Synthesis of 6-amino-6-deoxy-d-gulono-1,6-lactam and l-gulono-1,6-lactam derived from corresponding 5,6-O-sulfinyl hexono-1,4-lactones

Syntheses of 6-amino-6-deoxy-2,3-O-isopropylidene-d-gulono- and l-gulono-1,6-lactams 3 and 4 from corresponding glycono-1,4-lactones are described. Activation of the primary hydroxyl group requires 5,6-cyclic sulfite intermediate to obtain 6-azido-6-deoxy derivatives, which are cyclized after reduction.     

Efficient synthesis of new N-alkyl-d-ribono-1,5-lactams from d-ribono-1,4-lactone

d-Ribono-1,4-lactone was treated with ethylamine in DMF to afford N-ethyl-d-ribonamide 9a in quantitative yield. Bromination of amide 9a by the system SOBr₂ in DMF or PPh₃/CBr₄ in pyridine led, after acetylation, to epoxide 7. However, treatment of amide 9a with acetyl bromide in dioxane followed by acetylation gave 2,3,4-tri-O-acetyl-5-bromo-5-deoxyl-N-ethyl-d-ribonamide 10a. Methanolysis of 10a, with sodium methoxide, afforded the N-ethyl-d-ribonolactam 11a in 51% overall yields. Using this method, N-butyl, N-hexyl, N-dodecyl, and N-benzyl-d-ribonolactams 11b-e were obtained in good yields (48-53%).     

Selection of synthetic receptors capable of sensing the difference in binding of d-Ala-d-Ala or d-Ala-d-Lac ligands by screening of a combinatorial CTV-based library

Screening of a combinatorial CTV-based artificial, synthetic receptor library 1 {1-13, 1-13, 1-13} for binding of a variety d-Ala-d-Ala and d-Ala-d-Lac containing ligands (6-11) was carried out in phosphate buffer (0.1 N, pH=7.0). After screening and Edman sequencing, synthetic receptors were found containing amino acid sequences, which are either characteristic for binding dye labeled d-Ala-d-Ala or d-Ala-d-Lac containing ligands. For example, receptors capable of binding d-Ala-d-Ala containing ligands 6, 7, 9 and 11 contained—almost in all cases—at least one basic amino acid residue—predominantly Lys—in their arms. This was really a striking difference with the arms of the receptors capable of binding d-Ala-d-Lac containing ligands 8 and 10, which usually contained a significant number of polar amino acids (Gln and Ser), especially in ligand 8, but hardly any basic amino acids. Use of different (fluorescent) dye labels showed that the label has a profound, albeit not decisive, influence on the binding by the receptor. A hit from the screening of the CTV-library with FITC-peptidoglycan (6) was selected for resynthesis and validation.     

One-pot inversion of d-mannono-1,4-lactone for the practical synthesis of l-ribose

l-Ribose was synthesized in a concise manner from d-mannono-1,4-lactone using one-pot inversion conditions. Treatment of d-mannono-1,4-lactone with piperidine, followed by mesylation-induced S_N2-type O-alkylation, afforded the desired one-pot inversion in an optimum yield, and the following straightforward transformations provided l-ribose in good yields.     

Anion recognition by d-ribose-based receptors

Anion recognition properties of d-ribose-based receptors α- and β-1 were measured by ¹H NMR in CDCl₃ and MeCN-d₃. Receptor β-1 showed effective binding with anions by cooperative hydrogen bonds of cis-diol. The anomeric isomer α-1 is a less effective anion receptor which has similar cis-diol as a recognition site, indicating that the stereo configuration of the anomeric position is of significant influence on the anion recognition ability.     

Combinatorial solid-phase synthesis and screening of a diverse tripodal triazacyclophane (TAC)-based synthetic receptor library showing a remarkable selectivity towards a d-Ala-d-Ala containing ligand

A large and diverse library of a TAC-based tripodal synthetic receptor library (6) has been prepared by split-mix synthesis on the solid phase. Each receptor of the 46,656-member TAC-based library (6) is attached to a solid support bead and contains three different dipeptide arms. On-bead screening for binding of a d-Ala-d-Ala containing ligand (7) by the TAC-based library (6) was performed in phosphate buffer (0.2 N, pH=7.0). Remarkable selectivity for particular library members was observed. The best binding members from the screening were manually selected using fluorescence microscopy and subjected to structural analysis by sequencing. The thus determined binding sequences showed a high consensus.     

