Chemistry 251 Laboratory -- Spring 2011
Xanthohumol Project Home Page

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 Synthesis of demethoxy-Xanthohumol C
Faculty Mentor: Bill Dasher

Reference: Yong Rok Lee and Likai Xia. Synthesis 2007, 620, 3240-3246.

This project follows a recent total synthesis of Xanthohumol, a natural products known as pyranochalcones which are a subclass of the flavanoids. Several pyranochalcones have significant biological activity, such as antimicrobial, antiulcer and antitumor properties. Also, pyranochacones are the medicinally active agents for numerous traditional medicines. To date synthetic routes to the pyranochacones were plagued by low yields, harsh conditions and difficult purification. This new porcedure utilizes a new method for the production of the benzopyran core. As such we now have a synthetic strategy which provides these valuable compounds in high yield and few steps. To keep our costs down we will be synthesizing the nor-methoxy (R=H) analogues.



Students Working on This Project

Lab Day Name Name
Monday Aaron Cutts John Rosasco
Tuesday Dan Guilak Jason Blanks
Wednesday Chris McDonald Molly Granger
Wednesday eve Molly Richardson Jessica Jaynes
Thursday Tracy Wormwood Magnolia Klee
Thursday Eve Liz Casey Jessic Bailin


Table of Reagents and Amounts Available for this Project

The table below lists the chemicals that we will have available for this project. If you need something that is not on this list, consult with the mentor for your project. Also note the "Amount/group" column. This is the total amount of material available for each group to use on the project.
Reagent Source Amount/group Location Comments
2,4-dihydroxy acetophenone Aldrich
Cat. #D107409		 5 g TA room
Benzyl chloride Aldrich
Cat. #185558		 25 mL TA room This material is a cancer suspect agent. It must be disposed of in a special container.
4-Hydroxybenzaldehyde Aldrich
Cat. #144088		 10 g TA Room
EDDA Aldrich
Cat #420352		 1 g TA Room
3-Me-2-butenal Aldrich
Cat. 304077		 1 mL TA Room


Notes on Xanthohumol

Spring 2011
  • By now you should have at least one part-reaction NMR showing the phenol peaks of the dihydroxyacetophenone and the product from step one. I would like you to email the percent of each and reaction time.
  • For week two you should set up the reaction to make the protected hydroxybenzaldehye. As in previous years follow the procedure given below.
  • You will also setup and flash your product from step one.

    Notes on Xanthohumol

    Spring 2010
  • Following the procedure in the Lee paper but modified based on the comments from previous years. Note that we will be scaling this up to 2x that of last year.
  • To be clear, the scaling up results in using the following amounts: Dihydroxyacetophenone (608 mg), butenal (672 mg), EDDA (72 mg).
  • You may use GC to determine the final ratio of product to starting dihydroxy acetophenone of your crude product after workup. Use method C251Xantho. Your product elutes around 9 minutes and gives a parent ion at 218 and a base peak at 203 (P-Me). Starting material elutes earlier, has a parent peak at 152 and will be correctly identified if you run a search, (double click on the generated mass spec.).
  • Follow the procedure given below from 2009 to make your protected aldehyde. You may substitute Cesium carbonate for potassium carbonate. The former is reputed to work better although our yields for this reaction are generally very good anyway. You will need this for the next step so for week two of the projects you should purify step one and prepare the protected aldehyde. Eventually (as soon as you can) you should characterize your purified first product by NMR (H,C), IR, m.p., color and form. Now, write the final draft of that experimental step.
  • To summerize, by the end of week two you should have purified step one, fully characterized it and completed your experimental for that step. You should also have run the reaction to make the protected benzaldehyde which probably will not need to be purified.

