Macrolide Core Synthesis of Calysolin IX Using an Intramolecular Glycosylation Approach

Abstract

The utility of intramolecular glycosylation for the synthesis of the 27-membered macrocyclic ring is highlighted in this first total synthesis of the most complex resin glycoside isolated to date -Calysolin IX. Oligosaccharide-containing macrolides core was effectively constructed by TfOH/NIS-promoted intramolecular glycosylation of thioglycosyl donor. As the glycosidic bond must be created en route to target structure, we [a] Mirosław Nawój,

Total Synthesis of Starfish Cyclic Steroid Glycosides

“…To our delight, addition of Ph 3 PAuNTf 2 (0.3 equiv) to a solution of 4 in toluene at −10 °C gave rise to the desired cyclic trisaccharide 33 , albeit in a moderate 21 % yield. The yield of 33 was increased to 33 % when the concentration of 4 was decreased from 7.0 mg mL −1 to 1.7 mg mL −1 [28, 29] . Similar results were achieved in the ring‐closing glycosylation of 5 and 6 , affording 34 and 35 in 33 % and 49 % yield, respectively, testifying the robustness of the present ring‐closing methods.…”

“…The yield of 33 was increased to 33 % when the concentration of 4 was decreased from 7.0 mg mL À 1 to 1.7 mg mL À 1 . [28,29] Similar results were achieved in the ring-closing glycosylation of 5 and 6, affording 34 and 35 in 33 % and 49 % yield, respectively, testifying the robustness of the present ringclosing methods.…”

“…Therefore, a conceptually new approach to install the hexopyranosyl residues at the steroidal C6 position was planned, which would invoke a de novo synthesis [21–24] from a steroidal C6β‐ O ‐allyl ether (i.e., 10 ) and a 5 C olefin derivative (i.e., 11 ) via cross metathesis and subsequent elaboration [25] . Then, we envisioned steroidal trisaccharides 4 – 6 as capable precursors to the strained macrocycles via intramolecular glycosylation [26–30] . To secure the elusive ring‐closing glycosylation, an olefinic pyranose unit endowed with a highly reactive allylic C2′’‐OH was devised as the acceptor moiety [31] .…”

“…[25] Then, we envisioned steroidal trisaccharides 4-6 as capable precursors to the strained macrocycles via intramolecular glycosylation. [26][27][28][29][30] To secure the elusive ring-closing glycosylation, an olefinic pyranose unit endowed with a highly reactive allylic C2''-OH was devised as the acceptor moiety. [31] A pyranosyl ortho-alkynylbenzoate prefabricated at C6 was employed as the donor, considering it would remain intact during stepwise installation of the disaccharide residues at C3 (with imidate donors 7-9) and afterwards could proceed glycosylation under the mild gold(I)-catalyzed conditions.…”

Progress in the total synthesis of resin glycosides

“…Zhang's group tried the Keck macrolactonization method to synthesize the macrolactone structures 159, 173, and 174 (Huang et al, 2015). The intramolecular glycosylation method was used for the construction of the macrolide cores 175 and 176, which were the intermediates for tricolorin A (11) and calysolin IX (177) (Son et al, 2009;Nawój et al, 2020). In addition, a suitably protected trichloroacetimidate (178) was synthesized by a block synthesis approach, which could serve as an exocyclic intermediate in the total synthesis of resin glycoside merremoside H 2 (179) (Shen et al, 2009).…”