Chemistry 251 Laboratory -- Spring 2011
Equol Project Home Page

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Synthesis of Equol
Faculty Mentor: Bill Dasher

Reference: Gupta, A; Ray, S. Synthesis, 2008, 3783-3786.

Isoflavonoids are an interesting class of natural products derived from shikimic acid starter molecules which have condensed with polyketides. They differ from the flavonoids by having a radical-cyctochrome P-450 dependent migration of the phenol group. Isoflavonoids are found almost exclusively in the leguminosae family. The touted medicinal properties of soy are due to its isoflavonoid content and equol is a biologically active metabolite of daidzein which is one of the two major phytoestrogens in soy. This project is aimed at the synthesis of Equol as outlined below. The syntheses begin with a Freidel-Crafts type reaction to couple the two benzene moeities. After flash column purification we reduce and remove the ketone group followed cleavage of the two phenyl ethers to afford dehydro equol. Hydrogenation of the alkene group gives equol. An interesting future addition would be to work out conditions for the stereospecific reduction to afford optically pure equol.





Students Working on This Project
Lab Day Name Name
Monday Mathew Breuer Preston Van Buren
Tuesday Kat Schmidt Amber Higgins
Wednesday Jackie Braun Kari Hanson
Wednesday Eve
Thursday Awbrey Anderson Cody Silva
Thursday Eve Josh Schnidlein James Estevez


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
3-methoxyphenol Aldrich
Cat. #328456		 5 g TA room [150-19-6]
4-hydroxy phenylacetic acid Aldrich
Cat. #H50004		 5 g TA room [156-38-7]
BF3 - Et20 Aldrich
Cat. #216607		 10 mL TA Room [109-63-7] Caution - Poison!
paraformaldehyde Aldrich
Cat. #158127		 1 g TA Room [30525-89-4]
NaBH4 Aldrich
Cat #452890		 2 g TA Room[16940-66-2]
pyridine hydrochloride Aldrich
Cat. #243086		 5 g TA Room [628-43-7]


Notes on Equol

2011

  • Now that we've done reaction one we need to purify by flash chromatography. Do a tlc using the solvent system given in the 2009 discussion. There is an authentic sample of product you can use to match your tlc. Also GC/MS (as noted below) can be useful in determining how well the reaction went.

    2010
  • From the group meeting discussion we will do this at 2x scale from 2009. Plan to react for at least 7 hours. Overnight is probably OK. You should report your yield and time as soon as you know so I can share this with other groups. Use ~10 mL of BF3-etherate.
  • Be sure to work out your tlc conditions by using the standards I've put in the hoods. 2010
  • We've run this reaction at 2x scale from 2009. I haven't seen any crude NMRs yet. By now you should have worked up your reaction and are getting setup for purification by flash chromatography. Take an NMR of your crude product and compare it to the NMR of the authentic sample located in the hood. Determine if you have product by matching NMR peaks and comparing tlc of your crude product with the tlc standard from last year. Note that you will have a mixture of product with one of the phenols ethylated (our desired product) mixed some free phenol (diphenol).
  • As noted from last year you should determine a flash/tlc solvent. Use the recommendations from 2009. By the end of the week we should have flashed our crude product, determined yield and fully characterized it by NMR (C,H), IR and m.p. Once characterized, you should complete the experimental section for step one. Now we can gear up for the next step.

    2009
  • From our discussion follow this rescaled (from the paper) reaction procedure:

    In a flame dried 25 mL RB equipped with stir bar add 5 mL of BF3-etherate followed by 3-methoxyphenol (372 mg, 3 mmol) and 4-hydroxypheynylacetic acid (456 mg, 3 mmol). Heat at 100 ¡C for 3-5 hours. On completion of the reation, the mixture is poured into ice-water (~10 mL) and extracted with 5 x 10 mL of EtOAc, dried with Na2SO4 and the solvent removed in vacuo to afford the crude product. Purify by flash chormatography using EtOAc/hexane.


  • I will attempt to setup a sand-filled heating mantle and determine a variac setting which puts the sand bath at 110 ¡C.
  • Note that BF3 is water sensitive so we will be using flame-dried apparatus and run the reaction under nitrogen using a N2 filled balloon.
  • It appears that even though we are doing this reaction at a much reduced scale we still need at least 7 hours reaction time.
  • For flash column purification use roughly 15% ethyl acetate in hexane. An ideal solvent will bring our product off in the first 10 fractions.

  • I am seeing some good NMRs of the first product and they match the NMR listing in the orginal paper so make sure you do that comparison. For all NMRs print full with integration and a blow-up of the aromatic region that has line listing in kilohertz. Take a carbon NMR as well, no integration but line list the peaks and compare with the literature values.
  • We should attempt a GC/MS of our first step product to see if it works. Use 251high.m for the method.
  • We have ben using 15-20% ETOAc in hexane to flash. I would like to see a tlc using 1/1 dichloromethane/hexane for comparison. The 1/1 is a guesstimate so if the product runs low then up the dichloromethane amount and visa versa if it runs too high.
  • Once you have purified product from the first reaction you should scale the next step, most likely around 100 mg scale. See the original paper for the procedure. Note that they run this at 60¡C in an aqueous solution so I will set up another sand bath set to 60¡C. Keep in mind when you read the procedure that in a basic solution the reacting phenol will be deprotonated and thus soluble in water. The product will not be water soluble.
  • At the same time you might consider running reaction #1 at double scale, (6 mmole). Use 10 mL of BF3 etherate but the workup amounts may remain the same. However, we may need to up the amount of silica get we use in the flash column and/or try loading the sample on silica as we did with the Jacobsen product purification you did at the end of Fall term.

    This page last modified Saturday, March 26, 2011