First Total Synthesis of the Bioactive Arylnaphthyl Lignan 4‐O‐Glycosides Phyllanthusmin D and 4′′‐O‐Acetylmananthoside B

Abstract

Based on the application of phase‐transfer‐catalysis and Yu glycosylations, the first total syntheses of the arylnaphthyl glycosides phyllanthusmin D and 4′′‐O‐acetylmananthoside B, which have been claimed to be ideal antitumoral lead compounds in terms of cytotoxicity, cytotoxic selectivity, and a new mechanism of action, were achieved. Starting from easily accessible compounds, the two target molecules were obtained with longest linear sequences of 9 and 15 steps, in overall yields of 29 and 9 %, respectively. As part of this synthetic investigation, an efficient and scalable synthetic route to diphyllin was established, and the atropisomeric phenomenon in the arylnaphthyl glycosides was also confirmed.

Phyllanthusmin Derivatives Induce Apoptosis and Reduce Tumor Burden in High-Grade Serous Ovarian Cancer by Late-Stage Autophagy Inhibition

“…PHY30 and PHY34 (Supplemental Figures 1B and1C, respectively) were prepared from their respective glycosyl starting materials via an acid catalyzed acetal formation (38). The experimental data for PHY30 is in agreement with the same compound that was recently disclosed as in intermediate in the first total synthesis of phyllanthusmin D (39).…”

Total Synthesis and Structural Revision of Rebaudioside S, a Steviol Glycoside

“…The subsequent cleavage of silyl ester was effected under buffered conditions, efficiently delivering the carboxylic acid acceptor 13 (90%), which was ready for C-19 sugar chain incorporation under PTC conditions. Under the previously optimized conditions (K 2 CO 3 , TBAB, CHCl 3 /H 2 O, 40 °C), all 13 was consumed, leading to three new compounds, among which the desired 14 was isolated in 41% yield, accompanied by C4- O -benzoyl group migrated and cleaved byproducts ( 14a and 14b ) elicited by the free OH in the C-13 sugar residue. Global saponification of all ester-type PGs of 14 gave the proposed Reb-S ( 1 ), yet with compromised overall efficiency because of the undesired intervention of the free OH of 13 (36%, two steps).…”

“…HRMS (ESI) calcd for C 74 H 74 O 18 K [M + K] + 1289.4507, found 1289.4531. (23). A similar procedure as that used for the synthesis of 14 was applied to mediate the coupling between 22 (80 mg, 0.064 mmol) and 4 (107.6 mg, 0.13 mmol) to provide 23 (110 mg, 0.055 mmol, 86%) as a white solid: [α] D 25 = +59.4 (c 1.0, CHCl 3 ).…”

Synthesis and antiproliferative activity of derivatives of the phyllanthusmin class of arylnaphthalene lignan lactones

“…Although numerous elegant recent approaches to the synthesis of similar arylnaphthalene core ring systems have been reported, they are either not specifically amenable to the synthesis of diphyllin or are potentially limited by scale-up cost. 44–51 The route of Charlton and coworkers, 52 however, has previously been employed 12,28,53–55 for the synthesis of diphyllin and related analogues based on the ease of access to the requisite starting materials and the overall efficiency of the route. Employing only minor modifications to the reported procedure, gram scale quantities of diphyllin ( 5 ) have been produced (Scheme 1).…”

“…The most significant modification to the reported procedure was made based on initial difficulties observed during the isolation and purification of diphyllin following the final reduction of diester 4 using the reported sodium borohydride reduction conditions. Despite early work that indicated the potential for over-reduction of the desired lactone product in the presence of lithium aluminum hydride (LAH), 56 there was literature precedent indicating that LAH could be utilized under careful dropwise inverse addition 44,57 or portion-wise addition 55 conditions to affect this type of transformation. In the present study, portion-wise addition of 4 equivalents of LAH cleanly and efficiently resulted in the regioselective reduction of diester 4 within five minutes as observed by thin layer chromatography.…”