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Chemical shifts: what's new in chemistry research? This bi-monthly column offers readers a concentrated look at the latest developments in chemistry from Canadian researchers. (Chemical Shifts).

Who Called in the Mimic?

Despite its reputation for toxicity, selenium is an essential element in the diet. Selenium deficiency, although rare, is associated with Keshan disease, which is a type of cardiomyopathy affecting mainly children and young women primarily in China where selenium intake is low.

Selenium's main function in the body is as an antioxidant. It is a key component of several enzymes, including glutathione peroxidase (GPx), which metabolizes peroxides generated during normal aerobic metabolism. This type of harmful oxidation has been implicated in a variety of disease states, and also in aging. Cells enlist help from natural antioxidants such as GPx to clean up oxidative damage of this type. To be an effective antioxidant, GPx needs to be regenerated by reaction with a stoichiometric reagent; in this case, the thiol glutathione (GSH). The overall catalytic cycle is shown in Figure 1.

In the first step, the selenium enzyme is oxidized by the substrate. In the second step the enzyme oxidizes GSH to the disulfide (GSSG) and water. It is critical that both steps be efficient in order for the reaction to be catalytic. Obviously the selenoenzyme must be carefully tuned, since it must act sequentially as a reducing agent and as an oxidant. For this reason, many small molecules designed to mimic GPx have not been successful. Compound 1 (Ebselen, Figure 2) has undergone extensive investigations, including clinical trials, but it is a poor catalyst for the second step, oxygen transfer to GSH.

In a recent J. Am. Chem. Soc. communication (2002:124, 12,104-12,105), chemistry professor Tom Back, FCIC, and co-worker Ziad Moussa, MCIC, from the University of Calgary have described an incredibly simple GPx mimic, which acts by an unprecedented mechanism. The new compound (3) is approximately 10 times faster at oxidizing [PhCH.sub.2]SH (as a model for GSH) with t-BuOOH than Ebselen, and four times faster than compound 2, previously reported by the Back group. What is most interesting is that 3 is not even the active catalyst! It is only after four in situ chemical transformations (oxidation to the selenoxide, [2,3]-sigmatropic rearrangement, a second oxidation and loss of allyl alcohol) that the true catalyst (4) is generated (equation 1).

Compound 4 is remarkable in several ways. Firstly, it is the first example of a simple, unsubstituted monocydic seleninate ester. Other examples all contain stabilizing rings or substituents. Secondly, it catalyzes the oxidation of [PhCH.sub.2]SH (BnSH) almost 20 times faster than Ebselen (1). Finally, and most remarkably, compound 4 seems to act via a different mechanism as shown in Scheme 1. The first step is addition of the thiol to the selenium centre opening the ring. A second thiol attacks this species generating BnSSBn and the selenenic acid 6. Oxidation and cyclization complete the catalytic cycle. The interesting thing about this mechanism is what doesn't appear. Compound 7 can be observed as a by-product at the end of the oxidation, but the Back group clearly demonstrated that the conversion of 6 to 7 is a deactivation pathway. This is remarkable considering that 7 is closely related to a key intermediate in oxidations with GPx.

Let Your Polymer Backbone Slide

Thanks to advances in combinatorial chemistry, automated synthesis and solid phase synthesis, chemists can now synthesize huge numbers of organic compounds in a short period of time. Since these compounds are usually directed towards a specific application, such as pharmaceuticals, the challenge then becomes testing them. One powerful method is preparing micro-arrays of synthetic precursors in which the exact position of each compound is known. The chemist can then look for interactions of the surface-bound compounds with a given analyte by tagging analytes with a fluorescent probe. A fluorescence microscope is then employed to determine exactly where on the surface interactions are taking place.

The disadvantage of this method is that it requires the addition of a photoactive, electroactive, or radioactive tagging agent on the analyte. Chemistry professor and Canada Research Chair Mario Leclerc, MCIC, has reported an interesting solution to this problem: make the support fluorescent or coloured! In this way, a wide variety of analytes can be employed, and the interaction witnessed by changes in the optical properties of the polymer on which the organic compound is localized. In order to accomplish this, Leclerc, along with co-workers Stephanie Bernier, Sebastien Garreau, Maite Bera-Aberem and Catherine Gravel at Universite Laval in Quebec City, QC, employed functionalized polythiophenes. These polymers translate chemical or physical information into an optical (or electrical signal, by changes in the conformation of the polymer backbone.

