Iminosugar idoBR1 Isolated from Cucumber Reduces Inflammatory Activity.

Cucumbers have been anecdotally claimed to have anti-inflammatory activity for a long time, but the active principle was not identified. idoBR1, (2,3,4,5)-3,4,5-trihydroxypiperidine-2-carboxylic acid, is an iminosugar amino acid isolated from fruits of certain cucumbers, (Cucurbitaceae). It has no chromophore and analytically behaves like an amino acid making detection and identification difficult.

d-Idose, d-Iduronic Acid, and d-Idonic Acid from d-Glucose via Seven-Carbon Sugars.

A practical synthesis of the very rare sugar d-idose and the stable building blocks for d-idose, d-iduronic, and d-idonic acids from -heptonic acid requires only isopropylidene protection, Shing silica gel-supported periodate cleavage of the C6-C7 bond of the heptonic acid, and selective reduction of C1 and/or C6. d-Idose is the most unstable of all the aldohexoses and a stable precursor which be stored and then converted under very mild conditions into d-idose is easily prepared.

Isolation from Stevia rebaudiana of DMDP acetic acid, a novel iminosugar amino acid: synthesis and glycosidase inhibition profile of glycine and β-alanine pyrrolidine amino acids.

DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-D-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and English bluebells, but that they are very difficult to purify. Reaction of unprotected pyrrolidine iminosugars with aqueous glyoxal gives the corresponding N-acetic acids in very high yield; Michael addition of both pyrrolidine and piperidine iminosugars and that of polyhydroxylated prolines to tert-butyl acrylate give the corresponding N-propionic acids in which the amino group of β-alanine is incorporated into the heterocyclic ring. These easy syntheses allow the identification of this new class of amino acid in plant extracts and provide pure samples for biological evaluation.

In silico analyses of essential interactions of iminosugars with the Hex A active site and evaluation of their pharmacological chaperone effects for Tay-Sachs disease.

The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a K value of 0.

Synthetic Chemical Inducers and Genetic Decoupling Enable Orthogonal Control of the rhaBAD Promoter.

External control of gene expression is crucial in synthetic biology and biotechnology research and applications, and is commonly achieved using inducible promoter systems. The E. coli rhamnose-inducible rhaBAD promoter has properties superior to more commonly used inducible expression systems, but is marred by transient expression caused by degradation of the native inducer, l-rhamnose.

Triacetonide of Glucoheptonic Acid in the Scalable Syntheses of d-Gulose, 6-Deoxy-d-gulose, l-Glucose, 6-Deoxy-l-glucose, and Related Sugars.

Ease of separation of petrol-soluble acetonides derived from the triacetonide of methyl glucoheptonate allows scalable syntheses of rare sugars containing the l-gluco or d-gulo structural motif with any oxidation level at the C6 or C1 position of the hexose, usually without chromatography: meso-d-glycero-d-guloheptitol available in two steps is an ideal entry point for the study of the biotechnological production of heptoses.

6-Deoxyhexoses from l-Rhamnose in the Search for Inducers of the Rhamnose Operon: Synergy of Chemistry and Biotechnology.

In the search for alternative non-metabolizable inducers in the l-rhamnose promoter system, the synthesis of fifteen 6-deoxyhexoses from l-rhamnose demonstrates the value of synergy between biotechnology and chemistry. The readily available 2,3-acetonide of rhamnonolactone allows inversion of configuration at C4 and/or C5 of rhamnose to give 6-deoxy-d-allose, 6-deoxy-d-gulose and 6-deoxy-l-talose. Highly crystalline 3,5-benzylidene rhamnonolactone gives easy access to l-quinovose (6-deoxy-l-glucose), l-olivose and rhamnose analogue with C2 azido, amino and acetamido substituents.

3-Fluoroazetidinecarboxylic Acids and trans,trans-3,4-Difluoroproline as Peptide Scaffolds: Inhibition of Pancreatic Cancer Cell Growth by a Fluoroazetidine Iminosugar.

