Ru(II)-Catalyzed Site-Selective Hydroxylation of Flavone and Chromone Derivatives: The Importance of the 5-Hydroxyl Motif for the Inhibition of Aurora Kinases

Abstract

An efficient protocol for Ru(II)-catalyzed direct C-H oxygenation of a broad range of flavone and chromone substrates was developed. This convenient and powerful synthetic tool allows for the rapid installation of the hydroxyl group into the flavone, chromone, and other related scaffolds and opens the way for analog synthesis of highly potent Aurora kinase inhibitors. The molecular docking simulations indicate that the formation of bidentate H-bonding patterns in the hinge regions between the 5-hydroxyflavonoids and Ala213 was the significant binding force, which is consistent with experimental and computational findings.

Second Generation Total Synthesis of (–)‐Preussochromone D

“…1 H NMR (300 MHz, CDCl 3 ) δ = 12.40 (s, 1H, 1‐OH), 7.83 (d, 1H, J = 6.0 Hz, 5a‐H), 7.52 (t, 1H, J = 8.4 Hz, 3‐H), 6.89 (dd, 1H, J = 0.6 Hz, 8.4 Hz, 4‐H), 6.80 (d, 1H, J = 8.3 Hz, 2‐H), 6.28 (d, 1H, J = 6.0 Hz, 7a‐H) ppm. The analytical data is in accordance with the literature …”

Directed Hydroxylation of sp2 and sp3 C–H Bonds Using Stoichiometric Amounts of Cu and H2O2

“…17–19 The Yu research lab showed that Cu can promote intramolecular ortho hydroxylation of phenylamides at high temperatures by using excess amounts of a metal source and adding external oxazoline ligands and various additives. 19 Very recently, Uchiyama reported the directed ortho hydroxylation of N,N -diisopropylamides by deprotonation using excess amounts of a cuprate base followed by oxidation with t BuOOH. 20 Inspired by our findings on Cu-directed hydroxylation of sp 3 C–H bonds using H 2 O 2 as an oxidant (see Figure 1A), we decided to determine if a similar methodology could be used for the synthesis of o -acylphenols under mild conditions.…”

Recent Advancements on Transition‐Metal‐Catalyzed, Chelation‐Induced ortho‐Hydroxylation of Arenes

“…(Scheme 53). [66c] The ratio of TFA/TFAA (1:65) and presence of Ag 2 CO 3 (1 eq.) played a significant role in this reaction to obtain best yield.…”