Rapid parallel synthesis

For a complete optimization of all factors, the above-described procedure is not practical. In order to perform this rapidly, parallel synthesis and screening techniques must be developed. These can consist of a scaled-down version of the MIPs in vials that can be handled automatically and analyzed in situ (Fig. 6-13) [85, 86]. 

In a dedicated combinatorial approach, Strohmeier and Kappe have reported the rapid parallel synthesis of polymer-bound enones [33]. This approach involved a two-step protocol utilizing initial high-speed acetoacetylation of Wang resin with a selection of common /i-ketoesters (Scheme 7.13) and subsequent microwave-mediated Knoevenagel condensations with a set of 13 different aldehydes (see Section 7.3.6). 

B. M. Glass, A. P. Combs, Case Study 4-6 Rapid Parallel Synthesis Utilizing Micro-wave Irradiation, in High-Throughput Synthesis. Principles and Practices (Ed. I. Sucholeiki), Marcel Dekker, Inc., New York, 2001, Chapter 4.6, pp 123—128. 

B. M. Glass, A. P. Combs, Rapid Parallel Synthesis Utilizing Microwave Irradiation Article E0027, Fifth International Electronic Conference on Synthetic Organic Chemistry" (Eds. C. O. Kappe, P. Merino, A. Marzinzik, H. Wennemers, T. Wirth, J. J. Vanden Eynde, S.-K. Lin), CD-ROM edition,... 

D. P. Curran, Z. Luo, Rapid, Parallel Synthesis of Homo-allylic Alcohols by Lewis Acid Mediated Allylations of Aldehydes with New Fluorous Allyl Stannanes , Med Chem. Res. 1998, 8,261. 

An efficient synthesis of 2-amino derivatives 256 is depicted in Scheme 70 2-halopyridines are first Ar-alkylated with various halides under microwave activation and next reacted with cyanamide under basic conditions <1999T2317>. A rapid parallel synthesis of derivatives bearing a benzoyl substituent at C-3 based on this reaction has been described <2002SL1544>. 

We chose to study the generation of alkoxycarbenium ion 26 from thioacetal 28. The electrochemically generated ArS(ArSSAr)+, 37 which was well characterized by CSI-MS, was found to be quite effective for the generation of alkoxycarbenium ions, presumably because of its high thiophilicity (Scheme 17). The conversion of 28 to 26 requires 5 min at -78 °C. The alkoxycarbenium ion pool 26 thus obtained exhibited similar stability and reactivity to that obtained with the direct electrochemical method. The indirect cation pool method serves a powerful tool not only for mechanistic studies on highly reactive cations but also for rapid parallel synthesis. 

Glass, B.M. and Combs, A.P., Case study 4-6 rapid parallel synthesis utilizing microwave irradiation, In Sucholeiki, I. (Ed.), High-Throughput Synthesis. Principles and Practices, Marcel Dekker, New York, 2001, Ch. 4.6, pp. 123-128,... 

Strohmeier, G.A. and Kappe, C.O., Rapid parallel synthesis of polymer-bound enones utilizing microwave-assisted solid phase chemistry, /. Comb. Chem., 2002, 4, 154-161. 

Senten K, Daniels L, Van der Veken P, De Meester 1, Lambeir 69. A-M, Scharpe S, Haemers A, Augustyns K. Rapid parallel synthesis of dipeptide diphenyl phosphonate esters as inhibitors of dipeptidyl peptidases. J. Comb. Chem. 2003 5 336-344. 70. 

The screening of single compounds in solution necessitates that the synthesis of the compound libraries are conducted in an array format. This is often termed rapid parallel synthesis. As mentioned above, either solution phase or solid phase synthetic methods may be used. Certain of the pioneering companies developed their own proprietary apparatus for automated... 

Rogers-Evans M, Alanine Al, Bleicher KH et al (2004) Identification of novel cannabinoid receptor ligands via evolutionary de novo design and rapid parallel synthesis. QSAR Comb Sci 23 426-430... 

If identifying an active pool of molecule is easy, identifying the active component within this pool in a reliable and meaningful way is very difficult. Thus, interest in combinatorial synthesis has gradually decreased because of the lengthy and uncertain hit identification process. Even though this trend might be reverted in the future, currently most of the combinatorial approaches focus on rapid parallel synthesis of individual compounds. 

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