Reverse aldol opening renders amides of 3-hydroxyazetidinecarboxylic acids (3-OH-Aze) unstable above pH 8. Aze, found in sugar beet, is mis-incorporated for proline in peptides in humans and is associated with multiple sclerosis and teratogenesis. Aze-containing peptides may be oxygenated by prolyl hydroxylases resulting in potential damage of the protein by a reverse aldol of the hydroxyazetidine; this, rather than changes in conformation, may account for the deleterious effects of Aze.

L-fucose from vitamin C with only acetonide protection.

Addition of human milk oligosaccharides (HMO) to baby foods may protect infants from disease. As many simple HMOs are fucosylated this is likely to increase the demand for L-fucose as a synthetic building block. Any chemical synthesis must be cheap to compete with a biotechnological process.

Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors.

All 16 stereoisomeric N-methyl 5-(hydroxymethyl)-3,4-dihydroxyproline amides have been synthesized from lactones accessible from the enantiomers of glucuronolactone. Nine stereoisomers, including all eight with a (3R)-hydroxyl configuration, are low to submicromolar inhibitors of β-N-acetylhexosaminidases. A structural correlation between the proline amides is found with the ADMDP-acetamide analogues bearing an acetamidomethylpyrrolidine motif.

2-N-Benzyl-2,6-dide-oxy-2,6-imino-3,4-O-iso-propyl-idene-d-allono-nitrile.

X-ray crystallography firmly established the relative stereochemistry of the title compound, C16H20N2O3. The acetonide ring adopts an envelope conformation with one of the O atoms as the flap and the piperidine ring adopts a slightly twisted boat conformation. The absolute configuration was determined by use of d-ribose as the starting material.

Short and sweet: (D)-glucose to (L)-glucose and (L)-glucuronic acid.

The scarcity and expense of access to L-sugars and other rare sugars have prevented the exploitation of their biological potential; for example D-psicose, only recently available, has been recognized as an important new food. Here we give the definitive and cheap synthesis of 99.4% pure L-glucose from D-glucose which requires purification of neither intermediates nor final product other than extraction into and removal of solvents; a simple crystallization will raise the purity to >99.

An approach to 8 stereoisomers of homonojirimycin from (D)-glucose via kinetic & thermodynamic azido-γ-lactones.

Crystal structures were obtained for the two C2 epimeric azido-γ-lactones 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-ido-heptono-1,4-lactone and 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-gulo-heptono-1,4-lactone prepared from kinetic and thermodynamic azide displacements of a triflate derived from d-glucoheptonolactone. Azido-γ-lactones are very useful intermediates in the synthesis of iminosugars and polyhydroxylated amino acids. In this study two epimeric azido-heptitols allow biotechnological transformations via Izumoring techniques to 8 of the 16 possible homonojirimycin analogues, 5 of which were isolated pure because of the lack of stereoselectivity of the final reductive amination.

(3R,4S,5R,6R,7S)-3,4,5,7-Tetrahydroxyconidine, an azetidine analogue of 6,7-diepicastanospermine and a conformationally constrained d-deoxyaltronojirimycin, from l-arabinose.

The synthesis from l-arabinose of an azetidine analogue of 6,7-diepicastanospermine and its glycosidase inhibition profile are described.

3-Hydroxyazetidine carboxylic acids: non-proteinogenic amino acids for medicinal chemists.

The formation from D-glucose of both enantiomers of 2,4-dideoxy-2,4-iminoribonic acid is the first chemical synthesis of unprotected 3-hydroxyazetidine carboxylic acids. The long-term stability of 3-hydroxyazetidine amides is established at acidic and neutral pH and implies their value as non-proteinogenic amino acid components of peptides, providing medicinal chemists with a new class of peptide isosteres. The structure of N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid was established by X-ray crystallographic analysis.

