Combinatorial Synthesis on Solid Phases

Microwave-assisted Combinatorial Synthesis on Solid Phases [12] 

Some of the notable examples of these Hbraries generated via a MW-assisted solid phase are given below. MulHcomponent reactions (MCRs), in which three or more reactants combine to give a single product, have received much attenhon owing to their elegance, simpHdty, and overaU efficiency in comparison to mulHs-tep syntheses. 

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SCHEME 14.16 Kunz s stereoselective Ugi combinatorial synthesis on solid phase. 

A hybrid between combinatorial synthesis on solid phase and in solution phase is the liquid-phase method characterized by the application of carrier polymers completely soluble in one solvent and insoluble in another solvent, for example functionalized polyethylene glycol [32,33]. 

Combinatorial synthesis on solid phase can be performed in any organic laboratory without any need for dedicated instrumentation. 

Oertel, K, Zech, G, Kunz, H, Stereoselective combinatorial Ugi-multicomponent synthesis on solid phase, Angew. Chem. Int. Ed., 39, 1431-1433, 2000. 

Now that combinatorial and parallel syntheses are available, the number of possible selectors for chiral stationary phases can be drastically increased. Selector synthesis on solid phases and the testing in 96-well plate format have been used to make the CSP-screening process more efficient (Welch, 1999 Murer, 1999 Wang, 2000 Bluhm, 2000 Svec 2001). 

Products/technologies For automation of combinatorial chemistry on solid phase in a modular approach, the OntoBlock central piece of hardware consists of 96 2-ml polymeric reaction vessels containing beads on which the synthesis takes place. From there the test components are stored, are characterized, or... 

As a source of novel chemical structures, natural products are now rivaled by the revolution that is combinatorial chemistry by which a vast number of compounds may be made from a relatively small number of starting compounds, or monomers (87). An alliance of natural products chemistry with combinatorial chemistry has resulted m the development of several libraries of natural product derivatives, using natural products as templates (88) and as targets for total synthesis on solid phase (89). Whereas natural products have often been the target or the starting point for synthetic chemists, the use of natural products as combinatorial chemistry monomers is likely to increase enormously the numbers of natural product-denved structures available for testing. 

B.xiv.c. Intermolecular Heck Reactions on Polymeric Support. Combinatorial chemistry has initiated a reappraisal and consequent renaissance in synthesis of compounds attached to polymeric supports. Therefore, it comes as no surprise that Pd-catalyzed reactions are among the most widely explored reactions for the generation of combinatorial libraries on solid phase. The first example of the intermolecular Heck reaction on solid phase was reported in 1994. In this article, 4-vinylbenzoic acid was attached to Wang resin and coupled with aryl halides/triflates under catalysis with Pd(OAc)2 (Scheme 45). Similar... 

Wang, H. and Ganesan, A., The V-acyhminium Pictet-Spengler condensation as a multicomponent combinatorial reaction on solid phase and its application to the synthesis of demethoxyfumitremorgin C analogs, Org. Lett., 1, 1647, 1999. 

Certain types of molecules, especially polypeptides and polynucleotides, lend themselves to synthesis on solid supports. In such syntheses, the starting material is attached to a small particle (bead) or a surface and the molecule remains attached during the course of the synthetic sequence. Solid phase synthesis also plays a key role in creation of combinatorial libraries, that is, collections of many molecules synthesized by a sequence of reactions in which the subunits are systematically varied to create a range of structures (molecular diversity). 

Tietze and coworkers developed two new domino approaches in the field of combinatorial chemistry, which are of interest for the synthesis of bioactive compounds. Combinatorial chemistry can be performed either on solid phase or in solution using parallel synthesis. The former approach has the advantage that purification of the products is simple and an excess of reagents can be used. This is not possible for reactions in solution, but on the other hand all known transformations can be used. The Tietze group has now developed a protocol which combines the... 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

These results demonstrate that O-glycosyl trichloroacetimidate-based oligosaccharide synthesis on solid support may eventually become a valuable alternative to solution-phase synthesis because useful experience is available for the selection of the polymer support and choice of the linker system and the glycosyl donor. Further standardization of the building blocks and the protective group pattern will finally provide the yields and the anomeric control in order to successfully plan automated syntheses of oligosaccharides also in a combinatorial manner. 

