Stereoselective synthesis of alpha-C-Substituted 1,4-dideoxy-1,4-imino-D-galactitols. Toward original UDP-Galf mimics via cross-metathesis

[reaction: see text] Various alpha-C-substituted 1,4-dideoxy-1,4-imino-d-galactitols were prepared efficiently from 1-O-acetyl-2,3,5,6-tetra-O-benzyl-d-glucofuranose by a four-step sequence involving as the key step the highly syn-selective TMSOTf-catalyzed addition of silylated nucleophiles to a glycofuranosylamine. Cross-metathesis of the alpha-C-allylated iminogalactofuranose derivative with an original uridin-5'-yl vinylphosphonate led to novel UDP-galactofuranose mimics. Such compounds are of interest as potential inhibitors of the mycobacterial galactan biosynthesis pathway.     

Potent competitive inhibition of α-galactosidase and α-glucosidase activity by 1,4-dideoxy-1,4-iminopentitols: syntheses of 1,4-dideoxy-1,4-imino-d-lyxitol and of both enantiomers of 1,4-dideoxy-1,4-iminoarabinitol

The syntheses of 1,4-dideoxy-1,4-imino-D-lyxitol (3), 1,4-dideoxy-1,4-imino-d-arabinitol (4) and 1,4-dideoxy-1,4-imino-l-arabinitol (5) are reported; (3) is a potent competitive inhibitor of α-galactosidase (green coffee beans) and (4) a competitive inhibitor of α-glucosidase (Brewer's yeast) suggesting that iminopentitols have considerable potential as glycosidase inhibitors. (4) was found to be identical to an alkaloid recently isolated from $\text{Angylocalyx boutiqueanus}$.     

Asymmetric synthesis of 1,4-dideoxy-1,4-imino-d-ribitol via stereoselective addition of allylphenylsulfone to an aryl N-sulfinylimine

Asymmetric synthesis of 1,4-dideoxy-1,4-imino-d-ribitol was achieved utilizing the stereoselective addition of allylphenylsulfone to a chiral N-sulfinyl-2-furfuryl imine and ring-closing metathesis reactions as key steps.     

Asymmetric synthesis of 1,4-dideoxy-1,4-imino- -ribitol via stereoselective addition of allylphenylsulfone to an aryl N-sulfinylimine

Asymmetric synthesis of 1,4-dideoxy-1,4-imino- -ribitol was achieved utilizing the stereoselective addition of allylphenylsulfone to a chiral N-sulfinyl-2-furfuryl imine and ring-closing metathesis reactions as key steps.     

Polyhydroxylated pyrrolidines from sugar lactomes: Synthesis of 1,4-dideoxy-1,4-imino-d-glucitol from d-galactonolactone and syntheses of 1,4-dideoxy-1,4-imino-d-allitol, 1,4-dideoxy-1,4-imino-d-ribitol,and (2s,3r,4s)-3,4-dihydroxyproline from d-gulonolactone

The use of readily available sugar lactones in the synthesis of polyhydroxylated pyrrolidines is illustrated by the preparation of the glucosidase inhibitor 1,4-dideoxy-1, 4-imino-D-glucitol from D-galactonolactone and by the conversion of D-gulonolactone into 1,4-dideoxy-l,4-imino-D-allitol, 1,4-dideoxy-l,4-imino-D-ribitol, and (2S,3R,4S)-3,4-dihydroxyproline.     

Looking glass inhibitors: synthesis of a potent naringinase inhibitor l-DIM [1,4-dideoxy-1,4-imino-l-mannitol], the enantiomer of DIM [1,4-dideoxy-1,4-imino-d-mannitol] a potent α-d-mannosidase inhibitor

The synthesis of l-DIM [1,4-dideoxy-1,4-imino-l-mannitol] and of 1,4-imino-d-glycero-l-talo-heptitol from d-glycero-d-gulo-heptono-1,4-lactone depends on the use of pentan-3-one to form two five ring ketals as described by Burke, rather than the formation of one five ring and one six ring ketal formed with acetone. l-DIM, the enantiomer of the potent α-d-mannosidase inhibitor DIM [1,4-dideoxy-1,4-imino-d-mannitol] is a good inhibitor of naringinase (an α-l-rhamnosidase) with a K_i of 3.63 μM. 1,4-Imino-d-glycero-l-talo-heptitol is a moderate inhibitor of naringinase.     

Efficient stereodivergent synthesis of 1,4-dideoxy-1,4-iminohexitols from an (S)-glyceraldimine

A stereodivergent synthesis of 1,4-dideoxy-1,4-imino-d-mannitol I and d-allitol III from an (S)-glyceraldimine, which is easily prepared from d-mannitol, has been achieved with overall yields of 62% and 49%, respectively. The synthesis is based on the addition of vinylmagnesium bromide to N-benzylimine 1, derived from readily available (R)-2,3-O-isopropylideneglyceraldehyde, followed by N-allylation or N-acryloylation, ring-closing metathesis and asymmetric dihydroxylation.     

