A practical and scalable synthesis of KRN7000 using glycosyl iodide as the glycosyl donor

Abstract

KRN7000 is particularly useful because it is a powerful and specific CD1d agonist and has prompted intense interest in the context of immunology in the past 25 years. Its limited commercial availability and high price has led to the publication of many different syntheses. However, almost all of them focused on the methodology development rather than a scalable synthesis. Herein, we have described a practical and scalable procedure for the synthesis of KRN7000 basing on the glycosyl iodide method. This procedure involves total of eight steps to obtain the highly pure product KNR7000 on gram scale from the commercially available starting materials (d-galactose and the phytosphingosine) with only three column chromatographic purifications.

Potent Neutralizing Antibodies Elicited by RBD-Fc-Based COVID-19 Vaccine Candidate Adjuvanted by the Th2-Skewing iNKT Cell Agonist

“…Many synthetic routes to α-GC take the advantage of using commercially available phytosphingosine. Recently, a large-scale synthesis of α-GC has been developed . However, the synthetic routes using phytosphingosine as a starting material cannot be used to prepare OCH ( 3 ).…”

“…Recently, a large-scale synthesis of α-GC has been developed. 49 However, the synthetic routes using phytosphingosine as a starting material cannot be used to prepare OCH (3). Given the successful preparation of α-C-GC (2), we carried out the synthesis of O-glycosides via the same synthetic sequence.…”

Rationally Designed Highly Potent NKT Cell Agonists with Different Cytokine Selectivity through Hydrogen-Bond Interaction

“…For the preparation of these αGalCer analogues, the key building block α-galactosyl sphingosine (compound 14 ) was first synthesized from d -galactose and phytosphingosine efficiently according to the procedure published previously, ,− as outlined in Scheme A. Next, acyl chains containing sulfonamide moieties possessing an identical chain length were synthesized through facile approaches.…”

Stereospecific Synthesis and Biological Evaluation of KRN7000 Analogues with Thio-modifications at the Acyl Moiety

“…The key challenge in the synthesis of these compounds is stereoselective construction of the 1,2- cis -α-galactosidic linkage. Many elegant methods and strategies for stereoselective synthesis of α-galactosides have been developed, − during which 4,6-di- O - tert -butylsilylene (DTBS)-protected galactosyl donor for stereospecific α-galactosylation is attractive. , 4,6- O -DTBS-protected thioglycoside 9 , which can be readily synthesized by following previous report, was employed as galactosyl donor for stereospecifical construction of α-galactosidic linkage regardless of C-2 protecting groups. The coupling of glycosyl donor 9 with azide-phytosphingosine acceptor 10 in the presence of N -iodosuccinimide (NIS, 1.5 equiv) and catalytic trifluoromethanesulfonic acid (TfOH, 0.3 equiv) smoothly provided the common precursor 11 as only the α-anomer ( J H1–H2 = 3.7 Hz).…”