If interactions between functional groups on the side chain of the polymer and the analyte cause a change from a planar to a non-planar form, the extent of delocalization of electrons changes, which obviously changes the optical properties of the polymer. As a demonstration of this effect, the Laval group prepared polymer 1 which has pendant N-alkoxysuccinimide groups that react with amines A-C (Equation 1)

Designer amines were employed in order to test the polymers' ability to act as a sensor. Poly-2a contains a crown ether group for ion sensing. As shown in Figure 1, poly-2a changes colour from yellow to dark yellow to purple upon treatment with Li or K salts. The more dramatic change in colour upon doping with potassium is believed to be caused by the fact that the particular crown ether employed (15-crown-5) forms the most stable complexes when one [K.sup.+] ion is sandwiched between two crown ethers. This forces the aggregation of the polymer and the subsequent optical response (Figure 1). No change is observed for the starting polymer (poly-1) or for the control polymer with a simple butyl group (poly-2b).

The second designer polymer, poly-2c contains a biotin group which changes colour when exposed to Avidin, a protein known to bind to biotin (Figure 2). Again there was no response from poly-2b or poly-1. Interestingly, only 0.2 per cent of the available biotin groups need to be complexed in order to change the response of the polymer. This is explained by the large size of Avidin, such that binding in very few locations is sufficient to change the conformation of the backbone.

Cyclizing Cyclophones: A 12-Step Program

Strychnine (1) has been a target for total synthesis since Woodward's pioneering report of its preparation in 1954. After this groundbreaking work, several other syntheses appeared in the 1990s, including a notable one by Rawal at the University of Chicago. Total syntheses are commonly judged by several criteria: total yield, number of steps and overall design. Rawal prepared the complex polycyclic alkaloid in the highest yield of all reported syntheses (10 per cent), which is remarkable considering the number of steps required (15 steps from 2-nitrophenylacetonitrile). Rawal employed a [4 + 2] cycloaddition to affect the key transformation.

Vollhardt also employed a cycloaddition reaction, but in this case, it was a metal-mediated [2 + 2 + 2] cycloaddition, which led to the shortest overall route, 14 steps from propiolic acid. That is until now. In a recent issue of Angew. Chem. Int. Ed. (2002:41, 3261-3262), chemistry professor Graham Bodwell, MCIC, and co-worker Jiang Li, MGIG, from Memorial University of Newfoundland in St. John's, NF, have reported the shortest synthesis to date: 12 steps! Not only is their synthesis the shortest, it is also elegant in design, using a cycloaddition of a preformed cyclophane that generates a complex pentacyclic core in one step. The Bodwell synthesis is also characterized by very high yields throughout, with only one step contributing to the majority of the losses in material.

The synthesis begins with the reaction of tryptamine (A) with 3,6-diiodopyridazine. A three-carbon allyl chain which will become one of the cyclophane bridges is introduced by alkylation on nitrogen. The pendant olefin is then converted into an alkyl borane by hydroboration and the ring is formed using Suzuki-Miyaura technology (Scheme 1).

The cycloaddition of cyclophane D is facilitated by the presence of the diazo group in the aromatic ring. This group is extruded during the reaction as nitrogen gas, but has the important effect of improving the energetics of orbital overlap between the dienophile (indole olefin) and the diene (Bodwell and Li, Organic Letters 2002:4, 127). Thus, heating cyclophane D with N,N-diethylaniline at 217[degrees]C for 1 hour gives the pentacyclic intermediate E. With the basic skeleton intact, the Bodwell group then selectively reduces the double bond which is adjacent to the nitrogen (the enamide), and oxidizes the [CH.sub.2] group adjacent to the other amine. Although this reaction proceeds with low yield, it is remarkable in its selectivity, given the many possible sites for oxidation of this molecule. Finally, the [CO.sub.2]Me protecting group is removed to afford Rawal's key intermediate C (R = H). Since this compound was not very stable, an allyl group was attached to the secondary amine to give the stable prod uct G (R = allyl) (Scheme 2). This allyl group would then be properly positioned for creation of the final ring in strychnine.

The overall yield of this route is 15.8 per cent, with only eight steps required to prepare key compound G, which can be converted into strychnine in 4 steps as demonstrated by Rawal. Using these previously demonstrated reactions, the overall route described by Bodwell will provide strychnine in 12 steps from tryptamine, making his route the shortest to date.

Cathleen Crudden, MCIC, is an associate professor at Queen's University in Kingston, ON.
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Title Annotation:selenium, organic compound synthesis and cyclizing cyclophones
Comment:Chemical shifts: what's new in chemistry research?
Author:Crudden, Cathleen
Publication:Canadian Chemical News
Article Type:Column
Geographic Code:1CANA
Date:Jan 1, 2003
Words:1580
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