Dimethylcysteine (DiCys)/o-Phthalaldehyde Derivatization for Chiral Metabolite Analyses: Cross-Comparison of Six Chiral Thiols

Metabolomics profiling using liquid chromatography-mass spectrometry (LC-MS) has become an important tool in biomedical research. However, resolving enantiomers still represents a significant challenge in the metabolomics study of complex samples. Here, we introduced N,N-dimethyl-l-cysteine (dimethylcysteine, DiCys), a chiral thiol, for the o-phthalaldehyde (OPA) derivatization of enantiomeric amine metabolites. We took interest in DiCys because of its potential for multiplex isotope-tagged quantification. Here, we characterized the usefulness of DiCys in reversed-phase LC-MS analyses of chiral metabolites, compared against five commonly used chiral thiols: N-acetyl-l-cysteine (NAC); N-acetyl-d-penicillamine (NAP); isobutyryl-l-cysteine (IBLC); N-(tert-butoxycarbonyl)-l-cysteine methyl ester (NBC); and N-(tert-butylthiocarbamoyl)-l-cysteine ethyl ester (BTCC). DiCys and IBLC showed the best overall performance in terms of chiral separation, fluorescence intensity, and ionization efficiency. For chiral separation of amino acids, DiCys/OPA also outperformed Marfey’s reagents: 1-fluoro-2-4-dinitrophenyl-5-l-valine amide (FDVA) and 1-fluoro-2-4-dinitrophenyl-5-l-alanine amide (FDAA). As proof of principle, we compared DiCys and IBLC for detecting chiral metabolites in aqueous extracts of rice. By LC–MS analyses, both methods detected twenty proteinogenic l-amino acids and seven d-amino acids (Ala, Arg, Lys, Phe, Ser, Tyr, and Val), but DiCys showed better analyte separation. We conclude that DiCys/OPA is an excellent amine-derivatization method for enantiomeric metabolite detection in LC-MS analyses.     

‘Reverse biomimetic’ synthesis of l-arogenate and its stabilized analogues from l-tyrosine

l-Arogenate (also known as l-pretyrosine) is a primary metabolite on a branch of the shikimate biosynthetic pathway to aromatic amino acids. It plays a key role in the synthesis of plant secondary metabolites including alkaloids and the phenylpropanoids that are the key to carbon fixation. Yet understanding the control of arogenate metabolism has been hampered by its extreme instability and the lack of a versatile synthetic route to arogenate and its analogues. We now report a practical synthesis of l-arogenate in seven steps from O-benzyl l-tyrosine methyl ester in an overall yield of 20%. The synthetic route also delivers the fungal metabolite spiroarogenate, as well as a range of stable saturated and substituted analogues of arogenate. The key step in the synthesis is a carboxylative dearomatization by intramolecular electrophilic capture of tyrosine''s phenolic ring using an N-chloroformylimidazolidinone moiety, generating a versatile, functionalizable spirodienone intermediate.

l-Tyrosine provides a precursor for a practical synthesis of the unstable primary metabolite l-arogenate and some stabilised arogenate analogues.     

Production of 6-l-[18F]Fluoro-m-tyrosine in an Automated Synthesis Module for 11C-Labeling

6-l-[¹⁸F]Fluoro-m-tyrosine (6-l-[¹⁸F]FMT) represents a valuable alternative to 6-l-[¹⁸F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson’s disease. However, clinical applications of 6-l-[¹⁸F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-l-[¹⁸F]FMT using alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic Bu₄ONTf using a volatile iPrOH/MeCN mixture as reaction solvent. A simple and fast radiolabeling procedure afforded the tracer in 20.0 ± 3.0% activity yield within 70 min. The developed method was directly implemented onto a modified TracerLab FX C Pro platform originally designed for ¹¹C-labeling. This method enables an uncomplicated switch between ¹¹C- and ¹⁸F-labeling. The simplicity of the developed procedure enables its easy adaptation to other commercially available remote-controlled synthesis units and paves the way for a widespread application of 6-l-[¹⁸F]FMT in the clinic.     

