Chemical and enzymatic approaches to carbohydrate-derived spiroketals: di-D-fructose dianhydrides (DFAs)

Di-D-fructose dianhydrides (DFAs) comprise a unique family of stereoisomeric spiro-tricyclic disaccharides formed upon thermal and/or acidic activation of sucrose- and/ or D-fructose-rich materials. The recent discovery of the presence of DFAs in food products and their remarkable nutritional features has attracted considerable interest from the food industry. DFAs behave as low-caloric sweeteners and have proven to exert beneficial prebiotic nutritional functions, favouring the growth of Bifidobacterium spp. In the era of functional foods, investigation of the beneficial properties of DFAs has become an important issue. However, the complexity of the DFA mixtures formed during caramelization or roasting of carbohydrates by traditional procedures (up to 14 diastereomeric spiroketal cores) makes evaluation of their individual properties a difficult challenge. Great effort has gone into the development of efficient procedures to obtain DFAs in pure form at laboratory and industrial scale. This paper is devoted to review the recent advances in the stereoselective synthesis of DFAs by means of chemical and enzymatic approaches, their scope, limitations, and complementarities.     

A Julia olefination approach to the synthesis of functionalized enol ethers and their transformation into carbohydrate-derived spiroketals

A synthesis of spiroketals from carbohydrate lactones is reported. A modified Julia olefination is used to synthesize trisubstituted and highly functionalized exo-glycals, which were subsequently transformed into spiroketals under acidic conditions.     

Synthesis of cyclic hemiketals and spiroketals from dioxanorbornanes

[reaction: see text] A new method for the synthesis of substituted pyranone hemiketals from dioxanorbornanes via SmI(2) is described. Also reported is a synthesis of spiro[4.5]ketals from analogous intermediates via acid-promoted deprotection/ketalization.     

Synthesis of electron deficient 5,6-aryloxy spiroketals

[reaction: see text] A strategy for the construction of electron deficient 5,6-aryloxy spiroketal is reported. The process should prove useful for the synthesis of natural products containing similar spiroketals. The strategy uncovers an unexpected rearrangement between ortho and para quinone spiroketals.     

Synthesis and application of carbohydrate-derived morpholine amino acids

The synthesis of series of diversely functionalized epsilon-morpholine amino acids (MAAs, 5a-h) starting from an epsilon-sugar amino acid and following a two-step oxidative glycol cleavage/reductive amination strategy, is described. In an alternative synthetic scheme, diastereoisomerically pure delta-MAAs (12a,b) were obtained. Oligopeptides containing MAAs were prepared either by direct incorporation of a MAA building block or by subjecting a fully assembled SAA-containing peptide to the two-step glycol cleavage/reductive amination procedure.     

Synthesis of spiroacetals using functionalised titanium carbenoids

Alkylidenation of lactones with functionalised titanium carbenoid reagents (Schrock carbenes) followed by acid-induced cyclisation of the resulting enol ethers constitutes a new method for the preparation of [4.4], [4.5] and [5.5] spiroacetals (1,6-dioxaspiro[4.4]nonanes, 1,6-dioxaspiro[4.5]decanes and 1,7-dioxaspiro[5.5]undecanes, respectively, sometimes termed 5,5-, 5,6- and 6,6-spiroketals). The titanium carbenoids are easily generated from readily available thioacetals.     

Synthesis pathway to carbohydrate-derived salicylidene hydrazides as ligands for oxovanadium complexes

Salicylidene hydrazides represent important ligands forming oxovanadium complexes. Carbohydrate-derived chiral salicylidene hydrazides as ligands for metal ion complexation were synthesized for the first time. The pathway of the mild and selective synthesis starts from commercial saccharides like methyl-α-d-glucopyranoside and methyl-α-d-mannopyranoside. All synthesized carbohydrate-derived salicylidene hydrazides are able to form oxovanadium complexes. The mononuclear structure proposed for the complex of 1,2,3,4-tetra-O-methyl-α-d-glucopyranuronic acid salicylidene hydrazide is consistent with the analytical data (NMR, IR and MS).     

Synthesis of benzannulated steroid spiroketals by palladium-catalyzed spirocyclization of steroid alkynediols

Sonogashira coupling of 17β-acetoxy-4,5-secoandrost-3-yn-5-one with 2-iodobenzyl alcohol, followed by NABH₄ reduction afforded two epimeric steroid alkynediols that after separation underwent palladium-catalyzed spirocyclization to produce the corresponding benzannulated steroid spiroketals. The hitherto unknown spiroketals were characterized their NMR spectra and the structures were confirmed by X-ray diffraction studies.     

Synthesis and solution thermodynamic study of rigidified and functionalised EGTA derivatives

The synthesis of a new series of EGTA (ethyleneglycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid) derivatives incorporating aromatic and functionalized aromatic moieties into the oxoethylenic bridge is described. A solution thermodynamic study was carried out to determine the influence of structural modifications on the coordinating ability towards lanthanide and alkaline earth metal ions. The presence of remote functional groups on the aromatic moiety would allow the conjugation of the complexes to macromolecules or other biological targets.     

