Total Synthesis and Biological Evaluation of the Cytotoxic Resin Glycosides Ipomoeassin A–F and Analogues

Abstract

A multitasking C-silylation strategy using the readily available compound 26 as a surrogate for cinnamic acid represents the key design element of a total synthesis of all known members of the ipomoeassin family of resin glyosides. This protecting group maneuver allows the unsaturated acids decorating the glucose subunit of the targets to be attached at an early phase of the synthesis, prevents their participation in the ruthenium-catalyzed ring-closing metathesis (RCM) used to form the macrocyclic ring, and protects them against reduction during the hydrogenation of the resulting cycloalkene over Wilkinson's catalyst. As the C-silyl group can be concomitantly removed with the O-TBS substituent using tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) in acetonitrile, no separate protecting group manipulations were necessary in the final stages, thus contributing to a favorable overall "economy of steps". In addition to the naturally occurring ipomoeassins, a small set of synthetic analogues has also been prepared by "diverted total synthesis". The cytotoxicity of these compounds was assayed with two different cancer cell lines. The recorded data confirm previous findings that the acylation- and oxygenation pattern of these amphiphilic glycoconjugates is highly correlated with their biological activity profile. Ipomoeassin F turned out to be the most promising member of the series, showing IC(50) values in the low nanomolar range.

Total Synthesis and Biological Evaluation of Ipomoeassin F and Its Unnatural 11R-Epimer

“…7,10,11 Thus, ipomoeassin F was synthesized in 3.8% overall yield over 17 steps of the longest linear sequence from commercially available starting materials 11 and 21 , which is more efficient (9- and 4-fold) than the previously reported two syntheses (ca. 0.4% 10 and 1.0% 11 overall yield, respectively, calculated based on the non-commercially available starting materials). In our route, three highly regioselective reactions were developed: a) selective allyloxycarbonylation of the 2- OH -Glc p in diol 18 ; b) selective silylation of the 3- OH -Fuc p in triol 23a ; and c) selective glycosylation of 2- OH -Fuc p in diol 6a .…”

“…The known fucosyl donor 4 18 was prepared in 77% yield from compound 21 25 using a two-step sequence involving selective removal of anomeric acetate followed by trichloroacetimidate formation. Glycosylation of fucosyl donor 4 with ( S )- or ( R )-4-hydroxy-1-nonene ( 5a 11 or 5b ) was accomplished by using TMSOTf as the catalyst in the presence of 4Å molecular sieves, which then underwent global deacetylation to give triol 23a 10 or 23b in good to excellent yield over two steps. In the literature, 17 it has been established that in the galacto-configuration, the reactivity order for the secondary hydroxyl groups is 3- OH > 2- OH > 4- OH .…”

“…The only related biological studies that have been performed are cell cycle analyses. 11 The published data showed that a 24-hour treatment with the ipomoeassins led to the G1 arrest of mouse L-929 fibroblast cells, accompanied by a decreased cell number in the G2/M phase. The continued (48 h) exposure caused a significant number of sub-G1 cells and apoptosis.…”

“…( S )-4-hydroxy-1-nonene ( 5a ) 11 and ( R )-4-hydroxy-1-nonene ( 5b ) was synthesized from ( S )-(+)-Epichlorohydrin and ( R )-(−)-Epichlorohydrin through three steps with an overall yield of 68%, 58%, respectively.…”

“…To solve this problem, the Fürstner group found that trisubstituted alkenes can well survive hydrogenation catalyzed by Wilkinson’s catalyst; therefore, they elegantly designed the key intermediate 1 (Chart 1) with a C -silylated cinnammic acid ester and achieved the total synthesis of ipomoeassin F in ~1.0% overall yield. 11 By contrast, Postema and his coworkers decided to go through the orthogonally-protected intermediate 2 (Chart 1), thereby postponing the assembly of both cinnamate and tiglate to a later stage after RCM and hydrogenation. Intermediate 2 offers great flexibility for synthesizing ipomoeassin F analogs.…”