Solid-phase synthesis of core 3 and core 6 O-glycan-linked glycopeptides by benzyl-protection method

Core 3 and core 6 O-glycoamino acids were prepared in a protected form suited for Fmoc solid-phase peptide synthesis (SPPS). An N-trichloroacetyllactosamine derivative (2) was used as a highly β-selective glycosyl donor in 3-O-glycosylation of acceptors 3/4 and in 6-O-glycosylation of acceptors 5/6. Zn reduction of trisaccharides 7/8 and 13/14 was followed by acetylation to readily transform trichloroacetamido and azido groups to acetamido groups. Selective deprotection by Pd(0)-catalysis afforded core 3 O-glycan building blocks 11/12 and core 6 O-glycan building blocks 17/18. Usefulness of these building blocks for SPPS was demonstrated by the syntheses of the core 3-linked MUC2 tandem repeat glycopeptide and the core 6-linked glycopeptide segment of MUC6. The synthetic glycopeptides detached from the resin were debenzylated under the ‘low-acidity TfOH’ conditions.     

Ti(III)-promoted cyclizations. Application to the synthesis of (E)-endo-bergamoten-12-oic acids. Moth oviposition stimulants isolated from Lycopersicon hirsutum

The Ti(III)-promoted radical cyclization of epoxyenone 8 is described as the key step to access the diol 10 as a convenient starting material of the target molecules. The synthesis of β-(E)-endo-bergamoten-12-oic acid 2a from (+)-8,9-epoxycarvone 8 was successfully achieved by Suzuki-Miyaura coupling of the terminal alkene 20 with β-iodomethacrylate 21c, followed by deprotection and dehydration processes. Moreover, synthesis of the α-(E)-endo-1-hydroxy-bergamoten-12-oic acid derivative 34 was achieved by iterative elongation processes of the diol 10 lateral chain.     

N-Arylmethyl-7-azabicyclo[2.2.1]heptane derivatives: synthesis and reaction mechanisms

N-Arylmethyl-7-azabicyclo[2.2.1]heptane (I) derivatives have been synthesized by deprotection of N-protected, N-(arylmethyl)cyclohex-3-enamines, bromination of the resulting secondary cyclohex-3-enamines, followed by base-promoted cyclization (route a), or by bromination of N-protected, N-(arylmethyl)cyclohex-3-enamines followed by deprotection and base-mediated cyclization (route b). In these protocols we have observed that the bromination of the key intermediates (12, 13, and 19) is stereoselective leading to major trans-3-cis-4-dibromides (14, 17, and 20), whose mild base-mediated heterocyclization (on compound 14), or the two-step acid hydrolysis plus base-promoted cyclization (on compounds 17 and 20), gave products 6 and 7 in good yield. A mechanistic investigation using DFT has been carried out to explain the results observed in this work.     

Crotylation of (R)-2,3-O-cyclohexylideneglyceraldehyde: a simple synthesis of (+)-trans-oak lactone

Crotylations of (R)-2,3-cyclohexylideneglyceraldehyde (1) were utilized in a simple synthesis of trans-oak lactone (I), a representative example of chiral β,γ-disubstituted-γ-butyrolactones. In this endeavor, crotylations of 1 in THF mediated with four low valent metals were studied. All these reactions took place efficiently producing 2 in good yields but with varied stereoselectivities. Each reaction produced the corresponding secondary alcohol adduct 2b and 2c predominantly with diastereoisomer 2a only in trace amounts. Among these four reactions, only Sn-mediated addition yielded 2b as the major products. Later, 2c was converted into 2d through oxidation-reduction. Finally, 2c was transformed into trans-oak lactone I in a few steps. Following this route, 2a, 2b, and 2d would produce other stereoisomers of oak lactone.     

A general method for the synthesis of oligosaccharides consisting of α-(1→2)- and α-(1→3)-linked rhamnan backbones and GlcNAc side chains

