1 Experiment 8 Terpenoids: Investigations in Santonin Chemistry Santonin, (I) is a well-known sesquiterpenoid that has received much study in the past. Because it is a highly functionalized compound, and readily available, it has often been used as the starting material for the synthesis of more complex compounds. This experiment will study some of the methods of manipulating the structure of santonin. To complete the basic experiment, the focus will be on the stereochemistry of the A ring. Both double bonds will be reduced by hydrogenation. The reaction of an organic compound with hydrogen in the presence of a catalyst catalytic hydrogenation cannot be topped for its ability to achieve controlled transformations. The reaction is done in our laboratory by stirring or shaking a solution of the compound to be reduced with a heterogeneous (or homogeneous) catalyst under an atmosphere of hydrogen. The progress of the reaction could easily be followed by measuring the uptake of the hydrogen gas. Here, reaction of a methanolic solution of 1 with hydrogen in the presence of 2% palladium on strontium (or calcium) carbonate provides the fully saturated 4 H,6 -hydroxy-3-oxoeudesman- 12-oic acid, -lactone (2), also called tetrahydrosantonin. 1 The reaction product is isolated by simple filtration of the reaction mixture, and concentration of the filtrate. This experiment will continue by looking at the stereochemistry of bromination of the tetrahydrosantonin. This is shown as the conversion of 2 to 4 in the equation on the following page. The full experiment will demonstrate some of the differences between heterogeneous and homogeneous catalysis. Reaction of a toluene solution of 1 with hydrogen in the presence of the homogeneous catalyst tris(triphenylphosphine)rhodium bromide ((Ph 3 RhBr, also known as Wilkinson s catalyst) 2 selectively reduces the disubstituted double bond to provide the dihydrosantonin derivative 3.
2 Chem 463 Organic To complete the full experiment, one further transformation of the santonin molecule will be studied. The bromotetrahydrosantonin prepared above will be used as the starting material to synthesize the other dihydrosantonin derivative 4. Introduction of the double bond via removal of HBr is accomplished by refluxing 4 in collidine (an amine) for two days. This eliminates HBr (not an easy process in this system!) and provides the dihydrosantonin derivative 5. Notice that the complete stereochemistry is not described for structures 2, 4 and 5. One of the goals for this experiment is to deduce the stereochemistry of structures 2, 4 and 5 based on spectroscopic analysis. There will be a group discussion on the stereochemistry of santonin and its derivatives.
3 What to Do? Experimental The basic requirement is the completion of the synthesis of tetrahydrosantonin, and its conversion to 2-bromotetrahydrosantonin. To complete the full experiment, all reactions are done. A package of spectra (ir, NMR & uv of santonin) is available to those students. The hydrogenation procedures are started at the beginning of the lab period to allow for monitoring of the hydrogen uptake. 1. Tetrahydrosantonin (2) If this experiment is done as a full experiment, run this hydrogenation starting with 2 g of santonin. Charge a 125 ml Erlenmeyer flask with -santonin (1.0 g), methanol (25 ml), and the catalyst (100 mg, there may be more than one available check the bottle) and a magnetic stirring bar. Fit the flask with a rubber septum, and clamp the flask to the clamping frame. Fill a balloon with hydrogen gas, and fit the balloon to a syringe equipped with a 15 cm needle. Pinch the neck of the balloon to keep in the hydrogen. Place the needle through the septum, and below the surface of the solvent. Insert a second needle through the septum, and allow some (not all) of the hydrogen to flush the reaction flask. Remove the second needle when the flushing is finished. The reaction requires a minimum of 2.5 hours. Remove the catalyst by filtration through a celite sandwich 3. Keep the catalyst moist, and in the fume hood it may be pyrophoric. Evaporate the solvent under reduced pressure. Save the spent catalyst for recycling of the palladium. Crystallization of the residue from aqueous ethanol provides 2, mp 145.5-147 o C. Consult the appendix on recrystallization for help if necessary. 2. 2-Bromotetrahydrosantonin (4) Before beginning this procedure, have available a solution of sodium bisulfite (10% in water) to neutralize any bromine spills. Prepare solutions of tetrahydrosantonin (II) in chloroform (2 ml per mmole of II), and of bromine (1.0 eq) in chloroform (1.2 ml per mmole of II). Stir the solution of II, and add the bromine solution dropwise over a 5-8 minute period. Stir the reaction mixture for an additional 15 minutes after the addition is finished. Wash the reaction mixture with 10% aqueous sodium bisulfite solution (3 x 20 ml). Add more chloroform if necessary to make the extraction easier. Dry the organic solution with magnesium sulfate, and remove the drying agent by filtration. Add ethanol (15 ml) to the organic solution and concentrate on the rotary evaporator until crystal formation begins. Remove the flask from the rotary evaporator, and cool the flask in an ice bath. Overnight refrigeration may be required to complete the formation of the crystals. Isolate the 2-bromotetrahydrosantonin by filtration onto a sintered glass funnel, and wash with 2-3 ml of cold ethanol. Dry the crystals on the vacuum pump. Attempt to isolate a second crop of crystals if the yield is low. Provide a sample for NMR analysis (CDCl 3 ). Determine the stereochemistry of the product from the NMR analysis.
