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CEOverture...
The M's rule the day in this issue of our technical newsletter. Read on below to find out about recent innovation in fluorous miniaturization, microreactors, microfluidics, mass spec, multichannel HPLC and mixture synthesis. What can I say, except- magnificent! Marvelous!
Cheers,
Phil
Philip E. Yeske
President & CEO
Microreactor Synthesis of Beta Peptides
Researchers led by Peter Seeberger at the ETH in Zurich, Switzerland have recently reported the synthesis of beta-peptides using fluorous techniques within a microreactor.[1] The synthesis of beta-peptides on traditional solid supports has been a challenge to chemists due to their ability to easily form secondary structures. The authors have addressed these issues in the solution phase synthesis of a beta-peptide tetramer in a silicon continuous flow microreactor. They also reported that by utilizing a fluorous benzyl tagged beta-amino acid the synthesis and purification of these challenging molecules was greatly facilitated. The microreactor allowed a variety of reaction conditions to be quickly scanned without consuming large amounts of materials. After identifying appropriate reaction conditions using the microreactor, the fluorous microreactor synthesis was conducted and compared to other strategies. Although all procedures provided the tetramer in comparable overall yields, it was noted that the fluorous tagged peptides were much easier to purify than the non-fluorous tagged peptides. By combining the reaction capabilities of the microreactor with the separation and purification power of fluorous tags an efficient synthesis of an otherwise difficult class of molecules was achieved. FTI offers a variety of products to support the peptide synthesis community- click here to find out more.
Microfluidic F-SPE Chip Developed
Professor Li and colleagues at Vanderbilt University recently published their intriguing initial studies in applying fluorous based separations to a microfluidic chip.[2] The main objective of their research was to determine the feasibility of developing a microfluidic fluorous solid-phase extraction (F-SPE) device that could separate fluorous tagged amino acids from a mixture containing untagged components. To achieve the desired result, a poly(dimethylsiloxane) (PDMS) microfluidic F-SPE device containing a retaining chamber packed with 5micron FluoroFlash silica gel in a microchannel was produced. Through the use of electrokinetic pumping, a mixture of fluorous tagged and non-tagged amino acids was carried into the F-SPE chamber and successfully separated and extracted. By adding a reference material to the sample, the extraction efficiency of the eluted fluorous-tagged amino acid was calculated using MS detection. The F-SPE microchips showed good reproducibility and efficiency, yielding an average extraction efficiency of 55% with an RSD of 10.6% under the typical experimental conditions. This publication clearly demonstrates that fluorous techniques can be utilized in microfluidic devices, paving the way for a new world of fluorous applications. Microfluidic devices provide shorter time for reaction and analysis, integration and automation of multiple processes, and high throughput which is desired for parallel processing and portability.
MS-triggered Multichannel Fluorous HPLC in DOS Library Creation
Two recent papers on the topic of fluorous amino ester-based library synthesis and parallel fluorous HPLC demixing provide good examples of not only the productivity gained by using fluorous techniques, but also the ease in which fluorous chemistry can be incorporated into advanced automation platforms.[3,4] The first paper described the method development for diversity-oriented synthesis (DOS) to produce hydantoin-, piperazinedione-, and benzodiazepinedione-fused ring systems 1–3. Each of these three heterocyclic scaffolds has four stereocenters on the central ring and up to four points of diversity (R1 to R4).
In the second paper, Drs. Daniel Kassel and Lu Zeng at Takeda San Diego in collaboration with FTI researchers describe how the above protocol could be adapted to fluorous mixture synthesis (FMS) of hydantoin- and benzodiazepinedione-fused libraries 1 and 2. As illustrated below, a hydantoin-fused tricyclic library was produced by FMS to provide 84 5-component mixtures of urea compounds. These mixtures were then demixed based on F-tag length utilizing prep-scale F-HPLC to ultimately provide 380 of the 420 desired compounds in >90% purity in 5-30 mg quantities. A MS-triggered 4-column parallel F-HPLC analytical method was developed to analyze 4 mixtures containing 20 samples in a single run of 5 min thereby significantly increasing overall throughput. The potential for prep-scale high throughput parallel demixing was also demonstrated by translating the analytical method to a single prep F-HPLC column. In this example, the productivity of solution phase library synthesis was greatly enhanced by combining the reaction efficiency of FMS with the separation efficiency of parallel HPLC.
The above ilustration shows the multichannel F-HPLC analysis of 4 five-component fluorous mixtures. Note that F-HPLC elutes materials in order of F-tag length and in a narrow retention time window regardless of substrate structure. Under these elution conditions, Rf2 (~1.3 min), Rf4 (~1.9 min), Rf6 (~2.8 min), Rf8 (~3.5 min) and Rf9 (~3.8 min).
References:
1. Seeberger, P.; et. al. Angew. Chem. Int. Ed. 2006, 45, 1-5.
2. Hu, G. ; et. al. Journal of Colloid and Interface Science, 301, 2006, 697-702.
3. Zhang, W.; Lu, Y.; Chen, C. H.-T.; Curran, D. P.; Geib, S. Eur. J. Org. Chem. 2006, 2055-2059.
4. Zhang, W.; Lu, Y.; Chen, C. H.-T. Zeng, L.; Kassel, D. B. J. Comb. Chem. 2006, 8, 687-69