Polyhydroxylated pyrrolidines. Part 4: Synthesis from d-fructose of protected 2,5-dideoxy-2,5-imino-d-galactitol derivatives

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-5-O-methanesulfonyl-β-d-fructopyranose (5) was straightforwardly transformed into its d-psico epimer (8), after O-debenzoylation followed by oxidation and reduction, which caused the inversion of the configuration at C(3). Compound 8 was treated with lithium azide yielding 5-azido-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-α-l-tagatopyranose (9) that was transformed into the related 3,4-di-O-benzyl derivative 10. Cleavage of the acetonide in 10 to give 11, followed by regioselective 1-O-pivaloylation to 12 and subsequent catalytic hydrogenation gave (2R,3S,4R,5S)-3,4-dibenzyloxy-2,5-bis(hydroxymethyl)-2′-O-pivaloylpyrrolidine (13). Stereochemistry of 13 could be determined after O-deacylation to the symmetric pyrrolidine 14. Total deprotection of 14 gave 2,5-imino-2,5-dideoxy-d-galactitol (15, DGADP).     

Stereoselective synthesis of (2R,3S,4S)-3-hydroxy-4-methyl-2-tetradecyl-4-butanolide starting from 2,5-anhydro-d-mannitol

A novel approach to natural β-hydroxy-γ-lactone 2 from 2,5-anhydro-d-mannitol (1) is described. The key reactions in this synthesis include stereoselective methylation of aldehyde 3 with lithium dimethylcuprate, an intramolecular radical cyclization of seleno carbonate 11 and an intermolecular cross-metathesis of 3-allyl-4-hydroxy-γ-lactone 16 with 1-tridecene.     

In situ 1,3-dipolar azide cycloaddition reaction: synthesis of functionalized d-glucose based chiral piperidine and oxazepine analogues

Functionalized furanose-fused piperidines 4-6 and oxazepines 15-17, useful precursors for structurally unique bioactive nucleosides as well as for potential glycosidase inhibitors, have been synthesized by the application of 1,3-dipolar azide cycloaddition (DAC) reaction on d-glucose based substrates. The strategy works well even with the nucleoside analogue 8, affording the bicyclic nucleoside analogues 11 and 12.     

Glycine and l-glutamic acid-based dendritic gelators

Novel dendrons based on glycine and l-glutamic acid from the first generation (G1) to the third generation (G3) were synthesized and studied for their gelation properties by using transmission electron microscopy (TEM), atomic force microscopy (AFM), fluorescence, IR, circular dichroism (CD), and ¹H NMR spectroscopy. It was found that the gelation capability of these dendrons increased from the first generation (G1) to the third generation (G3), and that G3 exhibited the highest efficiency in forming gels. Both the focal and peripheral groups of dendrons had great effects on the formation of organogels. Hydrogen bonding and π-π stacking interactions were proved to be the main driving forces to form the fibrous networks at low concentrations (0.5 wt %). Small-angle X-ray scattering (SAXS) and wide-angle X-ray diffraction (WAXD) measurements indicate that the xerogels of the second generation (G2) from ethyl acetate and ethanol, and G3 xerogel from CH₂Cl₂ all display lamellar structures with the interlamellar spacing of ca. 36.0 Å for G2 and 40.5 Å for G3, respectively.     

Carbanucleosides: synthesis of both enantiomers of 2-(6-chloro-purin-9-yl)-3,5-bishydroxymethyl cyclopentanol from d-glucose

The key intermediate 1,2:5,6-di-O-isopropylidene-3-deoxy-3β-allyl-α-d-glucofuranose (8) could be conveniently prepared through radical induced allyl substitution at C-3 of appropriate 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose derivatives (7a,b) and used to synthesize enantiomeric bishydroxymethyl aminocyclopentanols 13 and 19 by the application of a 1,3-dipolar nitrone cycloaddition reaction involving the C-5 or C-1 aldehyde functionality. The products were subsequently transformed into carbanucleoside enantiomers 15 and 21. The diastereomeric isoxazolidinocyclopentane derivative 20 was similarly converted to carbanucleoside 22.     