4 Chem 463 Organic 3. Dihydrosantonin A (3) In a 250 ml three-necked round bottom flask, prepare a solution of -santonin (500 mg) in toluene (20 ml). Place a quantity of catalyst (either (Ph 3 RhCl or (Ph 3 RhBr, 60 mg) in the solid addition tube. The catalyst should be freshly prepared within the last 2 3 weeks. Connect the centre neck of the flask to the vacuum line, and fit a rubber septum into the remaining neck. Prepare a balloon full of hydrogen (as above), and insert the needle through the rubber septum. With the assistance of the instructor, evacuate the air from the flask and refill with hydrogen gas. Repeat this purge two or three more times. Add the catalyst to the flask by rotating the solid addition tube to the vertical position. Allow the mixture to stir overnight. Before working up the reaction mixture, remove about 0.5 ml of the solution, concentrate this sample and obtain a 1 H NMR spectrum of the residue. Discuss this spectrum with the instructor before proceeding. Upon completion of the reaction, remove the solvent on the rotary evaporator and dissolve the residue in ether (30 ml). Filter the etherial solution through a column of basic alumina (10 cm), using ether as the eluent. Remove the ether and recrystallize the residue from heptane/ethyl acetate to provide 3. 4. Dihydrosantonin B (5) Mix 2-bromotetrahydrosantonin and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 1.25 equivalents) in xylene (4 ml per mmole of 4). Reflux the reaction mixture overnight. Cool the reaction mixture, and dilute with ether (50 ml). Wash the ether solution with 2 M hydrochloric acid (6 x 30 ml) and once with brine (30 ml). Dry the organic layer with magnesium sulfate, filter to remove the drying agent, and concentrate the solution on the rotary evaporator. Obtain an NMR spectrum of the crude material. An alternative procedure mix 2-bromotetrahydrosantonin and collidine (4 ml per mmole 4). Heat the mixture at reflux for at least 40 h (over the weekend if possible). Workup the reaction as above. Recrystallize the residue from a mixture of hexane and benzene (6:1 ratio, 12 ml per mmole of IV). An oil will probably form which will not dissolve. Decant the hot solution from the oil, and cool in an ice bath. Scratch the side of the flask with a spatula to induce crystal formation. Isolate the dihydrosantonin B by filtration onto a sintered glass funnel, and wash the crystals with a small amount of cold hexane. Dry the crystals on the vacuum pump. Spectra Record the IR (thin solid film or KBr) and NMR ( 1 H and 13 C, CDCl 3 ) spectra of the products and compare them with the spectra provided of santonin. Provide a rationale for the differences. Interpret the 13 C NMR spectra of the compounds for all peaks to a lower field of 70 ppm, rather than attempt to assign every peak. Consider how the changes in the compound s structure can be seen in the various spectra. For the full experiment, you must also include the uv spectra of the compounds prepared (except the bromide). Calculate the uv absorption maximum for santonin and the dihydrosantonins using Woodward s rules for enones 4 and compare with the observed values.
5 References 1. Yanagita, M.; Tahara, A. J. Org. Chem. 1955, 20, 959 970. Also, Cocker, W.; McMurray, T.B.H. J. Chem. Soc. 1956, 4549 4557 and Hendrickson, J.B.; Bogard, T.L. ibid. 1962, 1678 1689. Note the numbering of the compound here (hint!). 2. Osborne, J.A.; Wilkinson, G. Inorganic Synthesis 1967, 10, 67 71. Osborne, J.A.; Jardine, F.H.; Young, F.H.; Wilkinson, G. J. Chem. Soc. A 1966, 1711 1732 (for inorganic chemists only!). 3. A celite sandwich is prepared by pouring a slurry of celite (7 8 g in methanol) onto a piece of filter paper in a Buchner funnel and drawing the solvent through to the top of the celite pad. The sandwich is completed by topping with another piece of filter paper. 4. Woodward, R.B. J. Am. Chem. Soc. 1941, 63, 1123 1126. idem., ibid. 1942, 64, 76 77. These are the original papers. For a slightly easier description of the use of Woodward s rules, see Pavia, D.L.; Lampman, G.M.; Kriz, G.S. Introduction to Spectroscopy Saunders College Publishing, 1979, pp 203 ff, or any introductory spectroscopy text. 5. Further reading: Rylander, P.N. Catalytic Hydrogenation in Organic Synthesis Academic Press, 1979. James, B.R. Homogeneous Hydrogenation J. Wiley and Sons, New York, 1973.