Liquid combinatorial synthesis

Liquid- and Liquid/Liquid-phase Reactions Serial combinatorial synthesis... 

Wu and Sun have presented a versatile procedure for the liquid-phase synthesis of 1,2, ,4-tctrahydro-/i-carbolines [77]. After successful esterification of the MeO-PEG-OH utilized with Fmoc-protected tryptophan, one-pot cyclocondensations with various ketones and aldehydes were performed under microwave irradiation (Scheme 7.68). The desired products were released from the soluble support in good yields and high purity. The interest in this particular scaffold is due to the fact that the l,2,3,4-tetrahydro-/f-carboline pharmacophore is known to be an important structural element in several natural alkaloids, and that the template possesses multiple sites for combinatorial modifications. The microwave-assisted liquid-phase protocol furnished purer products than homogeneous protocols and product isolation/ purification was certainly simplified. 

The first use of room temperature ionic liquids as potential novel soluble phases for combinatorial synthesis has recently been described. As model reaction the Knoevenagel condensation of salicyl aldehyde grafted on to an imidazolium-derived ionic liquid was studied under the action of microwave irradiation (Scheme 12.19) [66]. Reactions were performed without additional solvent in the presence of a basic catalyst, utilizing microwave irradiation in a designated monomode microwave reac-... 

D. P. Curran, S. Hadida, Tris(2-(Perfluorohexyl)tin Hybride A New Fluorous Reagent for Use in Traditional Organic Synthesis and Liquid Phase Combinatorial Synthesis , J. Am. Chem. Soc 1996,118,2531. 

Curran, D. P. Hoshino, M. Stille Couplings with Fluorous Tin Reactants— Attractive Features for Preparative Organic Synthesis and Liquid Phase Combinatorial Synthesis, J. Org. Chem. 1996, 61, 6480-6481. 

Bendale, P.M. and Sun, C.-M., Rapid microwave-assisted liquid-phase combinatorial synthesis of 2-(arylamino)benzimidazoles, /. Comb. Chem., 2002, 4, 359-361. 

As part of an efficient, facile and practical liquid-phase combinatorial synthesis of benzimidazoles under microwave irradiation, the reduction of a polymer bound o -nitroaniline with zinc metal in methanol was completed in a very short time (2 min)61 (Scheme 4.33). However, no detailed reaction conditions were given. 

The first monolithic materials initially emerged in the 1960s, but it is during the last 20 years that monoliths have been intensively developed in a variety of fields and particularly in analytical chemistry for separation techniques. Nowadays, these macroporous materials are widely used and have found numerous applications in different chromatographic modes such as liquid chromatography (LC) or CEC, as indicated by several reviews [150, 151]. Less commonly, monolithic materials can also be applied, for example, to solid-phase extraction, combinatorial synthesis and for enzyme immobilisation. 

A demonstration of liquid-phase combinatorial synthesis was recently introduced whereby the highly soluble, but highly crystalline, monomethyl polyethylene glycol (PEG) was employed to allow solution synthesis of a peptide library and solid phase-like purification by a change to a solvent where the PEG was insoluble. The demonstration penta-peptide library yielded the expected anti-P-endorphin binding sequence [65]... 

Song, G., Cai, Y., and Peng, Y. (2005) Amino-functionalized ionic liquid as a nucleophilic scavenger in solution phase combinatorial synthesis./. Comb. Chem., 7, 561-566. 

Han H, Wolfe MM, Brenner S, Janda KD, Liquid-phase combinatorial synthesis. Proc. Natl. Acad. Sci. USA, 92 6419-6423, 1995. 

The concept of liquid-phase combinatorial synthesis (LPCS) was introduced by Han et al. [171] in a paper where a peptide and a sulfonamide libraries were prepared using PEG (polyethylene glycol) as support. The support was chosen because of its successful application in peptide, oligosaccharide and... 

Curran DP, Hoshino M, Stille couplings with fluorous tin reactants Attractive features for preparative organic synthesis and liquid-phase combinatorial synthesis, J. Org. Chem., 61 6480-6481, 1996. 

Yandersteen, AM, Han H, Janda KD, Liquid-phase combinatorial synthesis In search of small-molecule enzyme mimics, Mol. Diversity, 2 89-96, 1996. 

Raecker R, Doering K, Reiser O, Combinatorial liquid-phase synthesis of [l,4]oxazepine-7-ones via the Baylis-Hillman reaction, J. Org. Chem., 65 6932-6939, 2000. 

Figure 3. Liquid phase combinatorial synthesis (LPCS) and recursive deconvolution.

Soluble PEG supports have been used for different applications such as the synthesis of peptides (241, 245) and peptidomimetics (246) soluble-supported catalysts (247-249), reagents (250-253), scavengers (254), and traceless linkers (255-257) to improve purification protocols (258, 259) and high-loading PEG-derived soluble supports (260), particularly in the synthesis of arrays of small organic molecules (261-275). Several recent reviews (276-281) illustrate their usefulness but also show how additional efforts could make PEG liquid-phase combinatorial synthesis more reliable. 

Each L13 individual was evaluated as a potential soluble support in liquid-phase combinatorial synthesis. A great variation in the solubility profiles was observed for the 20 copolymers, the most relevant of which are reported in Table 11.2. The copolymer Mi,2-M2,3 was selected, being very soluble in apolar solvents such as THE and diethyl ether, insoluble in polar solvents such as water and alcohol, and nonswelling in any solvent. It thus resulted complementary to PEG-based supports and... 

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