A short and efficient synthesis of 5-hydroxymethylcyclopent-2-enol from d-glucose and its elaboration to the carbanucleoside (−)-carbovir

Introduction of an allyl functionality at C-3 of 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose followed by olefination at C-5 and C-6 provided 1,6-diene 5 which, upon ring closing metathesis and subsequent functional group manipulation, furnished the key cyclopentene diacetate 7, which was elaborated to carbanucleoside (−)-carbovir 1.     

Stereo-conserved synthesis of syn-diarylheptanoids, active principles of Zingiber, starting from d-glucose

A highly efficient and stereo-controlled synthetic strategy has been developed to access syn-diarylheptanoids, for example, 2,3, 4, and 5b starting from d-glucose as a chiral pool. The 3-(R), 5-(S)-syn-diol stereochemistry present in these heptanoids was obtained after conserving C2 and C4 stereochemistry of d-glucose during the course of synthetic transformation. The key features of this synthetic strategy include: (i) conversion of d-glucose to a known chiral template 6 armored with the required 1,3-syn-diol stereochemistry as well as two terminal aldehyde functionalities for building up customized ‘diaryl wings’; (ii) conversion of 6 to 7 via an initial Wittig olefination at the C5-aldehyde; (iii) use of the hemiacetal 7 as a common intermediate to obtain the individual heptanoids via a second Wittig reaction at its anomeric center using appropriately chosen ylides.     

An efficient synthesis of l-allono-1,4-lactone from 2,3:5,6-di-O-isopropylidene-d-mannono-1,4-lactone

We reported herein an efficient synthesis of l-allono-1,4-lactone from 2,3:5,6-di-O-isopropylidene-d-mannono-1,4-lactone in five steps. The key feature of this method involved a one-pot, ‘double inversion’ procedure at the stereocenters of C-4 and C-5 of d-mannono-1,4-lactone to afford the target molecule.     

Polyhydroxylated pyrrolidines, III. Synthesis of new protected 2,5-dideoxy-2,5-iminohexitols from d-fructose

The readily available 3-O-benzoyl-4-O-benzyl-1,2-O-isopropylidene-β-d-fructopyranose (6) was straightforwardly transformed into 5-azido-3-O-benzoyl-4-O-benzyl-5-deoxy-1,2-O-isopropylidene-β-d-fructopyranose (8), after treatment under modified Garegg's conditions followed by reaction of the resulting 3-O-benzoyl-4-O-benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-α-l-sorbopyranose (7) with lithium azide in DMF. O-debenzoylation at C(3) in 8, followed by oxidation and reduction caused the inversion of the configuration to afford the corresponding β-d-psicopyranose derivative 11 that was transformed into the related 3,4-di-O-benzyl derivative 12. Cleavage of the acetonide of 12 to give 13 followed by O-tert-butyldiphenylsilylation afforded a resolvable mixture of 14 and 15. Compound 14 was transformed into (2R,3R,4S,5R)- (17) and (2R,3R,4S,5S)-3,4-dibenzyloxy-2′,5′-di-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (18) either by a tandem Staudinger/intramolecular aza-Wittig process and reduction of the resulting intermediate Δ²-pyrroline (16), or only into 18 by a high stereoselective catalytic hydrogenation. When 15 was subjected to the same protocol, (2S,3S,4R,5R)- (21) and (2R,3S,4R,5R)-3,4-dibenzyloxy-2′-O-tert-butyldiphenylsilyl-2,5-bis(hydroxymethyl)pyrrolidine (22) were obtained, respectively.     