A general method has been developed for the synthesis of oligosaccharides consisting of (1→2)- and (1→3)-linked rhamnans with GlcNAc side chains. As examples, highly effective and convergent syntheses of two decasaccharides in the O polysaccharide moiety of the lipopolysaccharide of the phytopathogenic bacterium Pseudomonas syringae pv. ribicola NCPPB 1010 were achieved. The two decasaccharides consist of O polysaccharide repeating units I+II and II+I, respectively. Allyl 3-O-acetyl-4-O-benzoyl-α-l-rhamnopyranoside, allyl 2-O-benzoyl-3-O-chloroacetyl-α-l-rhamnopyranoside, 2,4-di-O-benzoyl-3-O-chloroacetyl-α-l-rhamnopyranosyl trichloroacetimidate, and 3-O-acetyl-2,4-di-O-benzoyl-α-l-rhamnopyranosyl trichloroacetimidate, which were obtained by highly regioselective 3-O-acylations, were used as the key synthons to obtain the required α-(1→2)- and α-(1→3)-linked rhamnoocta saccharide acceptors with 3³- and 3⁷-free hydroxyl groups. Therefore, several disaccharides were synthesized, from which tetrasaccharides and hexasaccharides were then synthesized. Coupling of the hexasaccharide donors with the disaccharide acceptors gave the octasaccharide acceptors. Finally, the coupling of 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-d-glucopyranosyl trichloroacetimidate with the octasaccharide acceptors, followed by deprotection, afforded the two target decasaccharides. A repeating hexasaccharide unit of the cell wall polysaccharide of β-hemolytic Streptococci Group A was also synthesized in a similar way.     

Highly stereoselective addition of organozinc reagents to pentopyranose derived glycals: effect of protecting group and assignment of C-glycoside stereochemistry

The nucleophilic addition of ethyl 3-propionylzinc iodide to a variety of differently protected pentopyranose derived d-glycals 6a-g proceeds with good to high levels of diastereoselectivity to provide the corresponding β-C-glycosides 7. The stereochemistry of the para-nitrobenzoate derivative 7d has been confirmed by X-ray crystallography, and the stereochemistry of the other β-C-glycoside products has been correlated to 7d. The stereochemical outcome observed supports the earlier suggestion by Isobe that through-space effects are important in stabilising and controlling the reactivity of the intermediate oxonium species represented by 11.     

Kinetic versus thermodynamic access to imidazoisoindolones, benzimidazoisoindolones, and [1,4]diazepinoisoindolones: intramolecular nitrogen and π-aromatic trapping of N-acyliminium cation

Efficient assembly of substituted imidazo[2,1-a]isoindolones I is reported from suitable α,β-diamine IV (or corresponding β-nitroamine) and phthalic anhydride (1) in a three- or four-step sequence in good yields. The key step of this methodology is based on an intramolecular α-aza-amidoalkylation of the N-acyliminium species. Furthermore, when R₂ is an aromatic moiety a competing α-amidoalkylation took place and imidazo[2,1-a]isoindolones (or benzimidazo[2,1-a]isoindolones) I and/or isoindolo[1,4]benzodiazepines III were obtained under kinetic or thermodynamic control. The chemoselectivity of these transformations is also discussed.     

Synthesis of 3-deoxy-3,3-difluoro-d-ribohexose from gem-difluorohomoallyl alcohol

A novel synthetic route to 3-deoxy-3,3-difluoro-d-ribohexose 1 has been developed. Dihydroxidation of gem-difluorohomoallyl alcohol followed by several steps of protection and deprotection gave key intermediate 9. Oxidation of 1,5-diol 9 with 2 equiv. trichloroisocyanuric acid and catalytic TEMPO gave lactone 10. Reduction of 10 with DIBAL-H followed by deprotections afforded the target molecule 1.     

Stereoselective synthesis and biological activity of novel spiro-oxazinanone-C-glycosides

The stereoselective synthesis of novel spiro-oxazinanone nucleosides 9 and 10 has been achieved by microwave assisted 1,3-dipolar cycloaddition of exo-glucal (1) and nitrones (2), and followed by reduction, stereospecific recyclization, and catalytic deprotection. The structures of the spironucleosides were determined according to the ¹H NMR, ¹³C NMR, 2D NMR, MS, and X-ray analyses, and the biological activities of the title compounds against glycosidases (α-amylase, α-glucosidase, and β-glucosidase) and cytotoxicity were also evaluated.     

Simple preparation of phenylpropenoid β-d-glucopyranoside congeners by Mizoroki-Heck type reaction using organoboron reagents

Palladium(II)-catalyzed carbon-carbon bond formation between allyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (3) and arylboronic acid congeners gave the corresponding cinnamyl 2,3,4,6-tetra-O-acetyl- β-d-glucopyranosides (4a-m) in good yield. Among them, coupling products 4a-m were converted to not only the naturally occurring phenylpropenoid β-d-glucopyranoside analogues (1a-e) but also the unnaturally ones (1f-m).     

Chemoenzymatic resolution of epimeric cis 3-carboxycyclopentylglycine derivatives

Epimeric 3-carboxycyclopentylglycines (+)-10/(−)-10 and (+)-11/(−)-11 were efficiently prepared by the way of a sequence of Diels-Alder and retro-Claisen reactions. The synthesis incorporates a concise and inexpensive chemoenzymatic resolution of racemic compounds 4,5a, the N,O-protected derivatives of amino acids 10,11. Systematic screening with different enzymes and microorganisms was performed to select a very efficient catalyst for the separation of the racemic mixtures. The reaction conditions allowing deprotection of both ester and amino functions and to avoiding epimerization processes were studied. Enantiomers (i.e., (+)-10/(−)-10 and (+)-11/(−)-11) were obtained in high enantiopurity. The absolute configuration of all stereocenters was unequivocally assigned.     

