the microscale laboratoru Microscale Synthesis of the Natural Products Carpanone and Piperine Joseph C. Sloop United States Military Academy West Point, NY 10996
edited by ARDENP. ZIPP SUNY-Cortland
However, reasonable attention to detail in each of the synthetic seauence steps will indeed provide the ~roduct.&e an invaluilbie intnduction into the ~ ~ c a ~ e s o f n a t u r a l ' & d u c t synthesis, and solidify the students'micmscale techmques. Sesamol Allyl Ether (lb)
Experimental Procedure. To 2.50 mL anhydrous ethanol add 250 mg (36 mmol) sodium ethoxide in a 10-mL round-bottomed flask equipped with a water-jacketed reflux condenser, stir bar and calcium chloride drying tube. Add sesamol, (la), 500 mg (36 mmol) dissolved in 0.60 mL anhydrous ethanol, dropwise slowly to this solution and stir at room temperature for 10 min. Then, add 340 mg (36 mmol) of allyl chloride slowly with continued stirring. Reflux the reaction mixture for 45-60 miu and allow the reaction to cool to room temperature. The Synthesis of carpanone3 Product IsolationlPurification. After cooling, add 5.0 mL water to the reaction mixture. Extract the resulting Carpanone (le),a natural product known as a lignan, is aqueous solution with three 1.5-mL portions of diethyl found in trees from the island of Bou~anvillein the Pacific ether. Wash the ether extracts with 1.0 mL each of 5% Ocean. At first, the synthesis may seem formidable, especiallv when one considers the presence of five s t e r e o ~ e ~ c NaOH, 5% HzS04,water, and finally a saturated NaCl solution. After theae washings, remove the aqueous layer, cent& in the molecule. and dry the organic layer hy passing it through a Pasteur filter pipet filled with 500 mg MgSOa and 500 mg silica gel. Evaporate the ether in the hood with gentle heating in a sand bath with a slow stream of nitrogen. The intermedilb ate product, sesamol allyl ether, is a Seam01 Allyl Ether brownish liquid, which is used without further purification. If in doubt, the purity may be checked by TLC (1:l v:v ethyl acetate: hexane).
In recent years, microscale laboratory techniques have found a very popular niche i n undergraduate organic chemistry courses throughout the nation. While many organic laboratory texts now incorporate such techniques1, relatively few natural product syntheses are available. We report two complete natural product preparations successfully scaled down to the microscale level: the syntheses of carpanone and p i ~ e r i n e . ~
This preparation provides students with a firsthand look at how reactions that are studied in a typical two-semester organic chemistry course can be coupled to produce a wmplex molecule. Sesamol ally1 ether ( l b ) is obtained via a Williamson ether synthesis. This ether, when heated, undergoes a Claisen rearrangement, producing 2-allylsesamol (lc).Base isomerization yields a conjugated alkene, 2-pmpenylsesamol (Id) which is subsequently dimerized and cyclized via a 4 + 2 cycloaddition, producing carpanone. 'See for instance. Mayo, Pike, and Butcher (1). 'The microscale experiments may be performed using the standard microscale kits available from Cornina. 3Tn~spreparat on was aoapted from ~ieserand Will amson (2). 4Tne laboratory techn clan sno~ldprepare this as a stock SolLtlon oaily. because rkntox de ana DMSO are very hygroscopic.
