A ligand-directed divergent catalytic approach to establish structural and functional scaffold diversity

Abstract

The selective transformation of different starting materials by different metal catalysts under individually optimized reaction conditions to structurally different intermediates and products is a powerful approach to generate diverse molecular scaffolds. In a more unified albeit synthetically challenging strategy, common starting materials would be exposed to a common metal catalysis, leading to a common intermediate and giving rise to different scaffolds by tuning the reactivity of the metal catalyst through different ligands. Herein we present a ligand-directed synthesis approach for the gold(I)-catalysed cycloisomerization of oxindole-derived 1,6-enynes that affords distinct molecular scaffolds following different catalytic reaction pathways. Varying electronic properties and the steric demand of the gold(I) ligands steers the fate of a common intermediary gold carbene to selectively form spirooxindoles, quinolones or df-oxindoles. Investigation of a synthesized compound collection in cell-based assays delivers structurally novel, selective modulators of the Hedgehog and Wnt signalling pathways, autophagy and of cellular proliferation.

Gold(I)‐Catalyzed and Nucleophile‐Guided Ligand‐Directed Divergent Synthesis

“…We had observed that treating crotyl ether enyne substrate 6a ( E/Z = 3:1) with 5 mol‐% of a cationic gold(I) catalyst with different ligands could selectively provide spirooxindole 9a and quinolone 10a in good yields (Table , entries 1–3) . The cycloisomerization cascade catalyzed by NHC–gold(I) catalyst ( I ) delivered a spirooxindole 9a as the major product in 43 % yield along with quinolone 10a in 7 % yield.…”

Gold(I) Catalyzed Enyne Cycloisomerization – A Roadmap to Privileged Heterocyclic Scaffolds

“…Quinolone 229 was discovered as potent autophagy inhibitor (IC 50 =4.8 μM), and the df‐ oxindoles 230 and 231 were identified as Hedgehog inhibitor (IC 50 =3.31 and 2.75 μM). Moreover, further investigation on the most potent hedgehog inhibitor i. e. df‐ oxindole 231 revealed that it inhibited the transmembrane protein SMO trafficking to cilia …”

Nature Inspired Small Molecules for Chemical Biology

“…Moreover, further investigation on the most potent inhibitor i.e. df‐ oxindole 42 b revealed that it inhibited trafficking of the transmembrane protein SMO to cilia …”

“…However, unlike total synthesis of natural products or multistep synthesis of natural product analogues, often short and efficient synthesis designs delivering more than one scaffolds are required for library construction. For instance, Stockman et al designed a two-directional strategy using a symmetrical "rope-like" ketodienolate (23, Figure 4), which followed a number of separate tandem reactions to build many diverse and natural product-like scaffolds (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). The scaffolds were thus built up in a quick and elegant manner and were already equipped with functional groups for further elaboration.…”

“…df-oxindole 42 b revealed that it inhibited trafficking of the transmembrane protein SMO to cilia. [34] Natural product scaffolds encode interaction with various biological targets to modulate biological functions. The fragments of these complex structures arising from different biosynthetic origins are often used by nature to generate new secondary metabolites.…”