N-(2-Carb-oxy-eth-yl)-2,5-dide-oxy-2,5-imino-d-mannonic acid [(3R,4R,5R)-1-(2-carb-oxy-eth-yl)-3,4-dihy-droxy-5-hy-droxy-methyl-l-proline].

The absolute stereochemistry of the title compound, C(9)H(15)NO(7), was determined from the use of d-glucuronolactone as the starting material. The compound crystallizes as the zwitterion. The five-membered ring adopts an envelope conformation with the -CH(2)OH-substituted C atom forming the flap.

Glycosidase inhibition by all 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols prepared from the enantiomers of glucuronolactone.

The enantiomers of glucuronolactone are excellent chirons for the synthesis of the 10 stereoisomeric 2,5-dideoxy-2,5-iminohexitols by formation of the pyrrolidine ring by nitrogen substitution at C2 and C5, with either retention or inversion of configuration; the stereochemistry at C3 may be adjusted during the synthesis to give seven stereoisomers from each enantiomer. A definitive side-by-side comparison of the glycosidase inhibition of a panel of 13 glycosidases showed that 8 of the 10 stereoisomers showed significant inhibition of at least one glycosidase.

N-Benzyl-3,5-dide-oxy-3,5-imino-1,2-O-isopropyl-idene-β-l-lyxofuran-ose.

X-ray crystallography confirmed the formation, structure and relative stereochemistry of the title compound, C(15)H(19)NO(3), which contains a sterically congested four-membered azetidine ring system. The absolute configuration was determined by the use of l-arabinose as the starting material.

Synthesis from D-altrose of (5R,6R,7R,8S)-5,7-dihydroxy-8-hydroxymethylconidine and 2,4-dideoxy-2,4-imino-D-glucitol, azetidine analogues of swainsonine and 1,4-dideoxy-1,4-imino-D-mannitol.

Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.

2-N-Benzyl-2,6-dide-oxy-2,6-imino-3,4-O-isopropyl-idene-3-C-methyl-d-allono-nitrile.

X-ray crystallography firmly established the relative stereochemistry of the title compound, C(17)H(22)N(2)O(3). The absolute configuration was determined by use of 2-C-methyl-d-ribonolactone as the starting material. The compound exists as O-H⋯N hydrogen-bonded chains of mol-ecules running parallel to the a-axis.

Azetidine iminosugars from the cyclization of 3,5-di-O-triflates of α-furanosides and of 2,4-di-O-triflates of β-pyranosides derived from glucose.

Primary amines with either 3,5-di-O-ditriflates of α-furanosides or 2,4-di-O-triflates of β-pyranosides form bicyclic azetidines in high yield.

Eight stereoisomers of homonojirimycin from D-mannose.

Although there are 32 6-azidoheptitols, there are only 16 homonojirimycin (HNJ) stereoisomers. Two epimeric azidoalditols derived from d-mannose allow the synthesis in water of eight stereoisomers of HNJ.

6-De-oxy-3,4-O-isopropyl-idene-2-C-methyl-l-galactono-1,5-lactone.

X-ray crystallography unequivocally confirmed the stereochemistry of the 2-C-methyl group in the title mol-ecule, C(10)H(16)O(5), in which the 1,5-lactone ring exists in a boat conformation. The absolute stereochemistry was determined by the use of d-ribose in the synthesis. The crystal exists as O-H⋯O hydrogen bonded chains of mol-ecules running parallel to the a axis with each mol-ecule acting as a donor and acceptor for one hydrogen bond.

N-Benzyl-1,3-dide-oxy-1,3-imino-l-xylitol.

The structure determination confirms the stereochemistry of the title compound, C(12)H(17)NO(3), which contains a four-membered azetidine ring system. The absolute configuration was determined by the use of d-glucose as the starting material. In the crystal, O-H⋯O and O-H⋯N hydrogen bonds link the mol-ecules into layers in the ab plane.