Synthesis of spiroketals under neutral conditions via a type III ring-rearrangement metathesis strategy

A conceptually novel approach to spiro- and dispiroketals of various ring-sizes under neutral conditions has been designed which complements the classical thermodynamically driven tactic. Key steps involved the formation of α-alkoxyfurans, their [4+2] or [4+3] cycloaddition reactions and the ring-rearrangement metathesis of the resulting oxabicycles.     

Synthesis and Th(IV) sorption characteristics of functionalised graphene oxide

A functionalised graphene oxide (FGO) adsorbent was prepared via the γ-radiation-induced grafting of epichlorohydrin (ECH) onto graphene oxide (GO). X-ray photoelectron spectroscopy revealed that ECH was successfully introduced to the GO surface. The grafting yield of ECH increased with an increase of the irradiation dose and with a decrease of the irradiation dose rate. The sorption kinetics of Th(IV) on GO and FGO followed the pseudo-second-order model and the sorption isotherms can be described by the Langmuir model. The maximum sorption capacities of GO and FGO for Th(IV) are approximately 5.80 × 10^?4 and 2.88 × 10^?5 mol/L, respectively. GOs is considered as a kind of materials with high radiation resistance and large sorption capacities, ranking it has high potential industrial applications even under strong radiation environment. In addition, the amount of the oxygen-containing functional groups C=O and O=C–O in FGO decrease with the increase of the irradiation dose, which suggests that C=O and O=C–O contribute more than C–O to the sorption of Th(IV) onto GO and FGO.     

Synthesis of enantiomerically pure functionalised trianglamine macrocycles by N-acylation and N-alkylation reactions

The N-alkylation and N-acylation reactions of trianglamine macrocycles are described leading to an efficient synthesis of enantiomerically pure functionalised hexa-amide and hexa-amine trianglamine macrocycles.     

Synthesis of functionalised enantiopure steroids from estrone and cholestanone through organolithium intermediates

The reaction of epoxides 1 and 8 derived from estrone and cholestanone, respectively, with an excess of lithium and a catalytic amount of DTBB (7 mol%) in THF at −78°C led to formation of the corresponding β-oxido-functionalised organolithium intermediates 2 and 9, respectively, in a regio- and stereoselective manner. Treatment of these intermediates with different electrophiles [H₂O, D₂O, PhCHO, Me₂CO, Et₂CO, (CH₂)₅CO, CO₂] at −78 to 20°C afforded, after hydrolysis with water, enantiomerically pure derivatives 3 and 10, respectively. When protected ketones 5 and 6 derived from d-glucose and d-fructose were used as the electrophile, the reaction with 2 gave the expected mixed products 3g and 3h, respectively, which consist of a steroid and a carbohydrate fragment. The reaction of O-protected estrone 4 as the electrophilic component and intermediate 2 afforded the C₂-symmetric steroid dimer 3f. The stereochemistry of the products was unambiguously determined by correlation with X-ray data for compound 3d and by comparison with the known compound 6a. Finally, the addition of the dianions 13, resulting from the DTBB-catalysed lithiation of phthalan 12a and isochroman 12b, to the O-protected estrone 4 and to cholestanone 9 led to the formation of the diols 14, 15 and 16. Diols 14 were cyclised under Mitsunobu reaction conditions to the corresponding heterocycles 17.     

Synthesis of melamine-formaldehyde resin functionalised with sulphonic groups and its catalytic activities

Spherical melamine-formaldehyde resin (MFR) particles were synthesised using the condensation reaction of melamine and formaldehyde with PEG-2000 as an additive. After thermal treatment at 200°C and then sulphonation by chlorosulphuric acid, an MFR-supported strong acid catalyst (SMFR) was prepared with an acidity of 3.23 mmol g^?1. This new acid catalyst was evaluated in the reactions of esterification and acetalisation, with the results indicating that this novel acid catalyst was highly efficient in the traditional acid-catalysed reaction. Its high activity, stability and reusability give it great potential for “green” chemical processes.     

Synthesis of functionalised polyethylene glycol derivatives of naproxen for biomedical applications

The preparation of a series of mono-naproxen functionalised polyethylene glycol derivatives have been achieved. These compounds feature several different terminal functional groups, the identities of which have been chosen to facilitate conjugation of these hybrid molecules to nanomaterials.     

Intramolecular cyclisation of functionalised heteroaryllithiums. Synthesis of novel indolizinone-based compounds

The intramolecular cyclisation of heteroaryllithiums derived from N-heteroarylmethylpyrrole-2-carboxamides takes place smoothly at low temperature when N-methoxy-N-methyl and morpholine amides are used as internal electrophiles. Halogen-lithium exchange using n-BuLi is the method of choice to achieve metalation on the quinoline and pyridine derivatives, while directed lithiation (LDA) works better for furan. In the case of thiophene both methodologies can be applied. These metalation-cyclisation sequences provide a useful entry to several types of indolizidine based compounds (pyrrolo[1,2-b]acridinones, pyrrolo[1,2-g]quinolones, thieno and furo[3,2-f]indolizinones).     

Asymmetric synthesis of naturally occurring spiroketals

Spiroketals are widely found as substructures of many naturally occurring compounds from diverse sources including plants, animals as well as microbes. Naturally occurring spiroketals are biologically active and most of them are chiral molecules. This article aims at reviewing the asymmetric synthesis of biologically active spiroketals for last 10 years (1998-2007).