July 2nd, 2009
We’ve upgraded our main website, fluorous.com, and I’d like to invite all F-Blog readers to explore the new pages. As you know from reading this blog, the range of scientific disciplines using fluorous has increased tremendously in the past few years and our company has evolved with the technology. The new site recognizes this growth and evolution.
In addition to a sleek new look, we reorganized much of the content. The tabs across the top offer entry into the main sections. Each section has a menu in the left column. Hopefully the new navigation system will be easily understood and intuitive. But if not, we’ve also upgraded the search capability in the upper right corner.
What does this mean for F-Blog? Well, probably not much. In this forum, we’ll continue to focus on literature and technology discussion. Some of the more company-focused posts will shift over to our News section (RSS feeds now available), but there may be some overlap initially as we see what fits and what doesn’t.
Thanks for reading, and I hope you enjoy the new site!
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July 2nd, 2009
In the last year, they’re have been several papers using fluorous tags and methods in either the synthesis and purification of radioimaging agents, as an integral part of the imaging agent, or both. These include the production of 18F agents for PET imaging, 19F agents for fluorine MRI, and 125I for SPECT imaging. One of the most used isotopes in nuclear medicine is technitium in the form of 99mTc. Now a recent communication in International Journal of Pharmaceutics describes the use of fluorous tagged carbohydrates in liver imaging using 99Tc.
The researchers led by Dr. Nathalie Mignet at the University of Paris designed and prepared amphiphilic molecules containing a lactosyl moiety in order to target hepatocytic glycoprotein receptors. The molecule also included a pentaacetic acid unit for coordination to the Tc and a fluorous tag. The molecule is designed to be a glycolipid mimic with the fluorous chain replacing the hydrocarbon chain. The fluorous chain plays an important part by minimizing cytotoxicity, lowering the critical micelle concentration, and facilitating preparation, since FSPE is used during synthesis.
Once the molecule was in hand, the researchers produced nanoparticles which they demonstrated coordinated 99mTc, did not interact with blood proteins, and resulted in particles with the lactosyl component on the outside. They then optimized the pH and concentration of the compound for in vivo studies in rats and found that selctive distribution in liver tissue could be achieved.
Not only is this an example of fluorous tags in nuclear medicine, but also a demonstration of how fluorous tags can serve multiple purposes. In this case, imparting unique physical properties that hydrocarbons do not possess. Immobilization of fluorous tagged molecules for microarray formation is another example of fluorous multi-tasking resulting in simpler workflows.
Tags: carbohydrate, FSPE, Isotope chemistry, micelles, nanoparticles, radioimaging, technitium
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June 30th, 2009
Fluorous organosilanes have been used extensively as oxygen protecting groups analogous to traditional silanes. In addition fluorous silanes have also been used as traceless tags by protodesilylation by TBAF. Last year, Prof. Véronique Gouverneur’s group at the University of Oxford reported fluorodesilylation of fluorous silanes to produce C-F bonds from C-Si bonds. Prof. Gouverneur and co-workers have now published a report which extends the use of fluorous silanes a step further by demonstrating that Tamao-Fleming oxidations can also be conducted using fluorous silanes.
The oxidative cleavage of organosilanes resulting in the replacement of a carbon-silicon bonds with a carbon-oxygen bond was pioneered independently by Fleming and Tamao back in the 80’s. The transformation has found utility in many synthetic applications with silanes serving as latent hydroxyls. The advantage, of course, being that silanes are generally less reactive than oxygens and require no further protection and can be carried through multiple steps in synthesis.
The researchers chose to implement a light fluorous approach with an arylsilane so that Fleming oxidation conditions could be used. They cited the ability to use either standard chromatography or FSPE for purification and the minimal optimazation studies necessary when using light fluorous techniques as reasons to chose this method. After synthesis of the allyl silane 1 starting from the fluorous bromobenzene, the cycloannulation of 1 with unsaturated ketone 2 provided the substrate for the oxidation. Oxidation with HBF4-Et2O provided the alcohol 3 in yields comparable to that found in the non-fluorous oxidation. Compound 3 could be purified either with standard silica gel chromatography or FSPE.
Tags: Fleming oxidation, FSPE, Gouverneur, silane
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June 25th, 2009
On the heels of the last post which described some organocatalyst work from the Wang group comes a newly available report in Chemical Communications from Tibor Soós and co-workers describing a new CBS pre-catalyst, A. As seen below, the catalyst is a typical diphenyl prolinol derivative except that the aryl groups are substituted with two trifluoromethyl groups apiece.
