In the Laboratory
W
Catalytic Asymmetric Epoxidation Using a Fructose-Derived Catalyst Andy Burke, Patrick Dillon, Kyle Martin, and T. W. Hanks* Department of Chemistry, Furman University, 3300 Poinsett Highway, Greenville, SC 29613-0420; *
[email protected] Modern epoxidation methods are able to convert achiral alkenes into products containing two adjacent stereocenters with very high enantioselectivities. Opening of the epoxides with nucleophiles permits rapid entry into complex organic systems, making this methodology one of the essential reactions of organic synthesis. Yet until very recently, epoxidation had received virtually no attention from the chemical education community. One report examining the kinetics of a catalytic epoxidation appeared in the mid-1980s (1), while another report featuring an epoxidation–rearrangement sequence appeared in 1996 (2). More recently, a very nice treatment of the Sharpless reaction explored both the regioselectivity and enantioselectivity of the epoxidation of geraniol (3). Unfortunately, while this procedure clearly demonstrates that asymmetric induction can be achieved, the mechanism of the reaction is not discussed. Indeed, the description of intermediates in titanium-catalyzed reactions is challenging at the undergraduate level (4 ). Another very versatile method for generating epoxides from alkenes is through the use of dioxiranes (5). Typically, the dioxirane is generated in situ from a ketone and an oxidizing agent (eq 1). The dioxirane then transfers an oxygen to the alkene. If the ketone is chiral, enantiomerically enriched products can result. This approach has proven to be exceptionally effective with trans or trisubstituted alkenes, even when they are nonallylic. O HSO5–
O
C R2
R1
R4
R3
1
HSO4–
O O C R1 R2 2
R4
(1)
R3
Recent work by Yian Shi and coworkers at Colorado State University has introduced a ketone catalyst derived from fructose (1) (6 ). In the winter of 1998, we introduced an experiment based upon Shi’s report into our Techniques in Chemistry laboratory course for sophomore and junior chemistry majors.1 The multistep experiment described here is highly modular and may be effectively used at a variety of levels. The complete experiment, as described here, is designed for more advanced students with significant synthetic experience. The synthesis of the ketone catalyst, 1, can be
completed in two lab periods (eq 2). O
OH OH
O
OH
HO
HClO4 OH D-fructose
(2) O
O O OH
O O
3
O
PCC
O O
O
O O
1
CAUTION: Instructors should be aware that this synthesis makes use of potentially hazardous reagents (perchloric acid and pyridinium chlorochromate).
The catalytic epoxidation can be completed in a single period and would be appropriate for more junior students. Instructors contemplating this approach would want to prepare ketone 1 beforehand in sufficient quantities. The analysis portion of the experiment can be made as elaborate as desired. The full procedure, including modeling, would take at least three additional lab periods. Optical rotation can be used in place of the NMR shift experiment for determination of enantiomeric excess. Several analytical methods are appropriately applied to the analysis of the reaction products. Some of these are detailed in the supplemental materials, including an NMR shift experiment.W We are strong advocates of the use of molecular modeling in the undergraduate curriculum (7), and there are a number of modeling studies that can be used to explain the observed enantiomeric enrichment. Some of these are presented in the supplemental materials.W The first step in the preparation of catalyst 1 is a regiospecific ketalization that protects four of the five fructose hydroxyl groups and provides the steric interactions required for the enantioselectivity in the catalytic cycle. The reaction should be run under nitrogen, but simply stirring in a roundbottom flask capped by a rubber septum and under a N2
JChemEd.chem.wisc.edu • Vol. 77 No. 2 February 2000 • Journal of Chemical Education
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In the Laboratory
