Synthesis and in vitro evaluation of alpha-GalCer epimers

alpha-GalCer (also known as KRN7000) is an immunomodulatory glycolipid that is known to potently activate invariant natural killer T (NKT) cells upon CD1d-mediated stimulation. Because Th1 and Th2 cytokines, which are released after alpha-GalCer presentation, antagonize each other's effects, alpha-GalCer analogues that induce a biased Th1/Th2 response are highly awaited. In this context, we report the synthesis and in vitro evaluation of alpha-Gal-D-xylo-Cer and two alpha-Gal-L-lyxo-Cer analogues, one with the natural acyl chain, the other with a truncated chain.     

Crystallography and Structure–Property Relationships in 2,2′,2″,2′′′,4,4′,4″,4′′′,6,6′,6″,6′′′‐Dodecanitro‐1,1′ : 3′1″ : 3″,1′′′‐ Quaterphenyl (DODECA)

X‐ray crystallographic study of 2,2′,2″,2′′′,4,4′,4″,4′′′,6,6′,6″,6′′′‐dodecanitro‐1,1′ : 3′1″ : 3″,1′′′‐quaterphenyl (DODECA) has been carried out. Nonbonding interatomic distances of oxygen atoms inside of all the nitro groups are shorter than those corresponding to the intermolecular contact radii for oxygen. By means of the DFT B3LYP/6‐31(d, p) method a difference of 136 kJ mol⁻¹ between the X‐ray and DFT structures of DODECA was found. The bearer of the highest initiation reactivity in its molecule in solid phase should be the nitro group at 4′′′‐position, in contrast to those at 2′‐ or 2″‐positions in its isolated molecule. The most reactive nitro group in the DODECA molecule can be well specified by the relationship between net charges on nitro groups and charges on their nitrogen atoms, both of them for the X‐ray structure. The ¹⁵N chemical shift, corresponding to this nitro group for the initiation by impact and shock, correlates very well with these shifts of the reaction centers of the other six “genuine” polynitro arenes.     

Cationic copolymers of α,β‐poly‐(N‐2‐hydroxyethyl)‐DL‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy): synthesis and characterization

In the present study the derivatization of two water‐soluble synthetic polymers, α,β‐poly(N‐2‐hydroxyethyl)‐DL ‐aspartamide (PHEA) and α,β‐polyasparthylhydrazide (PAHy), with glycidyltrimethylammonium chloride (GTA) is described. This reaction permits the introduction of positive charges in the macromolecular chains of PHEA and PAHy in order to make easier the electrostatic interaction with DNA. Different parameters affect the reaction of derivatization, such as GTA concentration and reaction time. PHEA reacts partially and slowly with GTA; on the contrary the reaction of PAHy with GTA is more rapid and extensive. The derivatization of PHEA and PAHy with GTA is a convenient method to introduce positive groups in their chains and it permits the preparation of interpolyelectrolyte complexes with DNA. © 2000 Society of Chemical Industry     

The One‐Pot Wittig Reaction: A Facile Synthesis of α,β‐Unsaturated Esters and Nitriles by Using Nanocrystalline Magnesium Oxide

Nanocrystalline magnesium oxide was found to be an effective heterogeneous, solid base catalyst for the one‐pot Wittig reaction to afford α,β‐unsaturated esters and nitriles in excellent yields with high E‐stereoselectivity in the presence of triphenylphosphine under mild conditions.     

Ruthenium(II)‐Catalyzed Protocol for Preparation of Diverse α,β‐ and β,β‐Dihaloenones from Diazodicarbonyls

Efficient one‐step syntheses of α,β‐ and β,β‐dihaloenones were achieved by ruthenium(II)‐catalyzed reactions between cyclic or acyclic diazodicarbonyl compounds and oxalyl chloride or oxalyl bromide in moderate to good yields. This methodology offers several significant advantages, which include ease of handling, mild reaction conditions, one‐step reaction, and the use of an effective and non‐toxic catalyst. The synthesized compounds were further transformed into highly functionalized novel molecules bearing aromatic rings on the enone moiety using the Suzuki reaction.

