| Diversity-oriented synthesis is a novel subject emerging from genomics and proteomics research in recent years, which aims to synthesize small molecules with structural complexity and diversity for use in a systematic exploration in biology. By coupling with split-pool solid-phase technology, diversity-oriented synthesis offers a powerful means to access structurally complex and diverse small molecules by considering three distinct diversity elements: building blocks, stereochemistry, and skeletons. This thesis research addresses diversity-oriented synthesis of functionalized indole and benzimidazole skeletons starting from readily available and diverse building blocks.; After a brief overview in Chapter 1 on diversity-oriented synthesis and applications to heterocycle synthesis from recent literature, Chapter 2 describes the development of a novel methodology for the synthesis of indoles using commercially available and inexpensive 2-aminophenols. The Pd(0)-Cu(I)-catalyzed Sonogashira cross-coupling reaction of 2-carboxamidoaryl triflates with 1-alkynes, where a remarkable additive effect was observed, afforded 2-alkynylanilides. The latter underwent the base-mediated intramolecular heteroannulation, providing substituted indoles in good overall yields with two points of diversification originated from 2-aminophenols and 1-alkynes. This cross-coupling-heteroannulation approach, in both stepwise and one-pot fashion, was successfully extended to the general synthesis of C4, C5, C6, and C7 nitrogen-substituted indoles, and 4- and 7-azaindoles. These results are documented in Chapter 3.; Solid-phase organic synthesis (SPOS) in combination with encoded split-pool technology provides a powerful means for the preparation of small molecule libraries. In Chapter 4, a 96-member indole library was synthesized using radio-frequency (Rf)-encoded MicroKan reactors based on the developed solution chemistry. The key step to indole ring formation was accomplished by Cu(II)- or Pd(II)-catalyzed heteroannulation of 2-alkynylsulfonamides under controlled microwave irradiation. This synthetic method allows facile introduction of three points of diversity through (i) functional groups in the sulfonamide subunit, (ii) carbon chain length at C2 position, and (iii) substituent at N1 position of indole. A traceless version of the microwave-assisted solid-phase indole library synthesis was established as given in Chapter 5.; The final chapter outlines a new approach to the solid-phase synthesis of a 50-member benzimidazole library from commercially available 4-chloro-3-nitrobenzoic acid. (Abstract shortened by UMI.)... |
