Serial combinatorial synthesis

OS 30] ]R 30] [P 22] The synthesis of nine C-C bonded products was made from four carbamates and five silyl enol ethers [66, 67]. Conversions ranged from 49 to 69% the corresponding selectivities ranged from 67 to 100%. Similar performance was achieved when serially processing the same reactions (see Serial combinatorial synthesis). 

Figure 4.46 Schematic of serial combinatorial synthesis for creating a cation pool from diverse carbamates and silyl enol ethers [66. ...

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

OS 30] [R 30] [P 22] By simple flow switching, serial combinatorial synthesis for creating a cation pool from diverse carbamates and silyl enol ethers was accomplished (Figure 4.46) [66, 67]. The conversions and selectivities were comparable to continuous processing using three feed streams only (see Conversion/yield/selec-tivity, above). 

Serial Combinatorial Synthesis Based on the Cation Flow Method... 

Figure 4.3 Serial combinatorial synthesis based on the cation flow method. (a) Schematic diagram (b) example based on the reaction of N-acyliminium ion pools with carbon nucleophiles...

The examples shown in this review article demonstrate that a variety of methods for polymer synthesis have been developed in flow microreactors. Continuous flow synthesis enables serial combinatorial synthesis, in which a variety of polymers can be synthesized in a sequential way using a single flow reactor with a flow switch. Space integration, which enables the synthesis of structurally well-defined polymers without isolating living polymer ends, also enhances the power and speed of polymer synthesis. Because several test plants for continuous production have already been built, there is no doubt that flow microreactors can contribute to polymer production in industry. 

Figure 7.6 Continuous serial combinatorial synthesis using the cation flow system.

Figure 9.7 Serial combinatorial synthesis based on the cation flow method.

The major impetus for the development of solid phase synthesis centers around applications in combinatorial chemistry. The notion that new drug leads and catalysts can be discovered in a high tiuoughput fashion has been demonstrated many times over as is evidenced from the number of publications that have arisen (see references at the end of this chapter). A number of )proaches to combinatorial chemistry exist. These include the split-mix method, serial techniques and parallel methods to generate libraries of compounds. The advances in combinatorial chemistry are also accompani by sophisticated methods in deconvolution and identification of compounds from libraries. In a number of cases, innovative hardware and software has been developed tor these purposes. 

As C-C bond formation is an important step in organic synthesis, particularly for pharmaceutical applications, it is useful to look for operation modes of chemical micro processing that allow one to carry out combinatorial chemistry investigations. As such, the serial introduction of multiple reactant streams by flow switching was identified [66,67]. The wide availability of precursors for acyiiminium cations has led to the expression cation pool [66, 67]. 

The focus of this chapter has been on the synthesis of new catalysts by parallel and combinatorial methods. Another aspect important to the development of new catalysts by these methods is the screening of these large libraries. We will not attempt to cover this topic comprehensively but do feel it is necessary to summarize some of the approaches that have been taken. Methods for screening libraries can be divided into both serial and parallel methods. Generally, the serial methods are adaptations of standard methods that allow for rapid individual analysis of each member of a library. Serial approaches for the analysis of libraries can be as simple as use of an auto sampler on a GC or HPLC system or as advanced as laser-induced resonance-enhanced multiphoton ionization of reaction products above the head-space of a catalyst (16) or microprobe sampling MS (63). The determination of en-antioselectivity in catalysis is a particular problem. Reetz et al. (64) reported the use of pseudoenantiomers and MS in the screening of enantioselective catalysis while Finn and co-workers (65) used diastereoselective derivatization followed by MS to measure ee. 

In order to overcome the synthesis bottleneck in drug discovery, the concept of preparing many compounds at one time (parallel synthesis) rather than one compound at a time (serial synthesis) was bom. In its simplest form, this distinction constitutes the definition of combinatorial chemistry. The origin of the concept has been ascribed (1) to Furka and others as early as 1982. Early applications of parallel synthesis methods were primarily in the area of peptide library synthesis and have been extensively reviewed (2,3). In the early 1990s, however, application to small drug-like molecules was reported (4) and the explosion in combinatorial chemistry activity began. 

Combinatorial approaches make it relatively straightforward to generate chemical libraries with vast number of new compounds thus synthesis is often no longer the rate-limiting step in drug discovery. Since almost all analytical characterization tools are serial techniques, the purification and analysis of the chemical libraries has instead become a new bottleneck. This, of course, imposes new analytical challenges in the fields associated with... 

The serial method based on continuous flow synthesis by simple flow switching is useful. Although the parallel method needs to use many reactors in parallel, the serial method needs to use only one flow reactor. Different substrates and/or reagents are fed sequentially to the inlets of the flow reactor and different products are produced sequentially at the outlet of the reactor. CtMitinuous operation of this system leads to synthesis of many different compounds in a combinatorial manner. 

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