Chemistry By Design: Hippadine

Hippadine is naturally produced in plants and shows signs that it is good for the heart.¹

Figure 1, Synthesis of Hippadine

There were a total number of 4 steps shown on the Chemistry by Design site, but there were some left out.  In each step shown above the reagents used are readily available. (The availability of each was determined from the Sigma Aldrich website).

In step 1, the reagent is vinyl magnesium bromide and tetrahydrosfuran is used as the solvent.  Step 2 utilizes 5-bromo-6-bromomethyl-1,3-benzodioxole with potassium hydroxide (KOH) and dimethyl sulfoxide (DMSO).  The third step n-Butyllithium (n-BuLi) is used in THF and in the final step barium manganate is the reagent used in dichloromethane (DCM). 

Of the 4 steps, three have been discussed in class.  The first step uses a Gringard reagent, which follows the basic structure of R-Mg-X.  In this case the R group is CH₃ and the X group is Br.  The third step is one in which an organolithium reagent is used.  Since Li is an electropositive metal, it contains a very polar carbon-metal bond causing it to be very reactive.² An Ullman Reaction was utlizied in this step as well.  Such reactions were not discussed in class, but the Ullmann-type Reactions include copper-catalyzed nucleophilic aromatic substitution between various nucleophiles with aryl halides.³ The final step is an oxidation in which the oxygen is double bonded to the carbon using the reagent BaMnO₄.

Below is a different mechanism of the synthesis of Hippadine with a different starting material.

Figure 2, Synthesis of Hippadine⁴

Resources

¹Purgett, Thomas. https://honors.tcu.edu/QAwithStudentsCompletingDepartmentalHonors.asp

²Smith, Janice. Organometallic Reagents. Organic Chemistry, 3^rd Edition. McGraw Hill. New York. Print. Pp 739

³M. Cortes-Salva, C. Garvin, J. C. Antilla, J. Org. Chem., 2011, 76, 1456-1459

⁴Boger, D. L.; Wolkenberg, S. E. J. Org. Chem. 2000, 65, 9120-9124