A concise synthesis of tetrahydroxy-LCB, alpha-galactosyl ceramide, and 1,4-dideoxy-1,4-imino-L-ribitol via D-allosamines as key building blocks

The total syntheses of tetrahydroxy-LCB 1, alpha-galactosyl ceramide 2, and 1,4-dideoxy-1,4-imino-L-ribitol 3 via D-allosamine derivatives as common synthons are described here.     

Synthesis of 1,4-dideoxy-1,4-imino-derivatives of d-allitol, l-allitol and d-talitol: a stereo selective approach for azasugars

A stereo selective approach for the azasugars 1,4-dideoxy-1,4-imino-d-allitol, l-allitol, and 1,4-dideoxy-1,4-imino-d-talitol is described for different olefin compounds I derived from (R)-2,3-O-isopropylidine glyceraldehyde, l-ascorbic acid, and d-isoascorbic acid by using vinyl Grignard addition, allylation, RCM, and dihydroxylation as the key steps.     

Chiral building blocks from biomass: 2,5-diamino-2,5-dideoxy-1,4-3,6-dianhydroiditol

An efficient route towards the synthesis of 2,5-diamino-2,5-dideoxy-1,4-3,6-dianhydroiditol 4 has been developed resulting in significant improvements in both isolated yields and purity when compared to literature procedures. As a consequence, resin-grade 2,5-diamino-2,5-dideoxy-1,4-3,6-dianhydroiditol 4 has become available for laboratory scale step-growth polymer synthesis. Additionally, an interesting renewable chiral 2-amino-2-deoxy-1,4-3,6-dianhydroiditol 10, has been isolated.     

A concise enantioselective synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol using Co(III)(salen)-catalyzed hydrolytic kinetic resolution of a two-stereocentered anti-azido epoxide

A concise enantioselective synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol, (+)-DAB-1, has been described in good overall yield (18.1%) and with high enantiomeric purity (up to 98% ee) starting from a simple raw material, cis-2-butene-1,4-diol. The Co-catalyzed hydrolytic kinetic resolution of a two-stereocentered racemic azido epoxide followed by asymmetric dihydroxylation of the alkene and ‘one pot’ reductive cyclisation of the azido diol are key reactions in the synthetic sequence.     

Metal trifluoromethanesulfonate-catalyzed regioselective borane-reductive ring opening of benzylidene acetals: a concise synthesis of 1,4-dideoxy-1,4-imino-L-xylitol

[reaction: see text] A highly regioselective borane-reductive ring opening of the 4,6-O-benzylidene-D-hexopyranosides to the corresponding 6-alcohols in excellent yields at room temperature via various metal trifluoromethanesulfonates as catalysts is described here. Its application in the synthesis of 1,4-dideoxy-1,4-imino-L-xylitol is also highlighted.     

An efficient synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol and 1,4-dideoxy-1,4-imino-d- and l-xylitol from chiral aziridines

A highly efficient method for the synthesis of 1,4-dideoxy-1,4-imino-d- and l-arabinitol (d-AB1, 1 and l-AB1, 3) and 1,4-dideoxy-1,4-imino-d- and l-xylitol (d-DIX, 2 and l-DIX, 4) starting from commercially available chiral aziridines was developed. The general strategy employs a sequence involving two-carbon homologation, dihydroxylation, and regioselective aziridine ring opening/intramolecular five-membered iminosugar ring formation. The facile use of recrystallization to generate pure diastereomers makes the routes more amenable to large-scale synthesis.     

Preliminary studies on the transformation of nitrosugars into branched chain iminosugars: synthesis of 1,4-dideoxy-4-C-hydroxymethyl-1,4-imino-pentanols

A novel promising strategy for the transformation of nitrosugars into branched pyrrolidines, based on double Henry reaction with formaldehyde followed by reductive ring closure, allowed the first enantiospecific synthesis of a 4-C-hydroxymethyl branched derivative of the well-known glycosidase inhibitor 1,4-dideoxy-1,4-imino-pentanol. This strategy also afforded a new route to some other interesting derivatives, such as N-hydroxy, N-propyloxy, and imino derivatives, a new kind of compounds with promising biological properties. [reaction: see text].     

1,4:3,6-dianhydro-2,5-dideoxy-2,5-bis(diphenylphosphino)-l-iditol. A new chiral ligand for asymmetric hydrogenation with rhodium complexes as catalysts

A new chiral 1,4-diphosphine, 1,4:3,6-dianhydro-2,5-dideoxy-2,5-bis(diphenylphosphino)-l-iditol, has been prepared from d-mannitol. Rhodium complexes of this ligand are asymmetric homogeneous hydrogenation catalysts for dehydroamino acids, giving (S)-amino acids in 21–58% optical yields.     

