Synthesis of natural-product-like molecules with over eighty distinct scaffolds.
Synthesis of natural-product-like molecules with over eighty distinct scaffolds.
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DOI：
10.1002/anie.200804486
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发表时间：
2009
影响因子：
16.6
通讯作者：
Nelson, Adam
中科院分区：
文献类型：
--
作者：
Morton, Daniel;Leach, Stuart;Cordier, Christopher;Warriner, Stuart;Nelson, Adam
A key challenge in chemical biology is the design and synthesis of compound libraries spanning large tracts of biologically relevant chemical space.[1–3] Libraries with high molecular shape diversity, a prerequisite for broad biological activity,[2] are particularly valuable in phenotypic screens. Despite this, organic chemistry is dominated by a remarkably small number of molecular scaffolds: in a recent study [4] of known cyclic organic molecules, 0.25% of the molecular frameworks were found in 50% of the known compounds! The uneven distribution of frameworks may reflect the way that chemical space is generally explored, with chemists tending to prepare compounds based on frameworks that are already known.[4]Diversity-oriented synthesis (DOS) involves the preparation of compound libraries with high substitutional, stereochemical, and/or scaffold diversity.[5] Varying molecular scaffolds is challenging though ingenious innovations have allowed the parallel synthesis of libraries based on multiple (ca. 6–30) scaffolds.[6] Developing approaches in which the ethos of DOS is retained—that is, that the synthesis is deliberate and simultaneous—is, nonetheless, extremely demanding. High-throughput screens of DOS libraries have, however, yielded useful small molecule tools for chemical genetic studies of cellular protein functions.[7] Our approach to the combinatorial variation of molecular scaffolds involved the attachment of pairs of unsaturated building blocks to a fluorous-tagged linker (Scheme 1).[8] The fluorous tag allowed the removal of excess reagents at each stage by fluorous-solid phase extraction (F-SPE) alone.[9] We used two general types of building blocks:“propagating” and “capping” building blocks (Scheme2). To increase the structural diversity of the final compounds, we attached the building blocks using combinations of temporary silaketal tethers [10] and bonds that would remain as a vestige in the final compounds. For example, the cyclopentene building block 9 could be attached to the linker (1 or 2) using either a Fukuyama–Mitsunobu reaction [11](→ 3) or a diisopropylsilylene tether (→ 4). Following deacetylation, a “capping” building block, such as 15 (Sil, All)→ 5 or 25→ 6, was attached to yield metathesis substrates. Metathesis cascades were used to “reprogram” the scaffolds of the metathesis substrates to yield those of the final products (for example 5→ 7 or 6→ 8). Each metathesis cascade was expected to initiate at the terminal alkene [12] of the “capping” building block, leading to the release of only cyclized products from the fluorous-tagged linker. It was expected that the ability to vary the pairs of building blocks used, together with the nature of the attach-
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影响因子：
3.2
作者：
Cordier, Christopher;Morton, Daniel;Nelson, Adam
通讯作者：
Nelson, Adam
DOI：
10.1073/pnas.0503647102
发表时间：
2005-11-29
影响因子：
11.1
作者：
Koch, MA;Schuffenhauer, A;Waldmann, H
通讯作者：
Waldmann, H
影响因子：
1.8
作者：
FUKUYAMA, T;JOW, CK;CHEUNG, M
通讯作者：
CHEUNG, M
影响因子：
5.6
作者：
Lameijer, EW;Kok, JN;Ijzerman, AP
通讯作者：
Ijzerman, AP
影响因子：
7.3
作者：
Lewell, XQ;Jones, AC;Bradshaw, J
通讯作者：
Bradshaw, J