A Radical-Based Synthesis of Lingzhiol

Abstract

The polycyclic natural product lingzhiol [(±)-1] was synthesized from dimethoxytetralone 8 via cyclization of an intermediate benzylic radical, generated from spiroepoxide 14, onto an alkynyl substituent generating tetracyclic compound 13 with an exocyclic double bond. After oxidative cleavage of the double bond of 13 and reduction of the keto function of 23, the correct diastereomer, 12-syn, was converted to lingzhiol (1) via known steps. In a similar manner, lingzhiol analogue 39 was synthesized from 5-methoxy-1-tetralone (27).

Collective enantioselective total synthesis of (+)-sinensilactam A, (+)-lingzhilactone B and (−)-lingzhiol: divergent reactivity of styrene

“…On the other hand, we and others have previously reported the total syntheses of lingzhiol and lingzhilactone B. [5][6][7][8][9][10][11][12]27 In this communication, we have reported a distinctive strategy for the collective synthesis of four meroterpenoids, (+)-sinensilactam A, (+)-lingzhilactone B, (+)-lingzhilactone C and (À)-lingzhiol. The key step involves non-metal promoted selective nucleophilic opening of epoxide by an alkene moiety of styrene, which has not been explored in total synthesis, though a metalcatalyzed reaction of epoxide with styrene is known.…”

Structural diversity, hypothetical biosynthesis, chemical synthesis, and biological activity ofGanodermameroterpenoids

“…After oxidative cleavage of the double bond of 153 and reduction of the keto function of 154 , the correct diastereomer, 155 - syn , was converted to (±)-lingzhiol ( 3 ) via known steps (Scheme 2). 87…”

“…Aer oxidative cleavage of the double bond of 153 and reduction of the keto function of 154, the correct diastereomer, 155-syn, was converted to (±)-lingzhiol (3) via known steps (Scheme 2). 87 In order to optimize this route, Maier ′ s group further used a Friedel-Cras cyclization to directly construct the 6/5/5tricyclic skeleton. 88 Accordingly, 2,5-dimethoxyphenyl acetic acid (156) was the starting material and was reduced to the corresponding alcohol, which subsequently was converted to the iodide 157 using Appel-type conditions (Ph 3 P, I 2 ) in 83% yield.…”

Radicals in natural product synthesis

“…In 2017, the Maier group published a synthesis of lingzhiol ( 51 ), a potent inhibitor of the phosphorylation of Smad3 that has potential as a therapeutic for renal fibrosis. 25 Key structural features of 51 include an acylated hydroquinone core and a central cyclopentane with two vicinal quaternary centers. Though a number of syntheses of 51 are reported which involve Lewis-acid or transition metal-mediated cyclizations to furnish the tetracycle core, Maier’s route utilizes a radical cyclization involving a benzyl radical intermediate to access polycycle 50 (Scheme 7).…”