Triterpenoid Saponins from the Cultivar “Green Elf” of Pittosporum tenuifolium

Four oleanane-type glycosides were isolated from a horticultural cultivar “Green Elf” of the endemic Pittosporum tenuifolium (Pittosporaceae) from New Zealand: three acylated barringtogenol C glycosides from the leaves, with two previously undescribed 3-O-β-d-glucopyranosyl-(1→2)-[α-l-arabinopyranosyl-(1→3)]-β-d-glucuronopyranosyl-21-O-angeloyl-28-O-acetylbarringtogenol C, 3-O-β-d-galactopyranosyl-(1→2)-[α-l-arabinopyranosyl-(1→3)]-β-d-glucuronopyranosyl-21-O-angeloyl-28-O-acetylbarringtogenol C, and the known 3-O-β-d-glucopyranosyl-(1→2)-[α-l-arabinopyranosyl-(1→3)]-β-d-glucuronopyranosyl-21-O-angeloyl-28-O-acetylbarringtogenol C (Eryngioside L). From the roots, the known 3-O-β-d-glucopyranosyl-(1→2)-β-d-galactopyranosyl-(1→2)-β-d-glucuronopyranosyloleanolic acid (Sandrosaponin X) was identified. Their structures were elucidated by spectroscopic methods including 1D- and 2D-NMR experiments and mass spectrometry (ESI-MS). According to their structural similarities with gymnemic acids, the inhibitory activities on the sweet taste TAS1R2/TAS1R3 receptor of an aqueous ethanolic extract of the leaves and roots, a crude saponin mixture, 3-O-β-d-glucopyranosyl-(1→2)-[α-l-arabinopyranosyl-(1→3)]-β-d-glucuronopyranosyl-21-O-angeloyl-28-O-acetylbarringtogenol C, and Eryngioside L were evaluated.     

Effect of Amino Acids on the Phase Behavior of Aqueous Biphasic Systems Composed of 1-Butyl-3-methylimidazolium Tetrafluoroborate and Sodium Citrate

Ionic liquids (ILs) based aqueous biphasic systems (ABSs) have been successfully applied to the extraction and purification of biomolecules. Although much research has focused on the effect of ILs on the phase formation, there are few reports that describe the phase behavior of quaternary IL-based ABS systems using amino acids (AAs) as additives. Here, 1-butyl-3-methylimidazolium tetrafluoroborate ([C₄mim]BF₄) formed an ABS with sodium citrate (Na₃C₆H₅O₇) with the aid of AAs. The phase behavior and physical properties of the ABS were investigated at 298 K. The capacity of the AA to create the ABS (area of biphasic region) increases with increasing in solubility and decrease with the molecular weight of the ILs and follows the trend glycine?>?l-alanine?≈?l-lysine?>?l-threonine?>?l-proline?≈?l-arginine?>?none. Moreover, the pH of the top and bottom phases containing l-proline as additive are nearly neutral; l-threonine, glycine, and l-alanine result in mildly acidic environments, while l-arginine and l-lysine provide basic pH conditions. The results show that the effects of the addition of the AAs can be considerable and important in the simulation, design calculation and pH control of ABS for efficient separation and extraction processes.     

Study of the interaction between ethanol and natural amino acids containing ionic side groups in water at T = 298.15 K

The enthalpies of solution of l-α-aspartic acid, l-α-glutamic acid, l-α-arginine, l-α-lysine, and l-α-histidine have been measured in aqueous ethanol solutions at 298.15 K. From the obtained experimental results, the standard enthalpies of solution of amino acids in water–ethanol solutions have been determined. These data were used to calculate the heterogeneous enthalpic pair interaction coefficients based on McMillan–Mayer’s formalism. These values were interpreted in the terms of the ionic or no polar effect of the side chains of l-α-amino acids on their interactions with a molecule of ethanol in water.     

Biomimetic synthesis of calcium carbonate with different morphologies under the direction of different amino acids

Using three different amino acids (AAs) as organic matrices, including the highly nonpolar hydrophobic l-valine, the positively charged l-arginine and the less polar uncharged l-serine, calcium carbonate (CaCO₃) with different morphologies and polymorphs were synthesized by a facile gas diffusion reaction based on biomimetic strategy. Compared with the control cubic calcite obtained in the absence of AAs, the product from l-valine was cubic calcite aggregates assembled by nano-platelets. The product from l-arginine was spherical vaterite aggregates assembled by spherical nanoparticles. The product from l-serine was the mixture of cubic calcite and spherical vaterite. The structures and properties of the side chains of the AAs exerted the significant effects on the nucleation and growth of the CaCO₃. The formation mechanisms of the CaCO₃ in the presence of AAs are preliminarily discussed. The results suggest that the polymorphs and morphologies of the inorganic nanomaterials might be easily adjusted through the careful selection of the organic matrices.     

