Biological Chemistry Synthesis of N heterocycle from amino acid precursor Hetero
ID: 552500 • Letter: B
Question
Biological Chemistry Synthesis of N heterocycle from amino acid precursor Heterocycles are common motifs in biologically active natural products and biomimetic drug molecules. Pyrrole rings are particularly common. One route to destroying cancer cells or viruses is to target DNA function and/or synthesis. A number of natural products that contain the pyrrole functional group, such as the peptides distamycin and netropsin, have been found to bind in the minor groove of DNA1 and disrupting DNA replication and transcription. This disruption of DNA function and processing leads to cell death in the cancer and viral cells. These naturally occurring poly-pyrrole compounds are essentially peptides, and are most likely biosynthesised from amino acid precursors. So, it seems logical that to produce these types of compounds in a laboratory environment we might want to begin with amino acid starting materials The synthesis you will be performing today has been adapted from the work of Kolar and Tišler. You will be starting from a simple, cheap, readily available amino acid precursor and, in two distinct steps, synthesising a pyrrole that has a number of useful synthetic 'handles', i.e. it can serve as the basis for making a range of possible small molecules (or even large polymeric ones) that will contain a pyrrole moiety. Note that we will be using phenyl alanine today, i.e. the R group in () is a benzene ring but this procedure should work with any amino acid starting material. R- akyl, aryl, heteroaryl R, methyl, ethyl Synthetic procedure L-Phenylalanine ethyl ester (I, R benzyl, R1 ethyl) Dissolve Lphenylalanine ethyl ester hydrochloride (2.57 g, how many moles is this?) in 25 mL of water, cool on ice bath to 0 °C, and neutralise with a solution of 0.45 g of sodium hydroxide in 10 mL of water. Extract neutralised solution 4-5 times with 15-ml portions of diethyl ether, combine extracts, dry with anhydrous sodium sulphate, and evaporate in vacuo (using rotary evaporator). You should end up with a colourless oily product. Record the weight of your product before proceeding to the next step.
Explanation / Answer
Melting points of the intermediate and final product should be observed experimentally. If however, the melting points in literature do not match with the one obtained, recrystallization in a suitable solvent, preferably ethyl acetate or dichloromethane or chloroform will obtain the pure product, with proper melting points.
For both the synthesis steps, simple round-bottom flasks can be used. To prevent moisture from entering the reaction and noxious gases from exiting the flask, a guard tube of appropriate ground-joint fitting the round-bottom flask should be used in both cases. Considering the large quantity of the reaction, a single neck 100mL RB flask will suffice. Moreover, for concentrating in vacuo, a cone adapter equipped with a stopcock and ground-joint same as that of the RB flask should be used. Finally for the vacuum filteration in the second step, a Buchner funnel with proper ground-joint should be used to ensure zero vacuum leakage from the conical flask used.
The amino acid contains a phenyl ring, with extensive resonance and conjugation. This makes phenylalanine fluoresce in UV radiation. So, if the amino acid is applied onto a TLC plate, its location can be visualized under UV light. Usually, TLC plates' adsorbents fluoresce in UV light in bright white and when a UV active compound like phenylalanine is applied on them, the spot where the compound has been adsorbed tends to quench the adsobent's fluorescence casting a deep blue spot in the compound's location.
If the starting material is checked for TLC, running phenylalanine hydrochloride is not necessary as the starting material, being the ester of the amino acid will appear at a different retention factor compared to phenylalanine. Therefore, simply taking the starting materials for checking their presence/absence to determine the purity of the product is sufficient. Moreover, if phenylalanine is also run, it might complicate comparison as a material that is almost as polar as DMAD but never present in the solution is taken for comparision, misleading the observer into thinking DMAD has not been consumed when it might be quite the contrary.
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