Concise synthesis of (±)-Lingzhiol via epoxy-arene cyclization

Abstract

Concise synthesis of (±)-Lingzhiol has been achieved. The key reaction involves one-step construction of a 5/5/6/6 tetra-ring backbone of Lingzhiol via epoxy-arene cyclization.

Total Synthesis of Lingzhiol and its Analogues through the Wittig Reaction of an Oxocyclopentane Carboxylate

“…[12] Because we could not convert ketone 26 into epoxide 28 through aC orey-Chaykovsky reaction, [13] we wanted to preparei tb ye poxidation of the corresponding alkene. Even though the Qin group had reported that this reaction was unsuccessful, [6] we found conditions that could promote this crucial olefination reaction. Although classical Wittig conditions-Ph 3 PCH 3 I( 1.2 equiv), NaH (2.5 equiv), THF,0 8C; Ph 3 PCH 3 Br (2.5 equiv), tBuOK (2.5 equiv), toluene, 100 8C; Ph 3 PCH 3 Br (1.2 equiv), nBuLi (1.5 equiv), THF, À10 8C-and aT akai-Lombardo methylenation reaction [14] did not give the desired product (exo-15), we eventually found that the use of about three equivalents of methyltriphenylphosphonium bromide and 2.83 equivalents of potassium tert-butoxide were essential, as was their use from freshly opened bottlesi nT HF.…”

“…Because we could directly produce exocyclic olefin exo-15 from aW ittig reaction, we could shorten the synthetic route to lingzhiol reported by Qin and co-workers,whichwas published while our work was underway. [6] Thus, the allylic oxidation of exo-15 with tBuOOH in the presence of selenium dioxide led to allylic alcohol 33 as as ingle diastereomer (Scheme 7). This step was followed by epoxidation with mCPBA to give spiro epoxide 16 in 79 %y ield.…”

“…Previously reportedc onditions for this benzylic oxidation reaction( N-bromosuccinimide, (PhCO 2 ) 2 ,C Cl 4 /water;t hen MnO 2 ,C H 2 Cl 2 )d id not work in our hands. [5,6] Next, the acetate was cleaved under acidic conditions (3 m HCl, MeOH,8 58C) to give hydroxyketone 36 in almost-quantitativey ield. Cleavage of the aryl methyl ether groups was achieved as described by using AlCl 3 (22 equiv) in the presence of tBuSH to give (AE)lingzhiol(1)i n6 0% yield as ay ellow solid.…”

“…Although the cyclization reaction did not work in our hands, the shortened route to exo-alkene exo-15 enabled us to foreshorten the route reported by Qin and co-workers. [6] Thus, the synthesis of racemic lingzhiol can be completed in only nine steps. By using key polycyclic intermediate 17,f our lingzhiol analogues were prepared, that is, desoxyd erivative 37, quinone 38,m ono-methoxy desoxy compound 39,a nd ketone 40.T he formation of quinone 38 confirmed that the keto group at the C1' position of lingzhiol protected the hydroquinone against oxidation.…”

“…In 2015, Qin and co-workers reported ab iomimetics trategy that featured an epoxy-arene cyclization reaction of epoxide 16 to afford hydroxylactone 17 in the presence of BF 3 ·Et 2 O. [6] Epoxide 16 could be prepared from major alkene endo-15 in four steps. In total, startingf rom ethyl 2-oxocyclopentanecarboxylate (14), this route comprised 12 steps.…”