Synthesis and characterization of new Rh complexes bearing CO, PPh3 and chelating P,O- or Se,Se-ligands: Application to hydroformylation of styrene

The complexes [Rh(CO)(PPh₃){Ph₂PNP(O)Ph₂-P,O}] (3), [Rh(CO)₂{Ph₂P(Se)NP(Se)Ph₂-Se,Se′}] (5), and [Rh(CO)(PPh₃){Ph₂P(Se)NP(Se)Ph₂-Se,Se′}] (6), were synthesised by stepwise reactions of CO and PPh₃ with [Rh(cod){Ph₂PNP(O)Ph₂-P,O}] (2) and [Rh(cod){Ph₂P(Se)NP(Se)Ph₂-Se,Se′}] (4), respectively. The complexes 3, 5 and 6 have been studied by IR, as well as ¹H and ³¹P NMR spectroscopy. The ν(CO) bands of complexes 3 and 6 appear at approximately 1960 cm⁻¹, indicating high electron density at the Rh^I centre. The structure of complexes 3 and 6 has been determined by X-ray crystallography, and the ³¹P NMR chemical shifts have been resolved via low temperature NMR experiments. Both complexes exhibit square planar geometry around the metal centre, with the five-membered ring of complex 3 being almost planar, and the six-membered ring of complex 6 adopting a slightly distorted boat conformation. The C-O bond of the carbonyl ligand is relatively weak in both complexes, due to strong π-back donation from the electron rich Rh^I centre. The catalytic activity of the complexes 2, 3 and 6 in the hydroformylation of styrene has been investigated. Complexes 2 and 3 showed satisfactory catalytic properties, whereas complex 6 had effectively no catalytic activity.     

Facile synthesis of 4-phenylquinolin-2(1H)-one derivatives from N-acyl-o-aminobenzophenones

An efficient synthesis of 4-phenylquinolin-2(1H)-one derivatives has been achieved in a one-pot reaction from N-acyl-o-aminobenzophenones 1a-c (a: acyl=acetyl; b: acyl=propanoyl; c: acyl=heptanoyl) using NaH as a base. Treatment of 1 with NaH provided the quinolones 2a-c with 62-83% yields, whereas the reaction in the presence of alkyl iodide (alkyl=methyl, ethyl, n-octyl) gave the corresponding N-alkylated quinolones 3a-g in 75-95% yields. The alkylation reaction of 4-phenylquinolin-2(1H)-one 2a with alkyl halide gave a mixture of N-alkylated and O-alkylated products. Comparison of IR and NMR data of the N-alkylated and O-alkylated compounds with those of 2a-c indicated that 2a-c exist as the lactam form.     

Synthesis of the first examples of p-bromodienone and transannular spirodienone calixarene derivatives

The first examples of p-bromodienone calixarene derivatives (6-7 and 9-10) have been obtained by treatment of 1,5-dihydroxy-hexaalkoxycalix[8]arenes 5 or tripropoxycalix[4]arene 8 with trimethylphenylammonium tribromide and a saturated solution of NaHCO₃. The first transannular spirodienone derivative 11 was only obtained in the presence of NaOH or using the KOH/I₂/PEG-200 oxidizing system.     

Synthesis of branched tri- to pentasaccharides representative of fragments of Shigella flexneri serotypes 3a and/or X O-antigens

Fragments of the {2)-[α-d-Glcp-(1→3)]-α-l-Rhap-(1→2)-α-l-Rhap-(1→3)-[Ac→2]-α-l-Rhap-(1→3)-β-d-GlcpNAc-(1→}_n ((E)AB_AcCD)_n polymer were synthesized. D(E)A, CD(E)A, _AcCD(E)A were obtained according to a linear strategy, whereas BCD(E)A and B_AcCD(E)A were derived from the condensation of appropriate BC and D(E)A building blocks. Oligosaccharides were synthesized as their propyl glycoside, relying on (i) the efficient trichloroacetimidate chemistry, (ii) a common EA allyl glycoside, and (iii) a 2-trichloroacetamido-d-glucopyranose precursor to residue D. Final Pd/C-mediated deprotection, run under a high pressure of hydrogen, ensured O-acetyl stability. All targets are parts of the O-antigen of Shigella flexneri 3a, a prevalent serotype. Non-O-acetylated oligosaccharides are shared by the S. flexneri serotype X O-antigen.     