Heat Capacities of l-Histidine,l-Phenylalanine,l-Proline,l-Tryptophan and l-Tyrosine

In an effort to establish reliable thermodynamic data for proteinogenic amino acids, heat capacities for l-histidine (CAS RN: 71-00-1), l-phenylalanine (CAS RN: 63-91-2), l-proline (CAS RN: 147-85-3), l-tryptophan (CAS RN: 73-22-3), and l-tyrosine (CAS RN: 60-18-4) were measured over a wide temperature range. Prior to heat capacity measurements, thermogravimetric analysis was performed to determine the decomposition temperatures while X-ray powder diffraction (XRPD) and heat-flux differential scanning calorimetry (DSC) were used to identify the initial crystal structures and their possible transformations. Crystal heat capacities of all five amino acids were measured by Tian–Calvet calorimetry in the temperature interval from 262 to 358 K and by power compensation DSC in the temperature interval from 307 to 437 K. Experimental values determined in this work were then combined with the literature data obtained by adiabatic calorimetry. Low temperature heat capacities of l-histidine, for which no literature data were available, were determined in this work using the relaxation (heat pulse) calorimetry from 2 K. As a result, isobaric crystal heat capacities and standard thermodynamic functions up to 430 K for all five crystalline amino acids were developed.     

The Involvement of l-Arginine-Nitric Oxide-cGMP-ATP-Sensitive K+ Channel Pathway in Antinociception of BBHC,a Novel Diarylpentanoid Analogue,in Mice Model

The present study focuses on the possible involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K⁺ channel pathway in the antinociceptive activity of a novel diarylpentanoid analogue, 2-benzoyl-6-(3-bromo-4-hydroxybenzylidene)cyclohexen-1-ol (BBHC) via a chemical nociceptive model in mice. The antinociceptive action of BBHC (1 mg/kg, i.p.) was attenuated by the intraperitoneal pre-treatment of l-arginine (a nitric oxide synthase precursor) and glibenclamide (an ATP-sensitive K⁺ channel blocker) in acetic acid-induced abdominal constriction tests. Interestingly, BBHC’s antinociception was significantly enhanced by the i.p. pre-treatment of 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase (p < 0.05). Altogether, these findings suggest that the systemic administration of BBHC is able to establish a significant antinociceptive effect in a mice model of chemically induced pain. BBHC’s antinociception is shown to be mediated by the involvement of l-arginine-nitric oxide-cGMP-ATP-sensitive K⁺ channel pathway, without any potential sedative or muscle relaxant concerns.     

Analyses of Antioxidative Properties of Selected Cyclitols and Their Mixtures with Flavanones and Glutathione

The conditions for determining the antioxidant properties of cyclitols (d-pinitol, l-quebrachitol, myo-, l-chiro-, and d-chiro-inositol), selected flavanones (hesperetin, naringenin, eriodictyol, and liquiritigenin) and glutathione by spectrophotometric methods—CUPRAC and with DPPH radical, and by a chromatographic method DPPH-UHPLC-UV, have been identified. Interactions of the tested compounds and their impact on the ox-red properties were investigated. The RSA (%) of the compounds tested was determined. Very low antioxidative properties of cyclitols, compared with flavanones and glutathione alone, were revealed. However, a significant increase in the determined antioxidative properties of glutathione by methyl-ether derivatives of cyclitols (d-pinitol and l-quebrachitol) was demonstrated for the first time. Thus, cyclitols seem to be a good candidate for creating drugs for the treatment of many diseases associated with reactive oxygen species (ROS) generation.     

