A Suzuki–Miyaura Coupling of ortho‐Hydroxyaryl Bromide with Isopropenylboronic Pinacol Ester: Synthesis of the Potassium‐Channel Opener (+)‐Callitrisic Acid

Abstract

A Suzuki–Miyaura coupling reaction of ortho‐hydroxyaromatic bromide 8 with isopropenylboronic acid pinacol ester has been investigated. It was found that the catalyst of Pd2(dba)3/PCy3 in dioxan‐water gave good yield by suppressing the formation of isomeric side product 14. (+)‐Callitrisic acid was synthesized from (+)‐podocarpic acid using this condition with an overall yield of 54 % in about five steps. (+)‐Callitrisic acid was found to be almost three times more potent than dehydroabietic acid to open a voltage‐gated potassium channel.

Site and Mechanism of Action of Resin Acids on Voltage-Gated Ion Channels

“…methyloxime at C7 on the Bring), appear to have a deeper and/or tighter binding site to the Shaker KV channel, with a larger effect on closing kinetics than expected, than if they only acted on the voltage sensor via electrostatic interactions (Elinder and Arhem, 2003). We also show in Article II that minor modifications of the DHAA molecule, such as changing the chirality of the carboxyl group, can have a profound effect for the G(V)-shifting effect of a resin acid (Wu et al, 2018). Thus, only small changes of the resin acid molecule (anchor, stalk and effector) can be very powerful; each in combination with the others make it possible both to fine tune the binding of the resin acid to different channels, and/or increase or decrease the electrostatic interaction depending on the gatingcharge profile around the voltage sensor.…”

Total synthesis of naturally occurring abietane diterpenoids via a late-stage Fe(iii)-bTAML catalysed Csp3–H functionalization

“… 21 We envisioned a strategy to advance the abietane scaffold by synthesizing callitrisic acid (7) from abietic acid (14) using a modified literature procedure. 22 Then we focused our attention to perform selective oxidation of activated 3 °C–H bonds and activated 2 °C–H bonds via NO 2 [Fe- b -TAML] 5 complex (12) in the presence of the oxidant m -CPBA ( Fig. 2c ).…”

“…Initially, we wanted to synthesize the core structure of abietane diterpenoids, such as callitrisic acid 22 (7). On the basis of previous reports by two independent groups, Pelletier et al and Alvarez-Manzaneda et al , 24 we have started our synthesis from commercially available (+)-abietic acid (14).…”