Zeller, M. beta-acyloxysulfonyl tethers for intramolecular Diels-Alder cycloaddition reactions. Organic Letters 7, 3203-3206 (2005).

5. Novikov, Y. Y. & Sampson, P. 1-bromo-1-lithioethene: A practical reagent for the efficient preparation of 2-bromo-1-alken-3-ols. Organic Letters 5, 2263-2266 (2003).

Last Updated: 15 August 2008