Mg(ii) heterodinuclear catalysts delivering carbon dioxide derived multi-block polymers

Carbon dioxide derived polymers are emerging as useful materials for applications spanning packaging, construction, house-hold goods and automotive components. To accelerate and broaden their uptake requires both more active and selective catalysts and greater structural diversity for the carbon dioxide derived polymers. Here, highly active catalysts show controllable selectivity for the enchainment of mixtures of epoxide, anhydride, carbon dioxide and lactone. Firstly, metal dependent selectivity differences are uncovered using a series of dinuclear catalysts, Mg(ii)Mg(ii), Zn(ii)Zn(ii), Mg(ii)Zn(ii), and Mg(ii)Co(ii), each exposed to mixtures of bio-derived tricyclic anhydride, cyclohexene oxide and carbon dioxide (1 bar). Depending upon the metal combinations, different block structures are possible with Zn(ii)Zn(ii) yielding poly(ester-b-carbonate); Mg(ii)Mg(ii) or Mg(ii)Co(ii) catalysts delivering poly(carbonate-b-ester); and Mg(ii)Zn(ii) furnishing a random copolymer. These results indicate that carbon dioxide insertion reactions follow the order Co(ii) > Mg(ii) > Zn(ii). Using the most active and selective catalyst, Mg(ii)Co(ii), and exploiting reversible on/off switches between carbon dioxide/nitrogen at 1 bar delivers precision triblock (ABA), pentablock (BABAB) and heptablock (ABABABA) polymers (where A = poly(cyclohexylene oxide-alt-tricyclic anhydride), PE; B = poly(cyclohexene carbonate), PCHC). The Mg(ii)Co(ii) catalyst also selectively polymerizes a mixture of anhydride, carbon dioxide, cyclohexene oxide and ε-caprolactone to deliver a CBABC pentablock copolymer (A = PE, B = PCHC C = poly(caprolactone), PCL). The catalysts combine high activity and selectivity to deliver new polymers featuring regularly placed carbon dioxide and biomass derived linkages.

Carbon dioxide-based multiblock polymers are synthesised, in one-pot, from a mixture of monomers using a highly selective and active heterodinuclear Co(ii)Mg(ii) catalyst.     

1–D Framework l-arginine zinc(II) units bridged by oxalate: synthesis,structure, properties,and theoretical studies

We synthesized a l-arginine containing Zn²⁺ complex and oxalate ions. {[Zn₂(l-Arg)₂(ox)₂]·8H₂O}_n (1) (l-Arg =l-arginine, ox = oxalate) crystallize in the monoclinic space group P2₁ with a = 8.979(2), b = 9.840(2) (Å), c = 18.509(3) (Å), β = 95.58(3) (Å), V = 1627.6(6) ų, and Z = 2. The zinc centers are six-coordinate via one l-arginine zwitterion and two bridging oxalates. The binuclear [Zn₂(l-Arg)₂(ox)₂] units are linked via oxalate and form 1-D “stair-like” linear chains. The complex was characterized using FT-IR, FT-Raman, UV–vis spectroscopy, and thermal analysis techniques, as well as DFT methods. Electronic bands above 31,000 cm^?1 originate in ^1,3A_u (n→π*) transitions within oxalate ions. Theoretical studies were performed for the model compound {[Zn(l-Arg)(Hox)₂]·4H₂O} using the fragment of the crystallographic structure of 1. The interaction energy (ΔE) values for l-arginine and two oxalate ions are comparable at -145 kcal mol^?1. Natural bond orbital (NBO) analysis of the electronic structure and bonding is also discussed.     

Total synthesis and biochemical characterization of mirror image barnase

In this study we synthesized and characterized mirror image barnase (B. amyloliquefaciens ribonuclease). d-Barnase was identical to l-barnase, when analyzed by liquid chromatography and mass-spectrometry. Proteolysis of the mirror image enzyme revealed that in contrast to its native counterpart, d-barnase was completely stable to digestive proteases. In enzymatic assays, d-barnase had the reciprocal chiral specificity and was fully active towards mirror image substrates. Interestingly, d-barnase also hydrolyzed the substrate of the native chirality, albeit 4000 times less efficiently. This effect was further confirmed by digesting a native 112-mer RNA with the enzyme. Additional studies revealed that barnase accommodates a range of substrates with various chiralities, but the prime requirement for guanosine remains. These studies point toward using mirror image enzymes as modern agents in biotechnology.     