Asymmetric syntheses of 6-deoxyfagomin, d-deoxyrhamnojirimycin, and d-rhamnono-1,5-lactam

N-Allyl protected 3-O-benzyloxglutarimide 11 was synthesized as a useful variant of the chiral building block 10. This modification allowed a high-yielding deprotection of the allyl group from the lactam intermediate 14. Starting from this building block, the asymmetric syntheses of aza-sugars 6-deoxyfagomine (2), d-rhamnono-1,5-lactam (6), as well as d-deoxyrhamnojirimycin (5) have been achieved in high regio- and/or diastereo-controlled manner.     

Synthesis and biological activities of 5′-ethylenic and acetylenic modified l-nucleosides and isonucleosides

Two series of 6′-halovinyl-adenosine stereoisomers including 5′-ethylenic and acetylenic substituted l-adenosine, 5′-ethylenic and acetylenic substituted isonucleosides were synthesized. In the l-nucleoside series, compounds 6b, 8b, 10b and 13b showed modest inhibition of SAH hydrolase (21, 44, 50 and 26% respectively) at 100 μM. The l-isomers of 5′-ethylenic and acetylenic modified isonucleoside 23, 24 exhibited no activity for the inhibition of SAH hydrolase, however, the d-isomers 30 and 31 showed some activities in the same test (35 and 21%). It indicated clearly the strict stereochemical requirement for the substrate of SAH hydrolase. Compounds 6b, 8b, 8c, 11b exhibited modest to good inhibition effects on the growth of HeLa cells or Bel-7420 cells at 1 μM (64, 44, 53 and 82% respectively).     

Synthesis and characterization of alkali-metal aryloxo compounds and their catalytic activity for l-lactide polymerization

Three new alkali-metal compounds stabilized by aryloxo groups were synthesized and fully characterized. The reactions of carbon-bridged bis(phenol)s MBMPH₂ (MBMPH₂ = 2,2′-methylene-bis(6-tert-butyl-4-methylphenol)) with sodium and potassium metals in tetrahydrofuran (THF) gave the desired alkali-metal complexes [MBMPNa₂(THF)₃]₂ (1) and [(MBMPK₂)₂(THF)₅]₂ (2), respectively, in high isolated yields. A similar reaction of aminophenol [HNOH] ([HNOH] = N-p-methyl-phenyl(2-hydroxy-3,5-di-tert-butyl)benzylamine) with sodium gave the monosodium salt [HNONa(THF)]₂ (3). Compounds 1-3 were well characterized, including X-ray structure determination. Compound 1 has a dimeric structure, and each sodium atom is four-coordinated with four oxygen atoms to form a distorted tetrahedron. Compound 2 has a centrosymmetric tetrameric structure. The coordination environments around the four potassium atoms are different. K1 is four-coordinated, K2 is three-coordinated, K3 is five-coordinated, whereas the coordination sphere of K4 is completed by one aryloxo oxygen atom and two oxygen atoms from two THF molecules and six carbon atoms from one arene ring of the bis(phenolate) ligand. Compound 3 has a dimeric structure, and each of the sodium atoms is four-coordinated to form a distorted tetrahedron. It was found that compounds 1-3 can efficiently initiate the ring opening polymerization of l-lactide in the absence of alcohol, yielding polymers with high molecular weights for a wide range of monomer-to-initiator ratios.     

A concise total synthesis of (+)-deoxocassine and (−)-deoxoprosophylline from d-xylose

A concise total synthesis of (+)-deoxocassine (1) and (−)-deoxoprosophylline (2) has been achieved for the first time from d-xylose. The key steps involved in these synthesis are alkyl Grignard reaction, S_N2 substitution of mesylate by azide, Wittig reaction, and reductive amination.     

Concise and divergent approach to 3-O-acyl-l-noviose derivatives and their 3-amino bioisosteres: 3-O-benzoyl-l-noviose and N-benzoyl-3-amino-l-noviose

Generally applicable concise approaches to 3-O-acyl-l-noviose derivatives and their 3-amino bioisosteres, represented by 5 and 6, were described. Chiral aldehyde 7 was thus prepared from dimethyl l-tartrate in five steps, and converted into 5 and 6 by employing substrate induced asymmetric aldehyde or N-sulfinyl aldimine allylation and dihydropyrane epoxidation as key steps, respectively.