Phase tagging

Finally, the introduction of focused microwave instruments further enabled to speed up the synthesis of libraries, by reducing the actual time needed for reaction [28-34]. The combination of using dedicated microwave instruments and sohd or solution phase tagging subsequently became a very powerful tool for PASP and SPOS apphcations [25,26,33-51]. 

For this purpose, perfluorooctanesulfonyl-tagged benzaldehydes were reacted with 1.1 equivalents of a 2-aminopyridine (or 2-aminopyrazine), 1.2 equivalents of an isonitrile, and a catalytic amount of scandium(III) triflate [Sc(OTf)3] under micro-wave irradiation in a mixture of dichloromethane and methanol (Scheme 7.85). A ramp time of 2 min was employed to achieve the pre-set temperature, and then the reaction mixture was maintained at the final temperature for a further 10 min. The fluorous tag constitutes a multifunctional tool in this reaction, protecting the phenol in the condensation step, being the phase tag for purification, and serving as an acti-... 

Fig. 13. Calibration curve of phase-tag for the heat wave propagation in nickel foil. Chopping frequency 27.6 Hz. See text for other experimental detail...

An der Heiden, M. and Plenio, H. (2004) Homogeneous catalysts supported on soluble polymers biphasic Suzuki— Miyaura coupling of aryl chlorides using phase-tagged palladium—phosphine catalysts. Chem. Ear. ]., 10, 1789. 

A diphenylprolinol derivative, having hydrophobic perfluoroalkyl phase tags, has been synthesized and used as a pre-catalyst to generate in situ a fluorous oxaz-aborolidine catalyst for the reduction of prochiral ketones with borohydride. The system afforded high enantioselectivities and the pre-catalyst is easily separated and recycled.272 Reduction of enantiopure A-p-toluenesulfinyl ketimines derived from 2-pyridyl ketones with sodium borohydride affords A-p-toluenesulfinylamines with good yields and diastereoselectivities.273... 

Scheme 8. Phase-tagged phosphines as ligands in Pd-catalyzed cross-coupling reactions.

The mild, neutral electron-transfer conditions associated with the use of Sml2 make the reagent ideal for the selective cleavage of linkers in solid-phase organic synthesis and other types of phase tag-assisted synthesis. 

Unprotected Oligosaccharides as Phase Tags for Solution-Phase Glycopeptide Synthesis with Solid-Phase Workup... 

In this synthetic scheme, the reactions for peptide elongation are carried out in homogeneous solutions, while the product of each reaction is isolated and briefly purified in solid form with free oligosaccharides serving as phase tags. It... 

Phase-switching strategy was applied to the multistep synthesis of isoxazolines 45-47. The approach exploits the boronic acid functionality as a phase-tag which can be easily immobilized on diethanolaminomethyl polystyrene (DEAM-PS) resin and then released by treatment with wet THF. Each reaction step was carried out in solution and the products were purified by addition of the scavenging resin, followed by filtration, washing of the supported material, hydrolytic release and evaporation. Finally, the boronic acid could be used to introduce additional substituents on the molecule. For example, 46 was converted into the biaryl-containing isoxazoline 47 by a Suzuki cross-coupling reaction <07JCO193>. 

A somewhat different approach was used by Vincent in phase-switching reactions using pyridyl-labelled substrates and products. The pyridyl-containing tag is here thought of as a masked phase tag, which allows for phase switching with the help of a heavy fluorous copper(ll)-carboxylate complex. Comparison with a non-fluorous system indicated that a problem of release of the strongly coordinating pyridine linker was avoided in the fluorous approach. ... 

W. J. Qian, M. B. Goshe, D. G. Camp II, L.-R. Yu, K. Tang, and R. D. Smith, Phos-phoprotein isotope-coded solid-phase tag approach for enrichment and quantitative analysis of phosphopeptides from complex mixtures, A aZ. Chem.15 (2003), 5441-5450. 

Wen, S, Guo, Z, Unprotected oligosaccharides as phase tags solution-phase synthesis of glycopeptides with sohd-phase workups, Org. Lett., 3, 3773-3776, 2001. 

Fluorous chemistry integrates the characteristics of solution-phase reactions and the phase tag strategy developed for solid-phase chemistry [7-15], Perfluoroalkyl chains instead of polymer beads are used as the phase tags to facilitate the separation process. In 2001 the Curran group first reported the concept of fluorous mixture synthesis (FMS) for solution-phase library synthesis [16], FMS is able to produce individual pure compounds without the effort of deconvolution. It adapts literature procedures to synthesize complex natural products, their enantiomers and diastereomers. FMS can also be used for the development of new synthetic protocols and to make novel drug-like molecules [17, 18],... 

Enantiopure or enantioenriched compounds can be obtained by asymmetric synthesis or by separation of a racemic reaction mixture. Quasi-racemic FMS provides a new approach to enantiomeric compounds (see Scheme 13.2) [26, 27]. Quasi-racemic synthesis starts with two individual R- and 5-enantiomers attached to two different fluorous tags. After steps of mixture synthesis followed by F-HPLC demixing and detagging, two individual products as enantiomers are obtained (see Sections 13.2.1 and 13.2.2). The separation and identification of the final quasi-enantiomers are ensured by the phase-tag-based F-HPLC. In a more complicated quasi-racemic FMS, additional enantiomerically pure building blocks and fluorous tags can be used to generate more chiral centers and more than two products as stereoisomers (see Sections 13.2.3 to 13.2.8). 

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