Antispasmodic Effect of Asperidine B,a Pyrrolidine Derivative,through Inhibition of L-Type Ca2+ Channel in Rat Ileal Smooth Muscle

Antispasmodic agents are used for modulating gastrointestinal motility. Several compounds isolated from terrestrial plants have antispasmodic properties. This study aimed to explore the inhibitory effect of the pyrrolidine derivative, asperidine B, isolated from the soil-derived fungus Aspergillus sclerotiorum PSU-RSPG178, on spasmodic activity. Isolated rat ileum was set up in an organ bath. The contractile responses of asperidine B (0.3 to 30 µM) on potassium chloride and acetylcholine-induced contractions were recorded. To investigate its antispasmodic mechanism, CaCl₂, acetylcholine, Nω-nitro-l-arginine methyl ester (l-NAME), nifedipine, methylene blue and tetraethylammonium chloride (TEA) were tested in the absence or in the presence of asperidine B. Cumulative concentrations of asperidine B reduced the ileal contraction by ~37%. The calcium chloride and acetylcholine-induced ileal contraction was suppressed by asperidine B. The effects of asperidine B combined with nifedipine, atropine or TEA were similar to those treated with nifedipine, atropine or TEA, respectively. In contrast, in the presence of l-NAME and methylene blue, the antispasmodic effect of asperidine B was unaltered. These results suggest that the antispasmodic property of asperidine B is probably due to the blockage of the L-type Ca²⁺ channel and is associated with K⁺ channels and muscarinic receptor, possibly by affecting non-selective cation channels and/or releasing intracellular calcium.     

A crystal-structural study of Pauling–Corey rippled sheets

Following the seminal theoretical work on the pleated β-sheet published by Pauling and Corey in 1951, the rippled β-sheet was hypothesized by the same authors in 1953. In the pleated β-sheet the interacting β-strands have the same chirality, whereas in the rippled β-sheet the interacting β-strands are mirror-images. Unlike with the pleated β-sheet that is now common textbook knowledge, the rippled β-sheet has been much slower to evolve. Much of the experimental work on rippled sheets came from groups that study aggregating racemic peptide systems over the course of the past decade. This includes MAX1/DMAX hydrogels (Schneider), L/D-KFE8 aggregating systems (Nilsson), and racemic Amyloid β mixtures (Raskatov). Whether a racemic peptide mixture is “ripple-genic” (i.e., whether it forms a rippled sheet) or “pleat-genic” (i.e., whether it forms a pleated sheet) is likely governed by a complex interplay of thermodynamic and kinetic effects. Structural insights into rippled sheets remain limited to only a very few studies that combined sparse experimental structural constraints with molecular modeling. Crystal structures of rippled sheets are needed so we can rationally design rippled sheet architectures. Here we report a high-resolution crystal structure, in which (l,l,l)-triphenylalanine and (d,d,d)-triphenylalanine form dimeric antiparallel rippled sheets, which pack into herringbone layer structures. The arrangements of the tripeptides and their mirror-images in the individual dimers were in excellent agreement with the theoretical predictions by Pauling and Corey. A subsequent mining of the PDB identified three orphaned rippled sheets among racemic protein crystal structures.

Following the seminal theoretical work on the pleated β-sheet published by Pauling and Corey in 1951, the rippled β-sheet was hypothesized by the same authors in 1953.     

Thermodynamic and structural aspects of the interaction of l-histidine with urea and dimethylformamide in water

The solubility of l-histidine in water and aqueous solutions of dimethylformamide (DMF) at 25°C was determined. The thermal effects of solution of l-histidine in aqueous solutions of urea and DMF were measured. The standard enthalpies, free energies, and entropies of solution and transfer of the amino acid from water to aqueous solutions of amides were calculated. It was shown that the interaction of l-histidine with urea is attractive, and that with DMF, repulsive, with the change in the free energy determined by the enthalpy term in both cases. The enthalpy-entropy compensation taking place to a certain extent in the interaction of l-histidine and l-phenylalanine with amide was revealed. This effect is the most pronounced in the interaction of predominantly hydrophobic DMF and l-phenylalanine.     

Activity and Synergistic Antimicrobial Activity Between Diketopiperazines Against Bacteria In Vitro

