Synthesis of 1,3,4,6-tetra-O-acetyl-2-[3-alkyl-(aryl)-thioreido]-2-deoxy-α-d-glucopyranoses and their transformation into 2-alkyl(aryl)amino-(1,2-dideoxy-α-d-glucopyrano)[2,1-d]-2-thiazolines

Analysis of transition state mimicry by tight binding aminothiazoline inhibitors provides insight into catalysis by human O-GlcNAcase

“…Using three different approaches ( Scheme 1 ) we synthesized a series of 2′-alkylaminothiazoline derivatives. Using the common intermediate hydrochloride salt of 1,3,4,6-tetra- O -acetyl-2-amino-2-deoxy-β- d -glucopyranose 8 ( Scheme 1A and B ), which was conveniently accessed in three steps, 44 we prepared compounds 11a and 11b by reacting either N -fluorenylmethyloxycarbonyl (Fmoc)-protected isothiocyanate or N -allyl isothiocyanate with 8 in the presence of triethylamine to generate the respective thiourea intermediates 9a and 9b . Subsequent cyclization with excess SnCl 4 followed by a two step deprotection using catalytic NaOMe in anhydrous methanol, and piperidine catalyzed removal of the Fmoc group, afforded analogue 11a .…”

“…Inhibitors 15a–h were synthesized using an alternate route from the common isothiocyanate intermediate 1,3,4,6-tetra- O -acetyl-2-deoxy-2-isothiocyanato-β- d -glucopyranose ( Scheme 1C , 12 ), which was prepared from 8 via a biphasic reaction in H 2 O/DCM with thiophosgene. 44 Reaction of isothiocyanate 12 with a series of alkylamines and dialkylamines, or their respective hydrochloride salts, yielded thioureas 13a–h . Acid catalyzed cyclization of these thiourea-containing compounds using TFA provided protected aminothiazolines 14a–h , which after deprotection with K 2 CO 3 afforded 15a–h .…”

Oxidative Desulfurization of Azole‐2‐thiones with Benzoyl Peroxide: Syntheses of Ionic Liquids and Other Azolium Salts

“…Second, based on Johnson and Buchanan's synthesis of 1‐methyl‐2‐thiohydantoin,76 N ‐phenylglycine was dissolved in aqueous ethanolic potassium hydroxide and acylated with phenyl isothiocyanate. The putative intermediate α‐thioureido acid was precipitated, then cyclized in low yield, likely the result of competitive S ‐alkylation in the acylium intermediate 77,78. The specimens were indistinguishable by TLC, IR, and 1 H and 13 C NMR spectroscopy.…”

Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies

“…Access to analogues of 1 bearing a 5-fluoromethyl group with modifications to the thiazoline N -ethyl moiety was achieved as indicated in Scheme . Treatment of the isothiocyanate 62 with allylamine followed by TFA-mediated cyclization provided 63 . Sequential Boc-protection of the amino group, acetate deprotection, TBDMS-protection of the primary alcohol, and benzoyl-protection of the secondary alcohols led to the orthogonally protected material 65 .…”

“…Analogues of 1 bearing cyclic amino substituents at the 2′-position such as 34 and 48 were generated as shown in Scheme . Treatment of the isothiocyanate 62 with azetidine/HCl provided the corresponding thiourea, which was cyclized using TFA to furnish 94 . Deprotection with K 2 CO 3 /MeOH gave 34 , which could be selectively protected as the silyl ether 95 .…”