    Spring 2009
  • For the first attempt double the amount in the given procedure taken from the Lee paper in Synthesis (2007) for the synthesis of isoevodionol (19). That is start with 304 mg. of dihydroxyacetophenone. Reflux in xylene for around 5 hours, let cool a bit, then add a fresh portion of EDDA and the unsaturated aldehyde (see below) and continue refluxing overnight.
  • When you stop your reflux to add more catalyst material and take an NMR as follows. Transfer some of your reaction to an NMR tube. Use NO SOLVENT, gradient shim but not lock, and use the proton pulse sequence. We need to see the region between 10 and 15 ppm. The phenol peak for the product appears around 13ppm whereas the phenol for the starting dihydroxy acetophenone shows up at 12.5 ppm. Don't forget that the data slate will scale on xylene so you will need to enlarge the area of interest.
  • If you can, try to get a tlc of your reaction so see if that is a feasible way to follow the progress of the reaction. See the comments from last year for a suitable system.
  • Here are some notes on the first step product. NMR will show a sharp phenol peak around 13 ppm, four doublets for the aromatic ring and alkene at 7.5, 6.7, 6.3 and 5.6 ppm., a methyl ketone at 2.5 and the gem dimethyls just above 1.4 ppm. You can get a GC/MS. Use method 251Xantho.m The product elutes at 9.5 minutes and gives a great parent peak (218 amu) with a base peak at 203 (M-methyl).
  • Procedure For making the protected benzaldehyde, use the following procedure adapted from the Roefractine project. To a stirred solution of p-hydroxy benzaldehyde (10 mmole) in absolute ethanol (25 mL) is added finely ground K2CO3 (11 mmole) and benzyl chloride (10 mmole). The solution is refluxed under nitrogen and then stirred overnight. The solution is filtered through a bed of celite to remove the K2CO3 and the sovent removed in vacuo to give a crude oil. This is taken up in CH2Cl2 (25 mL) and washed with 5% NaOH to remove any unreacted phenol, then water, dried with Na2SO4 and the solvent removed in vacuo. See below for tips on purifying your product.

    After removing the reaction solvent you may have unreacted benzyl chloride in your mix. One trick to get rid of it and ease the purification process is to cover the oil (or crude solid) with cold hexane. This will draw up the benzyl chloride but not dissove your product. In may take a bit for the oil to crystallize. Once solid, three rinses with cold hexane should remove any unreacted benzyl chloride. You will need to pump on your sample (or rotovap) to remove traces of remaining hexane before you take an NMR. Check the purity by GC/MS (use xantho.m) to decide if you need to crystallize or not. Also, once solid, a melting point is a good indicator of purity. The CH2 in benzyl chloride resonates at 4.5 ppm.

    Spring 2008
  • This reaction seems to take a bit longer than the literature time of 10 hrs on a 150 mg scale. Perhaps the replacement of the methoxy by hydrogen lowers the rate. To date we've had several groups extend the time to between 48 and 72 hours and we'll have to see if that works.
  • You can note the presence of starting material, (2,4 dihydroxyacetophenone) by NMR. The phenolic protons resonates around 12.5 and is broader than the product phenolic hydrogen which resonates near 13 ppm. The aldehyde protons are also clear and appear as a pair of doublets around 10 ppm (cis/trans mix).
  • Flash chromatography brings off the product first. In addition to the 7/1 hexane/ethyl acetate I've seen some good tlcs using 7/1 dichloromethane/hexane.
  • You first goal should be to obtain excellent proton and carbon NMR on purified material. If you have at least 30-40 mg of the nice product you night consider getting a DEPT and COSY spectra as well.
  • Once you've got a handle on the first product you will need to prepare a batch of benzyl protected p-hydroxy benzaldehyde. Please modicfy and use the procedure given for protecting vanillin in the roefractine project. There are a few changes. First, note that you are working on a slightly different molecule so be sure to adjust for the correct amounts. Note that the given procedure uses 39 grams which is too much. You should scale this to 2 grams of starting aldehyde and adjust accordingly. Also we will be using benzyl chloride in place of benzyl bromide as it is less of a hazard. Grind the potassium carbonate well to provide maximum surface area. The more adventurous may try cesium carbonate which is Eric's method that he uses for the liquid crystal project. Use about 20 mL ethanol. The reaction runs under nitrogen overnight and the setup does not have to be flame dried.
  • To obtain pure product (the protected benzaldehyde) we will not have to flash or recrystallize. Once you have done your final solvent removal - after the hydroxide wash to remove unreacted phenol - do the following: Cover your protected phenol (which is likely a solid) with a layer of hexane and mix it in with the solid. Decant the hexane and repeat one or two more times. This will dissolve and remove any unreacted benzyl chloride. Careful, you need to take your hexane rinse containing the unreacted benzyl chloride and dispose of it in the designated container in the prep hood. Once the hexane dries you should have some nice material for the next step. Charaterize by proton NMR, IR and m.p..


    This page last modified Saturday, March 26, 2011