The aim of the present study was to determine the synergistic effects of diketopiperazines [cyclo-(l-Pro-l-Leu) (1), cyclo-(d-Pro-l-Leu) (2), and cyclo-(d-Pro-l-Tyr) (3)] purified from a Bacillus sp. N strain associated with entomopathogenic nematode Rhabditis (Oscheius) sp. on the growth of bacteria. The minimum inhibitory concentration and minimum bactericidal concentration of the diketopiperazines was compared with that of the standard antibiotics. The synergistic antibacterial activities of the combination of diketopiperazines against pathogenic bacteria were assessed using the checkerboard assay and time?Ckill methods. The results of the present study showed that the combination effects of diketopiperazines were predominately synergistic (FIC index <0.5). Furthermore, time?Ckill study showed that the growth of the tested bacteria was completely attenuated with 4?C12?h of treatment with 50:50 ratios of diketopiperazines. These results suggest that the combination of diketopiperazines may be microbiologically beneficial. The three diketopiperazines are nontoxic to normal human cell line (L231 lung epithelial) up to 200?m???g/ml. The in vitro synergistic activity of cyclo-(l-Pro-l-Leu), cyclo-(d-Pro-l-Leu), and cyclo-(d-Pro-l-Tyr) against bacteria is reported here for the first time. These findings have potential implications in delaying the development of resistance as the antibacterial effect is achieved with lower concentrations of both drugs (diketopiperazines).     

Structure Elucidation of Triterpenoid Saponins Found in an Immunoadjuvant Preparation of Quillaja brasiliensis Using Mass Spectrometry and 1H and 13C NMR Spectroscopy

An immunoadjuvant preparation (named Fraction B) was obtained from the aqueous extract of Quillaja brasiliensis leaves, and further fractionated by consecutive separations with silica flash MPLC and reverse phase HPLC. Two compounds were isolated, and their structures elucidated using a combination of NMR spectroscopy and mass spectrometry. One of these compounds is a previously undescribed triterpene saponin (Qb1), which is an isomer of QS-21, the unique adjuvant saponin employed in human vaccines. The other compound is a triterpene saponin previously isolated from Quillaja saponaria bark, known as S13. The structure of Qb1 consists of a quillaic acid residue substituted with a β-d-Galp-(1→2)-[β-d-Xylp-(1→3)]-β-d-GlcpA trisaccharide at C3, and a β-d-Xylp-(1→4)-α-l-Rhap-(1→2)-[α-l-Arap-(1→3)]-β-d-Fucp moiety at C28. The oligosaccharide at C28 was further substituted at O4 of the fucosyl residue with an acyl group capped with a β-d-Xylp residue.     

Structure,reactivity and luminescence studies of triphenylsiloxide complexes of tetravalent lanthanides

Among the 14 lanthanide elements (Ce–Lu), until recently, the tetravalent oxidation state was readily accessible in solution only for cerium while Pr(iv), Nd(iv), Dy(iv) and Tb(iv) had only been detected in the solid state. The triphenylsiloxide ligand recently allowed the isolation of molecular complexes of Tb(iv) and Pr(iv) providing an unique opportunity of investigating the luminescent properties of Ln(iv) ions. Here we have expanded the coordination studies of the triphenylsiloxide ligand with Ln(iii) and Ln(iv) ions and we report the first observed luminescence emission spectra of Pr(iv) complexes which are assigned to a ligand-based emission on the basis of the measured lifetime and computational studies. Binding of the ligand to the Pr(iv) ion leads to an unprecedented large shift of the ligand triplet state which is relevant for future applications in materials science.

The first observed luminescence emission spectra of Pr(iv) complexes are assigned to a ligand-based emission. Binding of the triphenylsiloxide ligand to the Pr(iv) ion leads to an unprecedented large red shift of its triplet state.     

Organocatalytic Synthesis of Higher‐Carbon Sugars: Efficient Protocol for the Synthesis of Natural Sedoheptulose and d‐Glycero‐l‐galacto‐oct‐2‐ulose

Herein we report a short and efficient protocol for the synthesis of naturally occurring higher‐carbon sugars—sedoheptulose (d‐altro‐hept‐2‐ulose) and d‐glycero‐l‐galacto‐oct‐2‐ulose—from readily available sugar aldehydes and dihydroxyacetone (DHA). The key step includes a diastereoselective organocatalytic syn‐selective aldol reaction of DHA with d‐erythrose and d‐xylose, respectively. The methodology presented can be expanded to the synthesis of various higher sugars by means of syn‐selective carbon–carbon‐bond‐forming aldol reactions promoted by primary‐based organocatalysts. For example, this methodology provided useful access to d‐glycero‐d‐galacto‐oct‐2‐ulose and 1‐deoxy‐d‐glycero‐d‐galacto‐oct‐2‐ulose from d‐arabinose in high yield (85 and 74 %, respectively) and high stereoselectivity (99:1).