An important difference between combinatorial or parallel DOS and, for example, total synthesis is the high number of synthesized compounds, which renders conventional purification procedures such as flash chromatography impractical, at least if they have to be performed after every step. Synthesis on solid support avoids these problems to some extent if high conversions can be achieved with excess reagent or selective release strategies (see above). To do solution phase DOS, selective, high yield reactions or selective purification processes are required. 

In view of the multicomponent nature of the tandem [4 + 2] / [3 + 2] cycloaddition, the potential for a combinatorial approach to the synthesis of nitroso acetals has been investigated on solid-phase supports. The incorporation of either the dipolarophile or the starting nitroalkene on a Wang-type resin is compatible with the tandem cycloaddition promoted at high pressures (Schemes 2.28 and 2.29). The solid-supported nitroso acetals are subsequently liberated (in moderate yields from the staring nitroalkene) upon the addition of a catalytic amount of potassium cyanide in triethylamine and methanol or by reduction with lithium aluminum hydride (LAH) (261,264). 

Combinatorial chemistry and solid-phase synthesis have evolved in the last decade to become one of the most important techniques to save time for drug discovery. To reach its full potential, the solid-phase synthesis has to incorporate many versatile organometallic reactions developed over recent several decades. The first example of the Nicholas reaction on solid phase was reported by Kann and his co-workers in 2002, which involves the reaction of polymer-bound cobalt complexes 51 with various carbon-centered nucleophiles in the presence of a Lewis acid to... 

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. 

As mentioned in the introduction, typically one of the most time-consuming steps in the synthesis of a combinatorial library by solid-phase methods is demonstrating the feasibility and generality of the synthesis of a particular core structure on resin. Hence a strategy wherein the synthetic transformations, once developed and optimized, can subsequently be reused in different contexts to produce an array of different compound classes has considerable merit. Having initially invested a considerable amount of time in establishing the practicability of the first scaffold chemistry (the ben-... 

The advent of combinatorial techniques and solid phase organic synthesis may lead to preparation of large numbers of structurally related molecules in short periods of time. This is important especially for the optimization of lead structures in the pharmaceutical industry [40]. It is now well established and documented that the combinatorial technology and solid phase techniques could offer sufficient latitude for preparation of corresponding chemical libraries with broad structural diversity. The diverse potentiality of (3-lactam moiety as specific pharmacophores and scaffolds has attracted ample interests from pharmaceutical industries for the synthetic methods based on polymer-supported techniques. 

In continuation of the research on solid-phase synthesis of biologically interesting (3-lactam compounds towards the development of combinatorial libraries, Mata et al. [102] investigated use of 2-chloro-l-methylpyridinium iodide (Mukaiyama s reagent) as a key reagent for the construction of the (3-lactam ring in a stereoselective manner. The popular explanation involves the reaction of ketene B with the imine to form a zwitterionic intermediate D (Scheme 13). Alternatively, it is the activated acid A that acylates the imine to form the zwitterion D by abstraction of proton with... 

Asymmetric synthesis on solid support is crucial for the generation of combinatorial libraries of novel optically active carbacephems and other polycyclic p-lactam derivatives [44]. Solid-phase Staudinger reaction of the homochiral... 

The algorithm described above is for a three-step combinatorial synthesis. However, the method is not limited to only three-step combinatorial libraries the solid-phase support can be derivatized before the directed split-and-pool synthesis on the Encore synthesizer. The necklace coding can also be a very useful tool during the chemistry development process. 

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