Instructors: Bill Dasher, John Hanson, Tim Hoyt, and Eric Scharrer
| Ibuprofen | Sulotroban | Xanthohumol | Equol | Roefractine | Frontalin | Lysozyme | Liquid Crystals |
Ibuprofen is the active ingredient in a number of over the counter pain relievers,
e.g. Advil, Motrin, and Nuprin. It is one of the top-ten drugs sold worldwide,
and, although it has been shown that only the S enantiomer has the desired biological
activity, it is currently sold as the racemate. Our synthesis of the racemate,
begins with reaction of 4-isobutylacetophenone with the sulfur ylide produced
by deprotonation of trimethylsulfonium iodide to yield an epoxide. (You should
look this reaction up in an advanced organic text, e.g. the one by Jerry March.)
In the JOC article listed above they found that the epoxide could be converted
to Ibuprofen by reduction to the alcohol using H2/Pd followed
by oxidation of the resulting alcohol to the acid using KMnO4.
We found that BF3-Et2O catalyzed rearrangement
of the epoxide to an aldehyde worked well. Some preliminary attempts at oxidizing
this aldehyde to Ibuprofen have been explored.
Sulfonamide containing molecules have played an important role in the history of medicinal chemistry. For example, some of the first antibiotics were sulfonamides. Sulotroban is an antithrombotic drug that also contains a sulfonamide. The synthesis of Sulotroban begins by forming the sulfonamide by reacting benzenesulfonyl chloride with 4-(methoxyphenyl)ethylamine. The phenolic methyl ether is then cleaved using the Lewis acid BBr3. Coupling of the resulting phenol with ethyl bromoacetate is then followed by hydrolysis to yield Sulotroban.
Pyranochalcones are an interesting class of natural products derived from shikimic acid starter molecules which have condensed with polyketides. They belong to the subclass of flavonoids and are wide spread in nature. Their biological properties include antimutagenic, antimicrobial and antitumor activities. Many of these compounds are found in plants used in traditional Chinese and Indian medicine. For example Xanthohumuol a component of hops has recently been in the news with articles touting its activity against tumor growth. Flavanoids and related molecules are also effective antioxidants. This project is aimed at the synthesis of Xanthohumol as outlined below. The syntheses begin with a remarkable cycloaddition to form the benzopyrans. This is followed by an aldol condensation with an aromatic aldehyde to produce the desired pyranochalcone derivatives which differs from the natural product by not having a methoxy at the R position.
Synthesis of a Xanthohumol C
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.
Synthesis of Equol
Dopamine is an important neurotransmitter. For example, cocaine acts by blocking dopamine uptake, while a deficiency of dopamine is associated with Parkinson’s disease. As part of a series of studies aimed at better understanding the binding of alkaloids to dopamine receptors, (R)-(+)-nor-Roefractine was recently synthesized and its binding to dopamine receptors was studied. The synthesis starts with isovanillin which is protected as the benzyl ether before condensation with nitromethane to give the b-nitrostyrene derivative. Reduction to the amine, followed by reaction with 4-methoxyphenylacetyl chloride gives a compound that can be cyclized using POCl3. Stereoselective reduction of the resulting cyclic imine followed by deprotection of the benzyl ether gives the desired (R)-(+)-nor-Roefractine.
Frontalin is a pheromone of the Douglas Fir Beetle (a northwest pest), and is manufactured by a company in Canada for use in traps. We have been trying to develop an effective synthesis of frontalin for several years now. Our current synthetic strategy is shown below. Acetylbutyrolactone is treated with HBr or HCl to form 5-halo-2-pentanone (1). (See if you can come up with a plausible mechanism.) Last year we protected the ketone as a ketal and then tried to convert the chloride or bromide to the iodoketal 3. Unfortunately the ketal kept falling off when we did this. So this year we will convert the chloride or bromide to the iodide 2 first, and then introduce the ketal protecting group to produce the desired iodoketal 3. Reaction of 3 with the cuprate formed from isopropenyl magnesium chloride should afford the desired intermediate 4. The ketal protecting group can then be removed, and the resulting enone 5 converted into the epoxide by treatment with MCPBA. Treatment with catalytic acid will then produce racemic frontalin.
T4 lysozyme is one of the most thoroughly studied enzymes from a structural point of view. Unfortunately, there is currently no convenient assay for the enzyme. As part of an effort to synthesize a substrate for this enzyme John Hanson would like to prepare the o-nitrophenyl muramic acid derivative 6. He has used a similar route to prepare the corresponding p-nitrophenyl derivative. N-Acetylgluosamine (1) is treated with acetyl chloride to produce the tetraacetyl chloride 2. Base-catalyzed substitution of o-nitrophenol should afford the glycoside 3. Removal of the acetate esters with methoxide, followed by selective protection of the 4 and 6 hydroxyls as an acetonide, affords the 3-hydroxy derivative 5. Alkylation with ethyl 2-bromopropionate or 2-bromopropionic acid should afford the desired muramic acid derivative.
