Library benzopyran

The primary library shown in Fig. 5.2, which was reported by Baldwin (1), was clearly designed as a source of biologically active molecules on several targets (why), thus compensating the efforts required for the chemical assessment and for a satisfactory characterization (when). The SP library was prepared in pools using chemical encoding (4, 5) to produce a population of around 62,000 individuals (how). The synthetic scheme was composed of both simple and more complex SP steps, and several monomer sets (A-F, Fig. 5.2) were used (what). These monomers were either commercially available or easily prepared from commercial precursors, while the library benzopyranic core was formed during the synthesis (how much). 

Another example in which literature results were reanalyzed in view of the PSSC concept concerns the development of ligands for the farnesoid X receptor. The farnesoid X receptor is a transcriptional sensor for bile acids, the primary products of cholesterol metabolism, and plays an important role in lipid homeostasis. The farnesoid X receptor was, until recently, an orphan receptor, which means that no specific ligands existed for this receptor. Selective ligands for this receptor have been found in natural product libraries described by Nicolaou et al. The group of Nicolaou developed solid phase synthesis methods to make combinatorial libraries based on a benzopyran core structure. " A 10,000-membered combinatorial library based on the benzopyran core structure was synthesized and screened for activity on the farnesoid X receptor. The first specific ligands for the... 

Nicolaou, K.C. Pfefferkom, J.A. Barluenga, S. Roecker, A.J. Cao, G.-Q. (2000C) Natural product-like combinatorial libraries based on privileged structures. 3. The libraries from libraries principle for diversity enhancement of benzopyran libraries. J. Am. Chem. Soc., 122, 968-76. 

The directed sorting approach has been widely applied both in industry and in academia. Two examples are detailed in this chapter. Some other recently published examples include a benzopyran library synthesized using the Nanokan system,15 libraries derived from phenolic amino acid scaffolds prepared with the Accutag system,16 and libraries of l,5-benzodiazepine-2-one derivatives.17... 

A combinatorial natural-product-like and diversity-orientated library of 10 000 benzopyran-based small molecules was constructed by Nicolaou and coworkers [74, 75]. They chose a solid-phase approach and an anchoring strategy that does not limit complexity building operations (Scheme 14.11). They used a polystyrene-based selenyl bromide resin (43) on which substrates can be immobilized by electrophilic cyclization reactions. Here, ortho-prenylated phenol 44 was reacted with the selenyl bromide (43) to form the benzopyran scaffold (45) via a 6-endo-trig cyclization. 

Scheme 14.11 Solid-phase synthesis of a benzopyran-based natural-product-like combinatorial library.

Breitenbucher and Hui (104) have recently reported the SP synthesis of a medium-large discrete library L3 of 8448 benzopyrans using the reductive amination cocktail formed from titanium isopropoxide and sodium triacetoxyborohydride, known in solution but whose applications to SP were rare and limited to single experiments (105, 106). The benzopyran scaffold is present in a number of biologically active compounds (107-110), and this library was tested in several biological assays (111). 

Figure 6.13 General structure of the SP benzopyran library L3 and retrosynthetic studies for its synthesis.

M4, 22 amines), and after the reaction the cleavage solutions were recovered by filtration into 96 corresponding microtiter plates to give crude L3 as 8448 spatially separated crude benzopyrans that were submitted to an automated purification procedure (step f) (115) and concentrated using commercially available vacuum centrifuges to give the final pure library (Fig. 6.15). 

Figure 6.16 Structure of fully characterized discretes 6.35-6.40 from the benzopyran library L3.

Figure 7.29 SP synthetic strategy to the SP benzopyran encoded (electrophoric tags) pool libraries L6-L9 synthesis of SP intermediates 7.50 and 7.51.

Figure 7.33 Monomer structures and tags for the SP benzopyran libraries L6-L9 Mi-Msa...

Nicolaou KC, Pfefferkorn JA, Mitchell HJ, Roecker AJ, Bar-luenga S, Cao, GQ, et al. Natnral prodnct-like combinatorial libraries based on privileged stmctnres. 2. Construction of a 10 000-membered benzopyran library by directed split-and-pool chemistry using NanoKans and optical encoding. J Am Chem Soc. 2000 122 9954-9967. 

Some of the peak assignments given in Table 6.7.2 are tentative. For example, the spectrum for the peak eluting at 97.91 min. was assigned to 3-ethyl-2H-1-benzopyran-2-one by similarity to the spectrum of 3-methyl-2H-1-benzopyran-2-one available in the NIST mass spectral library. The two spectra are shown in Figure 6.7,3. 

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