2-Ala,lvsesamol (lc) Experimental Procedure. Place t h e crude allyl ether in a 3-mL conical vial equipped with a water-jacketed reflux condenser. Heat the allyl ether a t 170°C for 1 h in a sand bath equipped with a thermometer. The product, 2-allylsesamol, will form as a dark solid material upon cooling to room temperature. Product IsolationlPurification . Upon woling, it is satisfactory to use the crude 2-allylsesamol in the next step of the synthesis without further purification. If desired, however, sublimation will effect purification. 2-Propenylsesamol (Id) Experimental Procedure. To a 10-mL round-bottomed flask equipped with a water-jacketed reflux wndenser, stir bar and septum, add 300 mg 2-allylsesamol, followed by 500 mg t-butoxide dissolved in 5.0 rnL dried DMS0.4Introduce a slow stream of nitrogen to this reaction svstem for 5 min. Reduce the pressure to'khereonly a small o;erpressure is maintained. B e ~ stirring n and heat in a water bath eauipwd with a thermometer at 80% for 30 min. Cool the reactio~mixture to room temperature. Volume 72 Number 2 February 1995
A25
the microscale laboratory Product Isolation /Purification After cooling, pour the solution into a 10-mL beaker containing a n ice chip. Stir the solution and make it acidic by adding HCl (about 1mL). Extract the resulting solution with three 1.5-mL portions of diethyl ether. Wash the ether extracts with 10 mL of water and a 10-mL saturated NaCl solution. After these washings, remove the aqueous layer, and dry the organic layer by passing it through a Pasteur filter pipet filled with 0.5 g MgS04. Evaporate the ether in the hood with gentle heating in a sand bath with a slow stream of nitrogen. The intermediate product, 2-propenylsesamol, will form as a brownish solid, which may be used without further purification.
28
methyl 2buienoate
2b
methyl Cbromo2-buienoaie
Carpanone (le)
Experimental Procedure To a 5.0-mL conical vial equipped with a stir vane, add 100 m a 2 - ~ r o ~ e "n v l s e s a m odisl. solved in 506 m i methanol and 1.0 mL water. While stirring, add 300 mg sodium acetate, followed by 100 mg copper(I1) acetate dissolved in 500 mL water dropwise. Stir the reaction mixture a t room temperature for a n additional 5 min. Product IsolationlPurification . Filter the cloudy suspension. After woling, pour the solution into a 10-mLbeaker wntaining an ice chip. Stir the solution and make it acidic by adding HCl (about 1mL). Extract the resulting solution with three 2-mL portions of diethyl ether. Wash the ether extracts with 10 mL of water and a 10-mL saturated NaCl solution. &r these washmgs, remove the aqueous layer, and dry the orpanic laver bv as sine it throueh aPasteur filter oioet filled wsh 0.5 g ~ g % , . ~ v a i o r a t et h i ether in the hood skth e n tle heatine in asand bath with a slow stream ofnitmrren.'lhe product, &anone (le), will form as a brownish rezdue. To purify, dissolve the crude product in wann CC14.S Upon cooling, the recrystallized carpanone has a melting point of 185°C.
Piperine mp 126-8%
A
acid chloride and finally undergoes aminolysis to produce piperine (compound 2e). Methyl 4-Bromo-2-Butenoate (2b)
Ex erimental ~roceduke. To 5.0 mL carbon tetrachloridePadd 3.0 g (14 mmol) N -bromosuccinimide, 1.5 mL (14 mmol) methyl 2-butenoate (2a) and 100 mg (4 mmol) benzoyl peroxides in a 10-mL round-bottomed flask equipped with a water-jacketed reflux condenser, stir bar, and calcium chloride drying tube. Reflux the reaction mixture while under a sunlamp for 45-60 min. Product IsolationlPurification . When the reaction is complete, remove the reaction flask and distill off-4 mL of the CC4. Using a vacuum pump, distill the residue, which is methyl 4-bromo-2-buteuoate (93-102T @ 15 mmHg)? Yields average around 50%. Caution: The product is a tearing agent. Perform all distillation and isolation in a hood.