After synthesis of the pre-catalyst A the researchers evaluated in CBS of several secondary ketones and found that it performed comparably to the standard diphenyl prolinol under the right reaction conditions with high yields and ee’s. The next step was to look for ways to recover the pre-catalyst.
The recovery of CBS catalysts has been the subject of many studies and methods. (For a recent review of the field, click here.) Not surprisingly fluorous approaches using both fluorous solid phase extraction (FSPE) and fluorous liquid-liquid extraction (FLLE) have been used. The most popular fluorous prolinol, C, contains two Rf8 chains and both FSPE and FLLE have been used to remove and recover the catalyst. Most recently, Curran has used C in a fully liquid immobilized mode with a very simple recycling protocol using an environmentally benign HFE solvent.
In this instance the researchers first tried FSPE with somewhat mixed results. They did achieve some separation, but not complete separation despite using 1:1 MeOH:H2O as the fluorophobic wash. Despite a fluorine content of 43% which would indicate that FSPE should be effective, it’s well known that fluorine content alone is not enough. The arrangement of the fluorines is also important with extended perfluroalkyls being most effective, which is why trifluoromethyls and isolated fluorines are generally not fluorous.
They then moved on to liquid-liquid extraction. In this instance they took advantage of the hydrophobicity of the trifluoromethyl groups. So as seen in the top graphic, evaporation of the reaction solvent, THF, followed by partitioning between hexanes and aqueous MeOH or CH3CN which resulted in complete separation of the pre-catalyst and the pyridyl alcohol product. With other less polar product alcohols, however, a simple partitioning was ineffective and multiple extractions of the hexane phase was necessary. In order to overcome that limitation, the researchers fabricated an ingenious continuous liquid-liquid extractor shown below.
This extractor is actually a combination of a triphasic separation in a U-tube and a continuous liquid-liquid extractor. The crude reaction mixture is dissolved in hexanes and placed in the left hand arm of the U-tube. The bottom of the U-tube contains the aqueous methanol which acts as a liquid membrane through which only the product can enter and pass through to the right arm containing hexanes. As the product migrates to the right arm it is removed by the continous extractor to prevent back transport to the left arm.
Tags: CBS reduction, organocatalyst, Soos, Triphasic
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June 23rd, 2009
Catalysis without the use of transitions metals has been a very popular area of research over the last decade or so, particularly for asymmetric transformations. The catalyst which are used have been termed organocatalysts to distinguish them from transition metal catalysts. The Dec. 2007 issue of Chemical Reviews was completely dedicated to organocatalysis and described the various types, mechanisms, and transformations.
One of the drawbacks of organocatalysts at this time is that relatively high loading levels (5-20 mol%) are often necessary to carry out the reaction. This means that removal of the catalyst from the product, recovery, and reuse is important. Many times this is not an issue since, the organocatalyst is often basic. As long as your product doesn’t contain basic functionalities, a simple acid wash can be used to separate the product from the organocatalyst. This isn’t always the case, however, and several research groups have made fluorous organocatalysts which are easily removed by FSPE. ( For a look at some past F-Blog posts discussing fluorous organocatalysts, please click here.)
One of the groups that has done so, is the Wang group from the Univeristy of New Mexico. Recently, they published an Organic Letters communication of their latest results using organocatalysts for the Michael addition of nitroalkanes to unsaturated ketones, as seen above. The organocatalyst they settled on was a cyclohexadiamine-based thiourea containing an aryl group with two trifluoromethyl substituents. The trifluoromethyl substituted aryl group enhanced the activity and selectivity of the catalyst relative to a phenyl group, presumably by increasing the acidity of the hydrogen-bond donating urea. They then used this organocatalyst in several examples. In each case the organocatalyst was removed and the product purified by chromatography. No mention of separation by aqueous acid was made. One of the examples given, however, would not have worked well using an acidic wash, since the beta-substituent on the ketone was a dimethylamino-arene.
The question then is “How would a fluorous version of this catalyst behave?” One could imagine replacing the trifluoromethyl groups with two Rf4 or Rf6 groups to provide the fluorous chains. In addition to providing an orthogonal method for separating the organocatalyst from the product, the presence of the additional fluorines should further reduce the pKa of the urea enhancing reactivity further.
Given their previous experience with fluorous sulfonamides as organocatalysts it will be interesting to see if they pursue that avenue of research.
Tags: organocatalyst
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