Direct Stereoselective Aziridination of Cyclohexenols with 3‐Amino‐2‐(trifluoromethyl)quinazolin‐4(3H)‐one in the Synthesis of Cyclitol Aziridine Glycosidase Inhibitors

Abstract

Cyclophellitol aziridine and its configurational and functional isomers are powerful covalent inhibitors of retaining glycosidases, and find application in fundamental studies on glycosidases, amongst others in relation to inherited lysosomal storage disorders caused by glycosidase malfunctioning. Few direct and stereoselective aziridination methodologies are known for the synthesis of cyclophellitol aziridines. Herein, we present our studies on the scope of direct 3‐amino‐2‐(trifluoromethyl)quinazolin‐4(3H)‐one‐mediated aziridination on a variety of configurational and functional cyclohexenol isosters. We demonstrate that the aziridination can be directed by an allylic or homoallylic hydroxyl through H‐bonding and that steric hindrance plays a key role in the diastereoselectivity of the reaction.

Xylose‐Configured Cyclophellitols as Selective Inhibitors for Glucocerebrosidase

“…The synthesis of xylo ‐cyclophellitol 1 , aziridine 2 , 5 and ABPs 6 and 7 ,[ 37 , 38 ] cyclophellitol aziridine 4 , [39] conduritol B‐aziridine 14 , [39] α‐ d ‐xylose‐configured cyclophellitol 11 and aziridine 12 was published previously, [37] whereas that of ABP 8 can be found in the SI and is based on synthetic procedures we reported on previously. [38] …”

“…The synthesis of xylo-cyclophellitol 1, aziridine 2, 5 and ABPs 6 and 7, [37,38] cyclophellitol aziridine 4, [39] conduritol B-aziridine 14, [39] α-d-xylose-configured cyclophellitol 11 and aziridine 12 was published previously, [37] whereas that of ABP 8 can be found in the SI and is based on synthetic procedures we reported on previously. [38] In the first instance, the inhibitory potency of 1 and 2 for GBA, GBA2, and GBA3 was assessed by competitive activitybased protein profiling (cABPP).…”

Conformationally constrained fused bicyclic iminosugars: synthetic challenges and opportunities

“…N-octyl conduritol aziridine 82d, a specific covalent inactivator of GBA1 (K i = 4.8 nM), was indeed found to be 500-fold more potent than 82b, its N-butyl analog. 62 Aziridination of compound 83, 62,63 obtained from diene 75, 55,64 with quinazolinone 84 in the presence of phenyl iododiacetate afforded the key intermediate 85 as a single diastereoisomer (Scheme 14). 62 First attempts to remove the protecting groups under Birch conditions were unsuccessful.…”

An Orthogonally Protected Cyclitol for the Construction of Nigerose- and Dextran-Mimetic Cyclophellitols

“…Treatment of 16 with m -CPBA and NaHCO 3 in anhydrous DCM yielded exclusively α-epoxide 17 in 70% yield. Conversion of precursor 16 to the aziridine was accomplished using 3-amino-2-(trifluoromethyl)­quinazolin-4­(3 H )-one (CF 3 -Q-NH 2 ) and BAIB in anhydrous DCM, exclusively yielding α-aziridine 18 in 76% yield . Birch reduction of compounds 17 and 18 resulted in the clean removal of the benzyl, trityl, and CF 3 -Q protecting groups, yielding compounds 19 and 20 in 71% and 86% yields, respectively.…”

“…Conversion of precursor 16 to the aziridine was accomplished using 3-amino-2-(trifluoromethyl)quinazolin- 4(3H)-one (CF 3 -Q-NH 2 ) and BAIB in anhydrous DCM, exclusively yielding α-aziridine 18 in 76% yield. 31 Birch reduction of compounds 17 and 18 resulted in the clean removal of the benzyl, trityl, and CF 3 -Q protecting groups, yielding compounds 19 and 20 in 71% and 86% yields, respectively. The synthesis of dextran analogue trisaccharidic compounds 27 and 28 (Scheme 4) started by subjecting alkene 15a to TFA and TES in anhydrous DCM, to selectively remove the trityl protecting group, followed by removal of the TBS protecting group by treatment with TBAF in THF, yielding compound 21 (72% over two steps).…”