First Total Synthesis of the Benzotropolone/Bis(pulvinone) Natural Product Aurantricholone Exploiting New Strategies for Establishing Benzotropolones andZ‐Configured Pulvinones

Abstract

Aurantricholone as well as its calcium and lithium salts, all of which represent the coloring principle of the fungus Tricholoma aurantium, were synthesized for the first time, namely in 15 steps, 10 of which were our longest linear sequence. We developed an access to benzotropolones after dibromocyclopropanating alkyl or silyl enol ethers of 1-tetralones. Successive treatments with DMAP-N-oxide and Ac 2 O effected ring-enlargement, oxidation, and acetylation. O-acetyl-1-bromo-3,4-dimethoxybenzotropolone obtained thereby -similarly as unsubsti-tuted benzotropolone -was brominated at C-8 in two steps by adopting our recently published bromination protocol for otherwise unsubstituted O-acetylbenzotropolone. Thereafter, a double and doubly Z-selective Suzuki-coupling with a newly introduced boronate established the O-methylated pulvinone moiety as well as the O-methylated "pulvinone-like" motif of what altogether equaled the completed aurantricholone scaffold. Its deprotection (two steps) furnished the title compound either as its protonated form or its calcium or lithium salt.

Second‐Generation Total Synthesis of the Pigment Aurantricholone

“…It soon turned out that a 1-step (!) biomimetic synthesis from a pulvinone [2] with a catechol moiety and another pulvinone with a pyrogallol moiety failed in our hands [3] (even if we questioned this interpretation many years later [4] because we learnt that aurantricholone was a pigment rather than a dye [5] ). This (at least apparent) failure let us pursue "purely chemical" rather than "biomimetic" approaches to many model benzotropolones, [6] including the unsubstituted parent compound.…”

“…[6a,c,d,f] In any of the resulting benzotropolones, the 7membered ring was established by a ring-closing olefin metathesis ("RCM" henceforth) reaction. [7] In the context of where our interest in the synthesis of benzotropolones arose from (vide supra), it was all but obvious why we realized the first total synthesis of aurantricholone [5] (10; synopsis: Scheme 1) without using any RCM reaction. [6] Instead, we accessed the benzotropolone moiety of our target molecule by a novel ring-enlargement strategy.…”

“…It entailed the α-tetralone 7 whose trimethylsilyl enol ether was cyclopropanated and yielded the hydroxycyclopropane 8 after hydrolytic workup. [5] Treatment of 8 with 4-(N,N-dimethylamino)pyridine-1-oxide cleaved the cyclopropane and effected an oxidation whereupon the addition of acetic anhydride led to the Oacetylbenzotropolone 3. [5] This compound was susceptible to an earlier developed Br 2 addition/HBr elimination sequence for introducing a bromine atom at C-8 regioselectively.…”

“…[5] Treatment of 8 with 4-(N,N-dimethylamino)pyridine-1-oxide cleaved the cyclopropane and effected an oxidation whereupon the addition of acetic anhydride led to the Oacetylbenzotropolone 3. [5] This compound was susceptible to an earlier developed Br 2 addition/HBr elimination sequence for introducing a bromine atom at C-8 regioselectively. [6e] The resulting dibromide 2 and an excess of the newly developed alkenylboronate 4 underwent a 2-fold doubly Z-selective Suzuki coupling.…”

“…[6e] The resulting dibromide 2 and an excess of the newly developed alkenylboronate 4 underwent a 2-fold doubly Z-selective Suzuki coupling. [5] It furnished tetramethyl-and monoacetyl-protected aurantricholone (9). [5] Global deprotection required two steps and provided totally synthetic aurantricholone (10) or dilithioaurantricholone (not depicted) or calcio-aurantricholone (neither depicted), depending on the reaction and workup conditions.…”