Looking glass inhibitors: both enantiomeric N-benzyl derivatives of 1,4-dideoxy-1,4-imino-d-lyxitol [a potent competitive inhibitor of α-d-galactosidase] and of 1,4-dideoxy-1,4-imino-l-lyxitol [a weak competitive inhibitor of α-d-galactosidase] inhibit naringinase,an α-l-rhamnosidase competitively

Benzhydryl protection by diphenyldiazomethane of an alcohol in enantiomeric base-sensitive ribonolactones allows short efficient syntheses of 1,4-dideoxy-1,4-imino-d-lyxitol (DIL) and of 1,4-dideoxy-1,4-imino-l-lyxitol (LIL). DIL showed potent [K_i = 0.13 μM]—and LIL showed weak [K_i = 113 μM]—competitive inhibition of α-d-galactosidase. Both enantiomers N-benzyl-DIL [K_i = 64 μM] and N-benzyl-LIL [K_i = 13 μM] were moderate competitive inhibitors of naringinase, an α-l-rhamnosidase.     

Regioselective intramolecular ring closure of 2-amino-6-bromo-2,6-dideoxyhexono-1,4-lactones to 5- or 6-membered iminuronic acid analogues: synthesis of 1-deoxymannojirimycin and 2,5-dideoxy-2,5-imino-D-glucitol

1-Deoxymannojirimycin (8c) was synthesised from 2-amino-6-bromo-2,6-dideoxy-D-mannono-1,4-lactone (7) by intramolecular direct displacement of the C-6 bromine employing non-aqueous base treatment followed by reduction of the intermediate methyl ester. Likewise, using aqueous base at pH 12, ring closure took place by 5-exo attack on the 5,6-epoxide leading to 2,5-dideoxy-2,5-imino-L-gulonic acid (9b), which was reduced to 2,5-dideoxy-2,5-imino-D-glucitol (9b). The method was further applied to 2-amino-6-bromo-2,6-dideoxy-D-galacto- as well as D-talo-1,4-lactones (14 and 15). However, only the corresponding six-membered ring 1,5-iminuronic acid mimetics, namely (2R,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-galactonic acid, 16) and (2S,3R,4S,5R)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-D-talonic acid, 17), were obtained. The corresponding enantiomers, L-galacto- as well as L-talo-2-amino-6-bromo-2,6-dideoxy-1,4-lactones ent-14 and ent-15, reacted accordingly to give the D-galacto- and L-altro-1,5-iminuronic acid mimetics, (2S,3S,4R,5S)-3,4,5-trihydroxypipecolic acid (2,6-dideoxy-2,6-imino-L-galactonic acid, ent-16) and (2R,3S,4R,5S)-3,4,5-trihydroxypipecolic acids (2,6-dideoxy-2,6-imino-L-talonic acid, ent-17), respectively.     

Palladium(II)-catalyzed highly regio- and diastereoselective cyclization of difunctional allylic N-tosylcarbamates. A convenient synthesis of optically active 4-vinyl-2-oxazolidinones and total synthesis of 1,4-dideoxy-1,4-imino-L-xylitol

A Pd(II)-catalyzed cyclization of difunctional allylic N-tosyl carbamates in the presence of halide ions was developed with high regio- and diastereoselectivity. The reaction involves aminopalladation of alkene and beta-heteroatom elimination to regenerate Pd(II) species. When the readily available homochiral alcohols were used as substrates, highly optically active 4-vinyl-2-oxazolidinones were easily obtained. The utility of this method was exemplified by the convenient synthesis of 1,4-dideoxy-1,4-imino-L-xylitol.     

Development and validation of a capillary electrophoresis-indirect photometric detection method for the determination of the non-UV-absorbing 1,4-dideoxy-1,4-imino-D-arabinitol in active pharmaceutical ingredients,solutions and tablets using an internal standard

A high speed, selective, and robust capillary electrophoresis (CE) method with high capacity was developed and validated for determination of assay of 1,4-dideoxy-1,4-imino-D-arabinitol in active pharmaceutical ingredients, solutions, and tablets during the development work at preclinical and Phase I and II clinical studies. 1,4-Dideoxy-1,4-imino-D-arabinitol, tartrate has (almost) no UV absorption. Therefore, the developed CE method for quantification was based on indirect UV detection. A cation CE principle was chosen using an electrolyte at pH 4.0 containing dimethyldiphenylphosphonium hydroxide, which has a strong UV absorbance. The quantification was performed using internal standard technique, by which piperidine was used as internal standard. The method was validated. The validation results showed that the CE method was suitable for the assay (and dissolution) analysis.