Abstract
Chemical synthesis based on the skeletal variation has been prolifically utilized as an attractive approach for modification of molecular properties. Given the ubiquity of unstrained cyclic amines, the ability to directly alter such motifs would grant an efficient platform to access unique chemical space. Here, we report a highly efficient and practical strategy that enables the selective ring-opening functionalization of unstrained cyclic amines. The use of difluorocarbene leads to a wide variety of multifaceted acyclic architectures, which can be further diversified to a range of distinctive homologative cyclic scaffolds. The virtue of this deconstructive strategy is demonstrated by successful modification of several natural products and pharmaceutical analogues.
Highlights
Chemical synthesis based on the skeletal variation has been prolifically utilized as an attractive approach for modification of molecular properties
While significant progress has been made in the development of appending processes for their peripheral variation[5,6,7,8,9,10], the skeletal diversification by means of ring-opening, -contraction, -expansion or -fusion approaches remains limited (Fig. 1a)[11]. This is pertinent for the unstrained cyclic systems, which is attributed to the fact that the structural reorganization is inevitably accompanied by highly demanding C–N12,13 or C–C14–16 bond cleavage
The ring-opening reaction would be followed by the installation of versatile motifs that can be further transformed for diversity-generating chemical synthesis[25,26,27]
Summary
CNBr, alkyl chloroformate, alkyl halide Nucleophilic attack of 4° ammonium salt Limited functions of N−CN moiety (CNBr) Limited scopes (alkyl chloroformate/halide). The increased bond polarity ameliorates the leaving group ability of amino moiety, allowing the C–N bond cleavage by means of elimination[34] or nucleophilic substitution reactions[35,36,37] This chemistry has been widely utilized in the ringopening reaction of strained rings[38,39,40,41,42], its use in unstrained cyclic systems is somewhat thwarted by the stability of the involved salts. Of a great potential for further development is the von Braun reaction, which employs cyanogen bromide (CNBr) in ring-opening bromination of azacyclic compounds[43,44] This reaction outperforms other strategies in terms of efficiency and applicability, but has found relatively narrower synthetic applications[45,46,47,48]. A wider range of cyclic amines can be deconstructively modified, but this strategy can be applied to complex molecules bearing labile functional groups
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