Synthesis of Cyclophellitol, Cyclophellitol Aziridine, and Their Tagged Derivatives

Abstract

Cyclitol epoxides and aziridines are potent and selective irreversible inhibitors of retaining glycosidases. We have previously reported on our studies on the use of activity‐based probes derived from cyclophellitol and from its aziridine analogue for activity‐based profiling of retaining β‐glucosidases in vitro, in situ, and in some examples also in vivo. In this work we disclose full details of the synthesis, purification, and analysis of a comprehensive panel of cyclophellitol analogues, all featuring the β‐glucose configuration and designed as tools for selective inhibition and/or imaging of human acid glucosylceramidase (epoxides) or as broad‐spectrum probes for retaining β‐glucosidases (aziridines).

The Synthesis of Cyclophellitol‐Aziridine and Its Configurational and Functional Isomers

“…The homoallylic alcohol embedded in partially protected cyclohexene 20 proved also ideal for the stereospecific introduction of an amine functionality, as we demonstrated in our synthesis of cyclophellitol‐aziridine ( 2 ) . Reaction of 20 with trichloroacetonitrile and DBU as base gave trichloroacetimidate 21 .…”

“…Madsen and co‐workers prepared cyclophellitol ( 1 ) via cyclohexene intermediate 20 , itself prepared through RCM on the appropriate diene (Scheme ). In this route (optimized by us recently), d ‐xylose is converted in three steps into iodofuranoside 16 . First, kinnetic Fischer glycosylation of d ‐xylose in methanol provided methyl xylofuranoside.…”

Furanosyl Oxocarbenium Ion Conformational Energy Landscape Maps as a Tool to Study the Glycosylation Stereoselectivity of 2‐Azidofuranoses, 2‐Fluorofuranoses and Methyl Furanosyl Uronates

“…All donors studied here were equipped with an N ‐phenyl trifluoroacetimidate anomeric leaving group . The uronic acid methyl esters 17 – 20 were obtained from their parent methyl furanosides 13 – 16 by a straightforward TEMPO/BAIB oxidation procedure of the primary alcohols, followed by methylation with MeI and K 2 CO 3 (Scheme A) . Aqueous TFA‐mediated hydrolysis of the anomeric methyl group and installation of the trifluoro‐ N ‐phenyl imidate group with Cs 2 CO 3 proceeded uneventfully to give donors 1 – 4 .…”

Carba-cyclophellitols Are Neutral Retaining-Glucosidase Inhibitors

“…8 Global benzylation of 7 gave cyclohexene 8 , and cyclopropanation with ethyl diazoacetate (EDA) 10,11 under the agency of Cu(acac) 2 resulted in the formation of product 9 as a mixture of α- and β-isomers (α/β, 2:1). After the reduction step 12 the β-isomer could be isolated by column chromatography to give alcohol 10 , which was oxidized, and ensuing esterification yielded enantiomerically pure β-ester 11 .…”