Fluorous mixture synthesis

A stereoisomer library of 16 murisoUn analogues was recently reported and early in 2005, an FMS strategy for the production of cyclopentenone scaffolds with Pauson-Khand-type reactions was published.  

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Fluorous Mixture Synthesis of Fused-Tricyclic Hydantoins. 114... 

Fig. 32 Fluorous mixture synthesis of fused-tricyclic hydantoins. Reagents and conditions a Mo(CO)6, DMSO, toluene, MW 150 °C, 35 min, closed system b TFA CH2CI2 (1 1), rt c PhC2H4NH2, PyBOP, i-Pr2EtN, MeOH, CH2CI2 followed by flash chromatography and F-HPLC d i-Pr2EtN, MeOH, MW 140 °C, 40 min, followed by F-SPE...

The application of fluorous mixture synthesis (FMS) for deriving natural products and their stereoisomers was demonstrated by the total synthesis of all 16 stereoisomers of the pine sawfly sex pheromoned ... 

Figure 1 Representative scheme for fluorous mixture synthesis...

Z. Luo, Q. Zhang, Y. Oderaotoshi, and D. P. Curran, Fluorous mixture synthesis A fluorous-tagging strategy for the synthesis and separation of mixtures of organic compounds, Science, 291 (2001), 1766-1769. 

W. Zhang, Y. Lu, C. H.-T. Chen, L. Zeng, and D. B. Kassel, Fluorous Mixture Synthesis of Two Libraries with Hydrantoin-, and Benzodiazepinedione-Fused Heterocyclic Scaffolds, / Comb. Chem. 8 (2006), 687-695. 

Fluorous Mixture Synthesis (FMS) of Drug-like Molecules and Enantiomers, Stereoisomers, and Analogues of Natural Products... 

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],... 

Fluorous mixture synthesis consists of the following general steps (see Scheme 13.1). 

Source Reproduced with permission from Zhang W., Luo, Z, Chen, C. H.-T. Curran, D. Solution-Phase Preparation of A 560-compound library of individually pure mappicine analogs by fluorous mixture synthesis, J. Am. Chem.Soc. (2002) 124, 10443-10450. Copyright (2002) American Chemical Society.)... 

D. B., Fluorous mixture synthesis of two libraries with hydantoin- and benzodiazepinedione-fused heterocyclic scaffolds, J. Comb. Chem. (2006) 8, 687-695. Copyright (2006) American Chemical Society.)... 

A short review article on FMS Zhang, W. (2004) Fluorous mixture synthesis (FMS) of enantiomers, diastereomers, and compound libraries. Arkivoc, (i) 101-109. 

Curran, D. P. and Oderaotoshi, Y. (2001) Thiol additions to acrylates by fluorous mixture synthesis Relative control of elution order in demixing by the fluorous tag and the thiol substituent. Tetrahedron, 57, 5243-5253. 

Dandapani, S., Jeske, M. and Curran, D. P. (2005) Synthesis of all 16 stereoisomers of pinesaw fly sex pheromones tools and tactics for solving problems in fluorous mixture synthesis. J. Org. Chem., 70, 9447-9462. 

Yang, F. and Curran, D. R (2006) Structure assignment of lagunapyrone b by fluorous mixture synthesis of four candidate stereoisomers. J. Am. Chem. Soc., 128, 14200-14205. 

Curran, D. P. and Furukawa, T. (2002) Simultaneous preparation of four truncated analogues of discodermolide by fluorous mixture synthesis. Org. Lett., 4, 2233-2235. 

Manku, S. and Curran, D. P. (2005) Fluorous mixture synthesis of 4-alkylidene cyclopentenones via a rhodium-catalyzed [2 + 2 + 1] cycloaddition of alkynyl allenes. J. Comb. Chem., 7, 63-68. 

This concept of fluorous mixture synthesis has been used and extended for the preparation of compound libraries of interest in medicinal chemistry [17, 20-22]. 

The introduction of additional substituent groups in combination with the discriminating perfluoroalkyl labels during the synthetic sequence enables convenient preparation and subsequent separation of relatively large libraries. For the library of 100 mappicine derivatives outlined in Scheme 3.20, 300 reactions would be required for the conventional, sequential approach. By application of fluorous mixture synthesis this was condensed into 26 steps. In addition, four tagging and 100 detagging operations are required to obtain the full, unprotected 100-member library from unprotected starting materials. 

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