Multi-step library synthesis

Another exemplar of the power of multi-step library synthesis is the optimisation of a PDE2 inhibitor HTS hit (Scheme 18.36). The HTS hit itself was derived from a library that was synthesised to enrich the Pfizer screening collection. Key steps in the library synthesis involved reaction of the commercial dichloro pyrazine H with a range of alcohols, followed by reaction of the intermediate chloroalkyoxy pyrazine with hydrazine. Finally, the hydrazine pyridazine I was reacted with a number of aldehydes under oxidative conditions to form the triazolo pyrazine derivatives. This library allowed the project team to find key SAR directions for improvinbg selectivity vs. other PDEs. ... 

I 2 Supported Reagents and Scavengers in Multi-step Organic Synthesis Automated library synthesis using solid-supported reagents... 

Ley, S.V., Baxendale, I.R., Bream, R.N., Jackson, P.S., Leach, A.G. etal, Multi-step organic synthesis using solid-supported reagents and scavengers a new paradigm in chemical library generation, J. Chem. Soc, Perkin Trans. 1, 2000, 3815. 

Salvino JM, Kumar NV, Orton E, Airey J, Kiesow T, Crawford K., Mathew R, KroUkowski P, Drew M, Engers D, Kro-likowski D, Herpin T, Gardyan M, McGeehan G, Labaudiniere R. Polymer-supported tetrafluorophenol a new activated resin for chemical library synthesis. J. Comb. Chem. 2000 2 691-697. Baxendale IR, Ley SV. Polymer-supported reagents for multi-step organic synthesis appUcation to the synthesis of sildenafil. Bioorg. Med. Chem. Lett. 2000 10 1983-1986. 

Ley, S.V, Bolli, M., Hinzen, B., Gervois, A.-G., and Hall, B.J., Use of polymer supported reagents for clean multi-step organic synthesis preparation of amines and amine derivatives from alcohols for use in compound library generation, J. Chem. Soc., Perkin Trans., 1, 2239, 1998. 

Some new synthetic approaches to tetrazolodiazines have recently been reported. Thus, a multi-step variation of the cyclization method discussed in Table 9 has been elaborated <2005S2597> with the aim of library synthesis. 

However, it is rather difficult to search a library of natural sugars for an appropriate sugar derivative for the synthesis of 30. It is necessary to find either 5-deoxy-L-arabinose (61) or 5-deoxy-L-ribose (62), neither of which is available from natural resources [69]. Chemical derivation from easily available sugars is the only way to obtain 61 and 62,however, simple deoxygenation of the terminal alcohol group from L-arabinose (63) and L-ribose (64) generally requires a multi-step process. For example, the deoxygenative transformation... 

Abstract Recent developments in the microwave-assisted synthesis of heterocycles are surveyed with the focus on diversity-oriented multi-component and multi-step one-pot procedures. Both solution- and solid-phase as well as polymer-supported methodologies for the preparation of libraries of heterocycles are reviewed. Advantages of microwave dielectric heating are highlighted by comparison with conventional thermal conditions. 

Peptides are not the only potential drug candidates. In most cases, other kinds of small organic molecules are preferred, because of their reduced susceptibility to enzymatic degradation. The split-mix method is fully applicable in the synthesis of organic libraries. Both sequential type and cyclic libraries can easily be prepared if the reaction conditions for solid phase are well developed. It has to be emphasized, however, that the advantages of the split-mix method can be fully exploited only in the case of multi-step synthetic procedures. For realization of the one-pot procedures suggested by Ugi [10], for example, the parallel procedures are better-suited. 

We have developed an automated, multi-step, solid phase strategy for the synthesis of libraries... 

A variety of cationic lipids have been studied as non-viral systems for nucleic acids including DNA and RNA. However, the collection of publicly described lipid materials used for delivery is limited in diversity due in part to their multi-step synthesis. We used high-throughput synthesis and screening techniques to develop a new class of lipid-like materials referred to as lipidoids. Over 1200 unique lipidoid structures were created in this combinatorial library. ... 

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