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CEOverture...
Supports, tags, purification handles- call them what you want, but the upshot is that life science researchers need easy ways to quickly separate materials of value away from complex mixtures. Polymeric beads dominate the field of medicinal chemistry, but the limitations are well-known: variable activity, poor mixing, difficult in-process analysis and lack of scalability are most often cited. Fluorous technology presents a technological alternative that addresses all of these while maintaining a straightforward purification process. In this installment of our Technical Newsletter, we’ve combined recent published findings in the area of fluorous supports with a summary of FTI’s offering. Capping things off we have a new patent to present and a summer sales promotion, so read on, dear colleague, and be sure and let us know if we can ever be of assistance with your research.
Cheers,
Phil
Philip E. Yeske
President & CEO
New Fluorous Patent
We are pleased to announce that US Patent 7,060,850 “Fluorous Tagging and Scavenging Reactants and Methods of Synthesis and Use Thereof” issued to FTI in June 2006. The patent broadly covers the use of fluorous tagging compounds and fluorous scavenging compounds to increase the fluorous nature of organic compounds. The increased fluorous nature facilitates the separation of fluorous tagged from untagged components of a reaction mixture and allows for subsequent chemical transformations to be performed without loss of the fluorous tagged organic compound. The fluorous tag can be easily removed from the organic compound which may then find use in a variety of applications, including drug discovery and systems biology.
“This patent, the first ever issued to FTI, represents a significant broadening of our intellectual property coverage and affirms our company’s leading position in the commercialization of this important technology” said Dr. Philip E. Yeske, President and Chief Executive Officer of Fluorous Technologies.
Latest Developments in Fluorous Tagging
In the development of new fluorous protecting groups for diversity-oriented synthesis of biologically-attractive bisindol derivatives (Kasahara, T. and Kondo, Y. Chem. Commn. 2006, 891-893), F-sulfonyl and F-BnBr tags were used to protect boronate-functionalized indoles. The authors opted to use the fluorous approach due to the difficulties encountered by the limited monitoring of the reaction which is often seen in optimizing the solid phase synthesis of bisindol derivatives using a Pd-catalyzed cross coupling reaction. The use of fluorous tagged molecules allowed for effective reaction monitoring since these fluorous compounds can be treated like typical soluble organic molecules. The reactions were followed by TLC analysis with normal or fluorous silica gel TLC plates and the intermediates and final products were purified by F-SPE. A series of bisindolyl-attached heterocycle scaffolds were easily synthesized by consecutive Pd-catalyzed cross-coupling reactions when utilizing the fluorous tags and fluorous purification techniques.
Another major application of fluorous protecting groups is for fluorous mixture synthesis (FMS). Fluorous silyl groups with varying lengths of Rf chains have been used to protect the hydroxyl group in the FMS of four stereoisomers of (-)-dictyostatin (Curran, D. P. et al. Org. Lett. 2006, 8, 301-304). (-)-Dictyostatin is a sponge-derived macrolactone that exhibits potent anticancer activity. All four C6,C7 stereoisomers of (-)-dictyostatin were desired in order to evaluate their activity. Curran et. al. were faced with the completion of a 22-25 step synthesis to make each of the target stereoisomers, but by utilizing FMS all four C6,C7 isomers were completed in a single set of operations. In this example of FMS, 22 steps were conducted, whereas conducting the same syntheses in parallel to provide the four target products would have required 88 steps. Subsequent analysis found that C6 epi-dictyostatin was 4 times more potent than (-)-dictyostatin. In short, FMS can be used in a complex total synthesis by providing more compounds without a proportional increase in work. Demixing by fluorous HPLC provided the opportunity to not only analyze and characterize the intermediate mixtures but also to obtain the pure target products through the final demixing step.
