CuAAC click chemistry with N-propargyl 1,5-dideoxy-1,5-imino-D-gulitol and N-propargyl 1,6-dideoxy-1,6-imino-D-mannitol provides access to triazole-linked piperidine and azepane pseudo-disaccharide iminosugars displaying glycosidase inhibitory properties

Iminosugars: Effects of Stereochemistry, Ring Size, and N-Substituents on Glucosidase Activities

“…Initially, target 1-deoxy-L- gulo -nojirimycin ( 26 - 29a ) and D- manno -azepane derivatives ( 26 - 29b ) were synthesized by a regiospecific C 2 -symmetric unprotected bis-epoxide opening strategy in the presence of primary amines, followed by an S N 2 aminocyclization reaction to give a mixture of both six- and seven-membered iminosugar isomers [45,46,47]. As previously reported, the synthesis of unprotected bis-epoxide 25 was promptly achieved from the simple and commercially available starting material, D-mannitol, in two steps, by tosylation of both D-mannitol primary alcohols (71%), followed by a base-promoted intramolecular S N 2 reaction to give 1,2:5,6-dianhydro-D-mannitol 25 (29%), Scheme 1A [43]. Opening of the homochiral C 2 -symmetric bis-epoxide 25 by alkylamines (at the less-hindered position of one epoxy function) led to the formation of secondary amines, which promoted an S N 2 aminocyclization reaction to give a mixture of polyhydroxy-piperidine and -azepane by 6-exo-tet or 7-endo-tet processes, respectively.…”

“…Inspired by a series of reported deoxynojirimycin disaccharides that were decorated with equal α- or β-glucopyranose units at C-2, C-3, and C-4 DNJ positions ( 12 - 17 ) [40,41], along with N -glycosylated deoxynojirimycin, MDL 73,945 ( 18 ) [42], we had reported an alternative approach, using functionalized isomeric 1,5-dideoxy-1,5-imino-D-gulitol (L- gulo -piperidines, with inverted configurations at C-2 and C-5 with respect to glucose or DNJ, 19 - 21 ) and 1,6-dideoxy-1,6-imino-D-mannitol (D- manno -azepane derivatives, 22 - 24 ) cores N -linked to different sites of glucopyranose units, such as C-1, C-3, and C-6 positions [43]. To reach this goal, we used a CuAAC reaction (copper azide alkyne cycloaddition reaction), as a click chemistry strategy, to connect six- and seven-membered iminosugars to glucose in different arrangements through triazole bridges to produce the most active α-glucosidase inhibitor ( 21 ) of the pseudo-disaccharide series, L-gulopiperidine attached to glucose C-6 position, with IC 50 approximately three-fold lower than that of DNJ (Figure 1) [43].…”

“…Despite the reported loss of α-glucosidase activity under modification at the C-5 position of the iminosugar, such as displayed by 1-deoxy-L- ido -nojirimycin (with an inverted configuration at C-5 with respect to DNJ) [24] and for 1,5-dideoxy-1,5-iminoxylitol (lacking the C-5 hydroxymethyl group of DNJ) [27,28], we have been encouraged to continue our studies on L- gulo -piperidines based on the remarkable α-glucosidase inhibition previously obtained for pseudo-disaccharides with simultaneous inverted configurations at C-2 and C-5 positions in relation to glucose stereochemistry [43]. Thus, to understand the relative contribution of the ring size, stereochemistry, and N -alkyl substitution on glycosidase inhibition, we proceeded with the synthesis of a small library of N -substituted 1-deoxy-L- gulo -nojirimycin and D- manno -azepane derivatives and compared them with the corresponding classical N -substituted of 1-deoxy-D- gluco -piperidine (DNJ) and L- ido -azepane counterparts as glucose-type carbohydrate mimetics.…”

“…Thus, to understand the relative contribution of the ring size, stereochemistry, and N -alkyl substitution on glycosidase inhibition, we proceeded with the synthesis of a small library of N -substituted 1-deoxy-L- gulo -nojirimycin and D- manno -azepane derivatives and compared them with the corresponding classical N -substituted of 1-deoxy-D- gluco -piperidine (DNJ) and L- ido -azepane counterparts as glucose-type carbohydrate mimetics. To reach this goal, N -hydroxyethyl and N -butyl groups of miglitol and miglustat drugs, respectively, were investigated as highly important N -alkyl substitutions for glucosidase inhibition, besides N -phenethyl [44], and N -propynyl [43] as a less-active counterpart.…”

Synthesis of Substituted Oxo-Azepines by Regio- and Diastereoselective Hydroxylation

“…Azepanols and oxo-azepines are typically constructed via the ring-expansion or cyclization of appropriately derivatized sugars or furans with pre-established substitution patterns and stereochemistry. Methods of ring-expansion and cyclization have most-commonly included reductive amination [ 19 , 20 , 25 , 26 , 27 , 28 , 29 ] or epoxide ring opening with suitable amines [ 30 , 31 ], ring-closing metathesis (RCM) [ 32 , 33 , 34 ], alkene–nitrone cycloaddition [ 35 ] and tandem Staudinger aza–Wittig reactions [ 36 ]. The Spiegel synthesis of glucosepane utilized commercially available diacetone- d -glucose ($3.20/g) as a precursor to oxo-azepine vi via a key Amadori rearrangement ( Scheme 1 b) [ 24 ].…”