Michael addition of chiral formaldehyde N,N-dialkylhydrazones to activated cyclic alkenes

The nucleophilic conjugate addition of chiral formaldehyde N,N-dialkylhydrazones 1 to doubly activated cyclic alkenes 2-8 proceeds smoothly to afford the corresponding Michael adducts 14, 16, 18, 20, 22, 24, and 25 in variable yields and selectivities. The reactions take place either spontaneously or in the presence of MgI₂ as a mild Lewis acid depending on the type of substrate. Release of the chiral auxiliary was achieved by transformation of the hydrazone moiety into acetals, dithioacetals or nitriles.     

Two tantalum fluorides templated with tren: [H4tren](TaF7)2·H2O and [H4tren](TaF7)2

Using tris(2-aminoethyl)amine [(C₂H₄NH₂)₃N] (tren) as a template, two new tantalum fluorides are obtained by slow evaporation of solutions: [H₄tren](TaF₇)₂·H₂O (I) and [H₄tren](TaF₇)₂ (II). The structure determinations are performed by single crystal X-ray technique. Structures of I and II are built up from isolated TaF₇ distorted monocapped trigonal prisms or pentagonal bipyramids; charge balance is achieved by tetraprotonated [H₄tren]⁴⁺ cations which possess a “scorpion” configuration. In I and II, TaF₇ polyhedra, connected by hydrogen bonds with water molecules in I, lie in corrugated layers; hydrogen bond networks ensure the cohesion between these layers and [H₄tren]⁴⁺cations.     

Alternative synthesis and novel oxidizing ability of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-dione derivatives

Synthesis of 6,9-disubstituted cyclohepta[b]pyrimido[5,4-d]pyrrole-8(6H),10(9H)-diones 7a-g was accomplished by ring opening and ring closure sequences of 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8,10(9H)-dione derivatives induced by several amines. Furthermore, alternative synthetic methodology for compounds 7a-e was also accomplished by single-step reaction of 2-chlorotropone with 6-aminouracil derivatives under mild conditions. X-ray crystal analysis of 7a was carried out to clarify the structural characteristics. The properties of 7a-e were studied by the UV-vis spectra and reduction potentials (−1.24 to −1.39 V vs Ag/AgNO₃). Novel photo-induced oxidation reaction of 7a-d toward some amines under aerobic conditions was carried out to give the corresponding imines in more than 100% yield [based on compounds 7a-d], suggesting the oxidation reaction occurs in an autorecycling process.     

The microbiological transformation of steroidal saponins by Curvularia lunata

The microbiological transformation of polyphyllin I (compound I), polyphyllin III (compound II), polyphyllin V (compound III) and polyphyllin VI (compound IV) by Curvularia lunata into their corresponding subsaponins, for example, diosgenin-3-O-α-l-arabinofuranosyl (1→4)-β-d-glucopyranoside (compound V), diosgenin-3-O-α-l-rhamnopyranosyl (1→4)-β-d-glucopyranoside (compound VI), diosgenin-3-O-β-d-glucopyranoside (compound VII) and pennogenin-3-O-β-d-glucopyranoside (compound VIII), were studied in this paper. Curvularia lunata is able to hydrolyze terminal rhamnosyls that are linked by 1→2 C- bond to sugar residues of steroidal saponins at C-3 position with high activity and regioselectivity.     

Preparation of new pyrido[3,4-b]thienopyrroles and pyrido[4,3-e]thienopyridazines

Two new types of pyrido-fused tris-heterocycles (1a,b and 2a,b) have been prepared from 3-aminopyridine in five/six steps. A synthetic strategy for the preparation of the novel pyrido[3,4-b]thieno[2,3- and 3,2-d]pyrroles (1a,b) and pyrido[4,3-e]thieno[2,3- and 3,2-c]pyridazines (2a,b) has been studied. The Suzuki cross coupling of the appropriate 2- and 3-thienoboronic acids (3,4) and 4-bromo-3-pyridylpivaloylamide (9) afforded the biaryl coupling products (10,11) in high yields (85%). Diazotization of the hydrolysed (2-thienyl)-coupling product (12) and azide substitution gave the 3-azido-4-(2-thienyl)pyridine intermediate (72%, 14). 3-Azido-4-(3-thienyl)pyridine (15) was prepared by exchanging the previous order of reactions. The desired β-carboline thiophene analogues (1a,b) were obtained via the nitrene by thermal decomposition of the azido precursors (14,15). By optimising conditions for intramolecular diazocoupling, the corresponding pyridazine products (72-83%, 2a,b) were afforded.