A Versatile Total Synthesis of Trachycladines A and B and Their Analogues

Abstract

The synthesis of marine nucleosides trachycladines A and B and two nucleoside analogues was accomplished following a versatile and high‐yielding scheme starting from D‐ribose. The key step involved a regio‐ and stereoselective direct Vorbrüggen glycosylation reaction between the appropriate nucleobase and a common intermediate, 2‐C‐methyl‐D‐5‐deoxyribofuranose triacetate.

Trachycladines and Analogues: Synthesis and Evaluation of Anticancer Activity

“…Triacetate 4,w hich was easily and stereoselectively prepared on ag ram scale from d-ribose in seven steps and5 7% overall yield, [19,21] served as the keyi ntermediate for the synthesis of all new trachycladinea nalogues. Three of thesea nalogues( 7-9)w ere prepared by glycosylationo f2 ,6-dichloropurine with 4 under Vorbrüggen conditions, [22] in the presence of TMSOTf and DBU (Scheme 2).…”

“…Heating as olution of crude diacetate 10 [19] in methanolic ammonia in as ealed tube resulted in the concurrent amination of the purine nucleusa nd removal of the protecting groups. Heating as olution of crude diacetate 10 [19] in methanolic ammonia in as ealed tube resulted in the concurrent amination of the purine nucleusa nd removal of the protecting groups.…”

“…Reagents and conditions: a) see Peitsinis et al; [19] b) NH 3 in MeOH (7 n), 110 8C, 8h,6 8% overall from 4;c)HOCH 2 CH 2 SH, CH 3 ONa, CH 3 OH, 60 8C, 3h,8 8%. Reagents and conditions: a) see Peitsinis et al; [19] b) NH 3 in MeOH (7 n), 110 8C, 8h,6 8% overall from 4;c)HOCH 2 CH 2 SH, CH 3 ONa, CH 3 OH, 60 8C, 3h,8 8%.…”

“…As olution of TMSOTf (2.2 mL, 12 mmol) in anhydrous CH 3 CN (12 mL) was added dropwise at the same temperature. Trachycladine B( 2):C hloro-purine derivative 6 (40 mg, 0.14 mmol) [19] was dissolved in anhydrous CH 3 OH (4 mL). After re-cooling to 0 8C, ac hilled saturated aqueous NaHCO 3 solution (100 mL) was slowly added, and the mixture was vigorously stirred for 30 min.…”

“…[16] The initial evaluation of the biological profile of 1 revealed potent in vitro cytotoxic activity against an umber of human colon, leukemia, and breast cancer cell lines (IC 50 :0 .3-3.0 mm) but no activity against several yeasts and bacteria. More recently,a nd almosts imultaneously,t he first total syntheseso fn atural trachycladines (1 and 2)w erep ublished by Wu et al [18] and our group, [19] apply-The synthesis of four new analogues of marinen ucleoside trachycladine Aw as accomplished by direct regio-and stereoselective Vorbrüggen glycosylations of 2,6-dichloropurine and 2chloropurine with a d-ribose-derived chiron. [12] About ad ecadea go, Enderse tal.…”