The Synthesis of Piperine
(E,E)-Meth 1 [3 4 (Methylenedioxy) Phenyl] -2,4-pentadi ' enoate (2~1-
Piperine is a natural product and component of black pepper which causes sneezing. Its presence in pepper was discovered many years ago, and its structure was elucidated near the besinning of this century. The preparation of piperine utilizes many familiar reactions. Allylic brominatiou transforms methyl 2-butenoate to a n intermediate product which then undergoes a baseinduced aldol-like condensation. The resulting unsaturated ester is saponified subsequently, transformed to a n
Experiment a1 P rocedure. To 500 mg (2.7 mmol) 2b, add 450 mg (2.7 mmol) triethyl phosphite in a 3-mL conical vial equipped with a hot water-jacketed reflux condenser and stir bar in a hood. Reflux the reaction mixture gently for 30 min. You may observe the production of a pale yellowish gas, ethyl bromide, during the reflux." lkansfer the reaction mixture via syringe to a two-necked round-bottomed flask equipped with a dry nitrogen line, stir bar, and thermometer containing 400 mg (2.7 mmol) piperonal and 10 mL dry dimethoxyethane. Using a second syringe, add dropwise 2.0 mL methoxide/methanol solution" while stirring so that the reaction temperature does not exceed room temperature. Stir for 15 miu. The crude product solution is dark in color. Product Isolation /Purification . Add the reaction mixture to 40 mL ice cold water in a 100-mL Erleumever flask and srir for an additional 15 min. Using vacuum filtration, collect the . ~ r e c.i ~ i t aand w air d w overnight. lJse the crude methyl piperate in the next step of the synthesis or recrys-
5CCl,vapors are hazardous. Do not breathe under vapors any circumstances! 6Thispreparation was adapted from Mohrig and Neckers (3), 'Methylene chloride is an alternative solvent. s~ransferthe benzoyl peroxide with a plastic spatula. 'Conduct the distillation rapidly or the product will decompose. 'It is critical to use a hot water condenser when removing the ethyl bromide. "Prepare a stock methoxide solution daily using 1.0 g (43 mmol) sodium to 25 mL dry methanol. A26
Journal of Chemical Education
-
tallize, if desired, from methanol [m.p. 145-1479C1. Purified yields average around 40%. Piperic Acid (2d)
Experimental Procedure. To 500 mg (2.2 mmol) 2c, a d d 250 mg (6 mmol) NaOH, and 6.0 mL methanol i n a 10-mL round-bottomed flask equipped with a water-jacketed reflux condenser and stir bar. Reflux the reaction mixture for 90 min. Product Isolation/Purification. Upon r o t a r y evaporation of t h e methanol, a pale yellow residue remains. Dissolve this solid in 20 mL water. Extract with two to three 5.0mL portions of diethyl ether. Add concentrated HC1 to the aqueous solution until a pH=l is reached. Using vacuum filtration, collect the precipitate and air dry 24 h. Recrystallize the crude acid from methanol [m.p. 145147"CI . Purified yields average 60%. Piperine (2e)
Experimental Procedure. To 250 mg (1.1mmol) piperic acid (2d), add 5.0 mL dry benzene in a 10-mL roundbottomed flask equipped with a stir bar and calcium chloride drying tube. Via syringe, add 2.0 mL (23 mmol) oxalyl chloride and reattach the drying tube. Stir for 45 min a t room temperature. Evaporation of the benzene and excess oxalyl chloride (using a rotary evaporator in a hood) leaves a residue. Add 3.0 mL dry benzene to the flask containing the residue followed by a solution consisting of 1.5 mL piperidinel2.5 mL benzene. Reflux the reaction mixture for 30 min. Product Isolation /Purification. Allow the reaction mixture to cool to room temperature. Pour the mixture into a flask containing 10 mL of water. Extract the resulting solution with three 10-mL portions of chloroform. Wash the organic extract with 10 mL 0.1 M HCI, 10 mI, saturated sodium bicarbonate solution, followed by 10 mL saturated NaCl solution. Dry the organic extracts with magnesium sulfate. Filter t h e chloroform solution and evaporate in the hood. Recrystallization from acetone yields piperine [m.p. 1 2 G 128 "C]. Purified yields average 50%. Literature Cited 1. Mayo. D.;Fike, R.; Butcher, S. Microseok O w n i e Lobomfory. 2nd ed., John Wiley and Sons: New Ymk, 1989; Landgrebe, J. O r g o n l e h b o r o f o ~ M i cmsmle and Standard Smk M r i m n f s , 4th ed., BmokdCole Publishing Company: Panfie, Grove. CA, 1993.
Volume 72 Number 2
February 1995
A27
