Solid-phase organic chemistry

An important tool for the fast characterization of intermediates and products in solution-phase synthesis are vibrational spectroscopic techniques such as Fourier transform infrared (FTIR) or Raman spectroscopy. These concepts have also been successfully applied to solid-phase organic chemistry. A single bead often suffices to acquire vibrational spectra that allow for qualitative and quantitative analysis of reaction products,3 reaction kinetics,4 or for decoding combinatorial libraries.5... 

The 1,2-addition in solid-phase organic chemistry is also known for the addition to alkenes [258], alkynes [120], carbonyl groups [259] and imines [260]. 

The preparation of five-membered rings in solid-phase organic chemistry has been reported in several publications. Versatile syntheses of these heterocycles with different numbers and kinds of heteroatoms have been described. The synthesis of five-membered rings containing one nitrogen atom (Fig. 3.6) as pyrrolidines (231) [311-316] pyrroles (232) [317-320] pyrrolidinones (233) [321-323] pyr-rolinones (234) [324—326] 2,5-pyrrolidinediones (235) [327-329] 2,4-pyrrolidine-diones (236) [330-332] 2,5-pyrrolinediones (237) [333] or heterocycles with one oxygen or one sulfur atom like tetrahydrofurans (238) [334—336] 2,5-dihydrofurans (239) [337], furans (240) [338, 339], yS-lactones (241) [340-343], 2,5-dihydrofura-nones (242) [344] (Scheme 3.35) and thiophenes (243) [345, 346] can be accomplished on solid supports. 

While much of the application of HRMAS to solid-phase organic chemistry has been via H NMR, 13C HRMAS NMR has been used to determine resin loading.78 Two methods were applied, using both internal standards added to the resin in known amounts, or using features of the resin structure itself as a standard for calibration of the spectral intensities. The first method... 

The first applications of solid phase synthesis were to peptides, hence it is no surprise that there have been several reports of HRMAS studies of peptide systems attached to a support. One of the earliest reports of HRMAS in a supported sample was that of Wang-bound lysine, whose structure was determined by TOCSY and HMQC HRMAS NMR.38 More recently, HRMAS NMR has been used to identify several peptidomimetic inhibitors of hepatitis C virus NS3 protease while on the resin.79 However, it is perhaps a bit surprising that more has not been made of HRMAS in attacking problems of relevance to peptide synthesis, although most recent interest is moving that way. Combinatorial chemistry and solid phase organic chemistry has been a much more active area using HRMAS techniques. 

P. Rousselot-Pailley, D. Maux, J. M. Wieruszeski, J. L. Aubagnac, J. Martinez and G. Lippens, Impurity detection in solid-phase organic chemistry Scope and limits of HR MAS NMR,... 

M. Gr0tH, . H. Gotfredsen, J. Rademann, J. Buchardt, A. J. Clark, J. O. Duus and M. Meldal, Physical properties of polyethylene glycol) (PEG)-based resins for combinatorial solid phase organic chemistry A comparison of PEG-cross-linked and PEG-grafted resins, J. Comb. Chem., 2000, 2, 108 119. 

Gosselin, F. Di Renzo, M. Ellis, T. H. Lubell, W. D. Photoacoustic FTIR Spectroscopy, a Nondestructive Method for Sensitive Analysis of Solid-Phase Organic Chemistry, J. Org. Chem. 1996, 61, 7980. 

Advanced Chemtech Handbook of Combinatorial and Solid-Phase Organic Chemistry, Louisville, USA, 1998. 

We are currently witnessing an explosive growth of solid-phase synthetic chemistry. In the years 1999 and 2000 approximately 700 articles were published, describing new synthetic sequences performed on insoluble supports. Almost all important organic reactions have now been carried out on solid phase, and the limits of solid-phase organic chemistry are becoming increasingly clear. 

Solid-phase organic chemistry (SPOC) has undergone a resurgence in recent years, largely brought on by its application to combinatorial chemistry. The solution-phase chemist has had for some time a number of excellent collections on available reactions. The solid-phase chemist has not had access to a similar comprehensive collection, although a few excellent reviews have been published (see the Reviews section). 

Gosselin F, Di Renzo M, Ellis TH, Lubell WD, Photoacoustic FTIR spectroscopy, a nondestructive method for sensitive analysis of solid-phase organic chemistry, J. Org. Chem., 61 7980-7981, 1996. 

Recently, the Suzuki reaction has been extensively developed for solid-phase organic chemistry as a method allowing the parallel synthesis of potential medicinal compounds [108]. Chan et al. reported a versatile polymer-supported 4-[4-methylphenyl(chloro)methyl]-phenoxy linker for the solid-phase synthesis of pseudopeptides based on the Suzuki coupling (Eq. (67)) [109],... 

Because no sample preparation is required, photoacoustic spectroscopy can be used to examine a sequence of reactions on the same resin sample without product loss (18). Concerning sensitive spectroscopic analysis of solid phase organic chemistry, photoacoustic spectroscopy offers a convenient, nondestructive alternative method to other IR techniques. 

Cyclatii/e Cleoi/age A Versatile Concept in Solid-Phase Organic Chemistry... 

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