Now that you've learned your way around an organic lab, you have the opportunity to work on a multi-step synthetic project. Over a five week period you and a partner will attempt to synthesize a natural product or drug. Before you leave for Spring Break you will be required to turn in a Project Proposal that will include a detailed experimental procedure for your first week in lab. During the course of these projects, your group will share information with other groups working on the same project. At the end of the semester your group will present a short talk and submit a final written report. This report will determine a major portion of your lab grade.
Piperine is a component of black pepper which causes sneezing.
Its presence in pepper was discovered many years ago, and its
structure was elucidated near the beginning of the century. The
synthesis starts with an allylic, radical halogenation to introduce
a bromine atom. An Arbuzov reaction with triethyl phosphite displaces
the bromine and produces a phosphonate that is then coupled to
piperonal using a modified Wittig reaction. Hydrolysis of the
ester, formation of the acid chloride using oxalyl chloride, and
coupling to piperidine completes the synthesis.
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. There are actually two syntheses worth exploring here. The first, a 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.) Last year we found that BF3Et2O catalyzed rearrangement of the epoxide to give the aldehyde worked well. What remains to be explored is the oxidation of this aldehyde to give the racemic Ibuprofen. An enantioselective synthesis of Ibuprofen could be accomplished by first performing a Wittig reaction to give the alkene and then performing an enantioselective epoxidation. The epoxide is then opened reductively by treatment with H2 and Pd catalyst to give an alcohol that is then oxidized to the acid, Ibuprofen, using KMnO4.
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.
Daubresse, N., R.; Francesch, C.; Mhamdi, F.; Rolando, C. Synthesis, 1998, 157-161.
Coniferin is an important metabolite in conifers, serving as an important intermediate in cell wall lignification, as well as having other biological roles. Last year a French group reported an elagent synthesis of this compound starting from vanillin. In a one-pot reaction, the vanillin is first glucosylated on the phenolic hydroxyl and then a Wittig reaction is used to introduce the double bond. After unmasking the aldehyde, and reduction to the alcohol, the acetates are removed with methoxide to afford the desired coniferin. (Note: It will be necessary to first prepare acetobromoglucose from glucose pentaacetate.)
Cabedo, N.; Protais, P.; Cassels, B.K.; Cortes, D. J. Nat. Prod., 1998 61, 709-712.
Dopamine is an important neurotransmitter. For example, cocaine acts by blocking dopamine uptake, while a deficiency of dopamine is associated with Parkinsonšs 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 an aggregation pheromone of the Southern Pine Beetle. It possesses an interesting tricyclic structure containing an acetal linkage. The Bartlett synthesis (shown below) is a five step process with the ring construction occurring in the last step by an acid catalyzed reaction on an acyclic precursor. Unfortunately, the second step in which a tosylate is displaced by an anion formed from ethyl acetoacetate does not work well. We need a new approach. A recent paper described an alternate synthesis of the 6-methyl-6-hepten-2-one using the cyclohexylimine of acetone. We will prepare this imine and try this reaction.
Chrysanthemic Acid, from the chrysanthemum flower, is a natural insecticide which has been known since ancient Persia. Its structure is that of a cyclopropane containing, irregular, monoterpene. Last year, most of the groups working on the synthesis of chrysanthemic acid were attempting to use the procedure described by Schatz in the J. Chem. Ed. article cited above, but were having trouble getting one of the reactions to work. One group found the procedure of Kelly to work fairly well. In this procedure the diene shown below was transformed in two steps to Chrysanthemic acid. Since Aldrich is discontinuing production of this diene, we need to find a method for preparing it. Preliminary studies suggest that dehydration of the diol shown below might be an effective method, but it needs some more work. In addition, this synthesis gives mixture of cis and trans isomers, and it would be useful to explore methods to improve the trans/cis ratio, such as using the t-butyl ester rather than the ethyl ester of the diazoacetate.