balloon is sufficient. The ketal, 3, is recrystallized to give pure white needles in a typical (student) yield of 33%. The second step is an oxidation of the remaining hydroxyl group to a carbonyl with pyridinium chlorochromate (PCC).2 Again, the reaction should be performed under a N2 balloon. Filtration through Celite, purification on silica gel, and recrystallization gives the highly crystalline product 1 in 89% yield. Complete spectroscopic data for the products of each step can be found in the supplemental material.W In the epoxidation reaction, the fructose derivative, 1, is converted in situ to a dioxirane (2) by potassium peroxomonosulfate (Oxone, DuPont). It is this dioxirane that performs the oxidation. Yields and enantiomeric excesses (ee’s) vary with the alkene, but are generally very good. Student results varied greatly, but with care were often within 10% of literature values. The reaction is particularly effective with trisubstituted olefins, even when large substituents are present. The epoxides can be easily isolated by flash chromatography and analyzed by a variety of methods, including NMR, IR and GC–MS. The protons on the epoxide ring make especially good NMR handles for chemical shift experiments to determine ee’s. Alternatively, polarimetry is useful if the optical rotations of the pure enantiomers are known. Molecular modeling easily shows why only bis-ketal 3 is formed in the first step. Geometry minimization of 1 and 2 reveals the asymmetry of the catalytic system, while docking of 2 and an alkene introduces some very interesting questions concerning the nature of the epoxidation transition state, though analysis of transition states is only appropriate for advanced students. We have used simple semiempirical methods coupled with a reading of ab initio and solvation studies (8) to help students gain insight not only into a subtle reaction pathway, but also into the tools used to investigate such questions. This experiment was first performed during our winter 1998 term as the culmination of our “research prep” major’s course. Students were encouraged to research and read background papers on the reaction. They then were able to prepare 1, react it with a model alkene, trans-β-methylstyrene, and compare their results with the literature. In addition, student teams wrote miniproposals designed to explore a particular aspect of the experiment. These ranged from designing new catalysts based on other sugars or ketals to alternative reaction conditions to improve yields or ee’s or to minimize reaction times. Each group was then able to attempt to carry out their proposed modifications and to report their results. While each step of this experiment can be used independently, we recommend a complete sequence involving (i) reading background literature, (ii) synthesizing the catalyst, (iii) performing the epoxidation, (iv) analyzing the products, (v) investigating the mechanism, and (vi) proposing and conducting a revised experiment. This admittedly involved process is a powerful way to move students from learning about chemistry to learning to do chemistry.
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Special Reagents and Equipment Dimethoxymethane Dimethoxypropane Ethylenediaminetetraacetic acid, disodium salt D-Fructose trans-β-Methylstyrene Molecular sieves, 3A, powdered Oxone Perchloric acid (70%) Pyridinium chlorochromate Tetrabutylammonium hydrogen sulfate Triethylamine W
Supplemental Material
Supplemental material for this article is available in this issue of JCE Online. Notes 1. This is a unique, all-laboratory course that runs during Furman’s two month winter term. Students work in the lab 5–6 hours a day, 5 days a week. A description of the course and the role it plays in our degree programs will be presented elsewhere. 2. It is likely that a Swern oxidation could be used for this step, avoiding the use of the chromium reagent. Instructors adopting this experiment for less experienced students are encouraged to explore this option. However, one of our purposes in designing this experiment was to have students reproduce a preparation directly from a current literature source. With proper supervision and training, students can use PCC safely.
Literature Cited 1. Hairfield, E. M.; Moonmaw, E. W.; Tamburri, R. A.; Vigil, R. A. J. Chem. Educ. 1985, 62, 175–177. 2. Garin, D. L.; Gamber, M.; Rowe, B. J. J. Chem. Educ. 1996, 73, 555. 3. Bradley, L. M.; Springer, J. W.; Delate, G. M.; Goodman, A. J. Chem. Educ. 1997, 74, 1336–1338. 4. Steadman, B.; Lee, M.; Hanks, T. W. Chem. Educator 1996, 5. See also http://journals.springer-ny.com/chedr (accessed Dec 1999). 5. For reviews, see: Murray, R. W. Chem. Rev. 1989, 89, 1187– 1201. Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989, 22, 205–211. 6. Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224–11235. Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806–9807. Wang, Z.X.; Tu, Y.; Frohn, M.; Shi, Y. J. Org. Chem. 1997, 62, 2328– 2329. 7. Hallford, R.; Wright, G.; Hanks, T. W. J. Chem. Educ. 1995, 72, 329–332. Hanks, T. W. J. Chem. Educ. 1994, 71, 62–66. Hanks, T. W. Syllabus 1993, 27, 14–16. 8. Jenson, C.; Liu, J.; Houk, K. N.; Jorgensen, W. L. J. Am. Chem. Soc. 1997, 119, 12982–12983 and references therein.
Journal of Chemical Education • Vol. 77 No. 2 February 2000 • JChemEd.chem.wisc.edu