Fluorous Protecting Groups
Fluorous protecting groups [1] have been used successfully in medicinal chemistry and compound library synthesis for several years, and FTI has a wide range of products available to serve this market. Fluorous tagged intermediates can be analyzed by conventional tools such as TLC, LC-MS, and NMR. Purification of reaction mixtures can be facilitated by fluorous techniques such as solid-phase extraction (F-SPE) or liquid-liquid extraction (F-LLE). The conditions for fluorous protection and deprotection are similar to the corresponding normal protecting groups.
- Fluorous Silane is the fluorous equivalent of TIPS and exhibits properties similar to most silicon protecting groups and has been used in both parallel and fluorous mixture synthesis. Tagging of an alcohol is done by in situ activation of the F-Silane to either the bromide or triflate followed by addition of the alcohol. Detagging can be accomplished by treatment with an acid or fluoride. [2]
- Fluorous BOC-ON is primarily used in the protection of amines and in the protection of amino acid side chains (His, Lys, Trp). It is acid labile but stable to a wide range of basic and nucleophilic conditions. F-BOC-ON can be used in tagging of diverse organic molecules and is easily purified through F-SPE. [3]
- Fluorous Cbz-OSu is used primarily in the protection of amino groups in peptide or multi-step organic synthesis. Deprotection is achieved under the same conditions as traditional Cbz, such as hydrogenation or hydride reduction. [4]
- F-PMB-OH is used in protecting alcohols in multi-step organic synthesis and can be deprotected either under acidic or oxidizing conditions. The reactivity of the F-PMB and conventional PMB are so similar that a DMB protecting group has been selectively cleaved in the presence of both reagents. [5]
- F-Benzyl Alcohol tagging of carboxylic acids and alcohols is conducted analogously to traditional benzyl alcohol. [6]
- FluoMar® is the solution phase equivalent of Marshall resin used in combinatorial and parallel synthesis as a stable acid activator for the formation of amides. [7]
- Fluorous t-Butanol is used as a protecting group for carboxylic acids in organic synthesis. [8]
Suggested References
1. Zhang, W. “Fluorous Tagging Strategy for Solution-Phase Synthesis of Small Molecules, Peptides
and Oligosaccharides” Curr. Opin. Drug Disc. Dev. 2004, 7, 784-797.
2. Zhang, W.; Luo, Z.; Chen, C. H.-T.; Curran, D. P. J. Am. Chem. Soc. 2002, 124, 10443-10450.
3. Luo, Z.Y.; Williams J., Read, R. W.; Curran D. P: J. Org. Chem. 2001, 66, 4261-4266.
4. Curran, D. P., Amatore, M.; Guthrie, D.; Campbell, M.; Go, E.; Luo, Z. S. J. Org. Chem. 2003, 68,
4643-4647.
5. Curran, D. P.; Furukawa, T. Org. Lett. 2002, 4, 2233-223.
6. Curran, D. P.; Oderaotoshi, Y. Tetrahedron 2001, 57, 5243-5253.
7. Chen, C. H.-T.; Zhang, W. Org. Lett. 2003, 5, 1015-1017.
8. Pardo, J.; Cobas, A.; Guitian, E.; Castedo, L. Org. Lett. 2001, 3, 3711-3714.
Promotion on Fluorous Protecting Groups
You’ve read the summary, maybe even heard the buzz- are you ready to try fluorous supported chemistry? Place an order for one or more of the fluorous tags shown above between now and August 15, 2006, and we’ll discount your order; 10% on a 2g purchase quantity, 25% on 10g or 25g! We look forward to seeing your purchase order soon. Be sure to mention the Protecting Group Promotion
when you order.
Just a Reminder...Our Fluorous Sorbent Promotion continues through the end of July
To encourage you to try fluorous purification techniques in your lab, we’re offering a great deal through the end of July on any of our standard sorbent products- just place a purchase order for sorbent products of more than $250 at list price and we’ll apply a 30% discount, plus we’ll throw in a free 10-pack of F-TLC plates (a $90 value!). Be sure to mention the Summer Sorbent Promotion when you order.