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. 2016 Sep 26;55(40):12479-83.
doi: 10.1002/anie.201606496. Epub 2016 Sep 6.

Partially Saturated Bicyclic Heteroaromatics as an sp(3) -Enriched Fragment Collection

David G Twigg  1 , Noriyasu Kondo  1   2 , Sophie L Mitchell  1 , Warren R J D Galloway  1 , Hannah F Sore  1 , Andrew Madin  3 , David R Spring  4
Affiliations

Partially Saturated Bicyclic Heteroaromatics as an sp(3) -Enriched Fragment Collection

David G Twigg et al. Angew Chem Int Ed Engl. .

Abstract

Fragment-based lead generation has proven to be an effective means of identifying high-quality lead compounds for drug discovery programs. However, the fragment screening sets often used are principally comprised of sp(2) -rich aromatic compounds, which limits the structural (and hence biological) diversity of the library. Herein, we describe strategies for the synthesis of a series of partially saturated bicyclic heteroaromatic scaffolds with enhanced sp(3) character. Subsequent derivatization led to a fragment collection featuring regio- and stereo-controlled introduction of substituents on the saturated ring system, often with formation of new stereocenters.

Keywords: drug design; drug discovery; fused-ring systems; nitrogen heterocycles; synthetic methods.

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Figures

Figure 1
Figure 1
Selected examples of bioactive compounds containing functionalized partially saturated bicyclic heteroaromatics (highlighted in red).
Scheme 1
Scheme 1
General synthetic strategy toward PSBH scaffolds 1 and subsequent incorporation of new functionalities (2) or rings (3).
Scheme 2
Scheme 2
Functionalization of PSBH scaffolds. For reaction conditions, see the Supporting Information.
See this image and copyright information in PMC

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