Total Synthesis of (+)-Galbulin and Unnatural Lignans

Abstract

The total synthesis of (+)-galbulin was achieved in 15% yield and 99% ee over eight steps from commercially available 4-veratraldehyde. The key steps include Meyer's asymmetric tandem addition to a chiral 2-oxazoline-substituted naphthalene, a Pdcatalyzed stereospecific decarboxylative γ-arylation, and a formal anti-Markovnikov hydromethylation. In addition, five unnatural lignans were synthesized using the same synthetic strategy.

Recent strategies and tactics for the enantioselective total syntheses of cyclolignan natural products

“…121) and several other unnatural lignans. 68 They were inspired by the total syntheses of podophyllotoxin completed by Sherburn and coworkers, 56 and epipodophyllotoxin carried out by Linker and coworkers, 63 each of which involved chiral dihydronaphthalenes as intermediates. a rearrangement of a 2,5-diaryl-2,3-dihydrofuran into a 4-aryltetralone as their key step forming a bond between C2 and C7 0 (Scheme 33) thus utilizing pathway D (Fig.…”

“…In 2020, Clausen and Studer synthesized (+)-galbulin ( 121 ) and several other unnatural lignans. 68 They were inspired by the total syntheses of podophyllotoxin completed by Sherburn and coworkers, 56 and epipodophyllotoxin carried out by Linker and coworkers, 63 each of which involved chiral dihydronaphthalenes as intermediates. Clausen and Studer's synthetic strategy involved the use of pathway C (Fig.…”

Recent advances in the total synthesis of 2,7′-cyclolignans

“…In 2020, Studer and co-workers reported a total synthesis of (+)-galbulin ( 4 ) in eight steps (Scheme 14). 29 The oxazoline 77 could be prepared from 4-veratraldehyde ( 78 ) and ( S )-valinol in 66% yield. A methyl group was then introduced at C(8) stereoselectively based on Meyers’ asymmetric tandem addition on naphthalene derivatives.…”

Taming the radical cation intermediate enabled one-step access to structurally diverse lignans

“…Notwithstanding the great progress recorded in the synthesis of lignans 14 , a concise and divergent synthetic approach allowing access to diverse subsets of lignan scaffolds from simple and cheap starting materials is still highly demanded in order to fully exploit the biological potential of these natural products [15][16][17][18][19][20][21] . While the structures of lignans are relatively simple, the control of stereochemistry in the cyclization step remains challenging [22][23][24][25][26] . Inspired by the pioneering work of Yoon [27][28][29] and Nicewicz 30,31 on the visible-light photoredox-catalyzed [2 + 2] and [4 + 2] cycloadditions of styrene derivatives, we recently reported an acridinium salt (Fukuzumi's salt, 16) [32][33][34][35] catalyzed intramolecular formal [4 + 2] cycloaddition of functionalized dicinnamyl ethers 17 to aryltetralin cyclic ethers 18 or 19 under blue LED irradiation (Fig.…”