Nickel-catalyzed α-glycosylation of C(1)-hydroxyld-myo-inositol: a formal synthesis of mycothiol

Abstract

Formal synthesis of mycothiol has been developed via nickel-catalyzed α-glycosylation of the C(1)-hydroxyl group of D-myo-inositols with C(2)-N-substituted benzylideneamino N-phenyl trifluoroacetimidate donors. The pseudo-oligosaccharides were obtained in good yield and with excellent α-selectivity. Removal of the C(2)-N-2-trifluoromethylphenyl-benzylidene group under mild conditions provides a pseudo-disaccharide, completing the formal synthesis of mycothiol.

Synthesis of a polymerizable, bivalent glycan mimetic of the HIV envelope spike gp120

“…In order to accomplish this, the traditional Lewis acid (TMSOTf) and the Ni(4-F-PhCN) 4 (OTf) 2 catalyst recently developed in our lab 27 were compared in the trihaloacetimidate glycosylation reactions. Our results demonstrate the ability of Ni(4-F-PhCN) 4 (OTf) 2 as an efficient catalyst for activating an acetimidate donor under a mild and operationally simple procedure.…”

Scalable Synthesis of Fmoc-Protected GalNAc-Threonine Amino Acid and TN Antigen via Nickel Catalysis

“…15 Additionally, we have illustrated that Ni(4-F-PhCN) 4 (OTf) 2 effectively promoted a coupling of Cbz-protected threonine residue 10 with C(2)- para -(trifluoromethyl)benzylidenamino trichloroacetimidate donor 9 to afford glycosyl amino acid 11 (Scheme 2a) in 81% yield with α:β = 15:1. 15b We postulated that an analogous nickel-catalyzed α-selective coupling would be possible with Fmoc-protected amino acid 13 (Scheme 2b).…”

“…On the basis of our recent successful results with the use of N -phenyl trifluoroacetimidates as effective donors, 15d–f we hypothesize that triacetyl galactosamine donor 16 (Scheme 3), bearing the C(2)- N - ortho -(trifluoromethyl)benzylidene group, is a suitable starting material for the rapid and gram-scale synthesis of glycoside 15 , its corresponding Fmoc-protected threonine amino acid 8 , and T N antigen ( 1 ). In contrast to our existing systems (Schemes 2a–b), 7–10 this process can promote the glycoyslation with both α- and β-anomers of 16 16 and only relies on substoichiometric amounts of the nickel catalyst.…”

“…While it was known that Ni(4-F-PhCN) 4 (OTf) 2 effectively promoted the glycosylation of a wide variety of carbohydrate acceptors with C(2)- ortho -(trifluoromethyl)benzylidenamino N -phenyl trifluoroacetimidate donors, 15e–f,17 it was unclear if the reaction of Fmoc-protected threonine amino acid 13 with substrate 16 would proceed with high yield and α-selectivity. Importantly, it was still unclear if the nickel method can be utilized in a large scale preparation of glycosyl amino acid 15 (Scheme 3).…”

“…The previous conditions (2N – 5N HCl, acetone, 25 – 50 °C) 15 for the exchange of C(2)-N-benzylidenamino functionality with N- acetyl group to form 22 (Scheme 4) may not be suitable for use in a large scale synthesis. Using the product 15 from Scheme 3c, we found that the benzylidene group could be removed with acetyl chloride (1.6 equiv) in methanol at 25 °C.…”