     

A Practical Synthesis of α‐Fluoroketones in Aqueous Media by Decarboxylative Fluorination of β‐Ketoacids

A practical and novel process for the decarboxylative fluorination of β‐ketoacids in water in the presence of phase transfer catalyst has been developed, affording a series of α‐fluoroketones in good to excellent yields. Furthermore, a preliminary investigation for the catalytic asymmetric transformation was performed and a proposed mechanistic pathway for this catalytic process was proposed.

     

Crystallography and Structure–Property Relationships of 2,2″,4,4′,4″,6,6′,6″‐Octanitro‐1,1′ : 3′,1″‐Terphenyl (ONT)

An X‐ray crystallographic study of 2,2″,4,4′,4″,6,6′,6″‐octanitro‐1,1′ : 3′,1″‐terphenyl (ONT) has been carried out. The dihedral angles between benzene rings vary from 84.9° to 89.4°. Nonbinding interatomic distances of oxygen atoms inside all the nitro groups are shorter than the intermolecular contact radii for oxygen. On the basis of the DFT B3LYP/6‐31(d, p) method it was found that the difference between the X‐ray structure in the solid phase and DFT result for the gas phase is 98 kJ mol⁻¹, and the bearer of the highest initiation reactivity of the ONT molecule in the solid phase should be the nitro group at 4″‐position, in contrast to those at 4′‐ or 6′‐position that play this role in the isolated molecule. It has been stated that the nitro groups at the reaction centers of the ONT molecule are relatively well specified by their ¹⁵N NMR chemical shifts.     

Atom‐transfer radical polymerization of methyl methacrylate with α,α′‐dichloroxylene/CuCl/N,N,N′,N″,N″‐pentamethyldiethylenetriamine initiation system under microwave irradiation

The atom‐transfer radical polymerization (ATRP) of methyl methacrylate (MMA), using α,α′‐dichloroxylene as initiator and CuCl/N,N,N′,N″,N″‐pentamethyldiethylenetriamine as catalyst was successfully carried out under microwave irradiation (MI). The polymerization of MMA under MI showed linear first‐order rate plots, a linear increase of the number‐average molecular weight with conversion, and low polydispersities, which indicated that the ATRP of MMA was controlled. Using the same experimental conditions, the apparent rate constant (k) under MI (k = 7.6 × 10^?4 s^?1) was higher than that under conventional heating (k = 5.3 × 10^?5 s^?1). © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 2189–2195, 2004     

Michael Reaction of Nitroalkanes with β‐Nitroacrylates under a Solid Promoter: Advanced Regio‐ and Diastereoselective Synthesis of Nitro‐Functionalized α,β‐Unsaturated Esters and 1,3‐Butadiene‐2‐carboxylates

A new class of nitro‐functionalized α,β‐unsaturated esters has been prepared by a regio‐ and diastereoselective Michael addition of nitroalkanes to β‐nitroacrylates, performed at room temperature, under carbonate on polymer as promoter, and in the presence of ethyl acetate as eco‐friendly solvent. Moreover, by the modular choice of the reaction conditions the method allows the synthesis of 1,3‐butadiene‐2‐carboxylates.     

Organocatalytic Enantioselective Aziridination of α‐Substituted α,β‐Unsaturated Aldehydes: Asymmetric Synthesis of Terminal Aziridines

The first example of a highly enantioselective organocatalytic aziridination of α‐substituted α,β‐unsaturated aldehydes is presented. The reaction is catalyzed by simple chiral amines and gives access to highly functional terminal azirdines containing an α‐tertiary amine stereocenter in high yields and enantiomeric ratios (95.5:4.5–98:2).     

One‐Pot Synthesis of Fluorovinyl Acetates and β,β‐Difluoro Carboxylates from a Hypervalent Iodine and Hydrogen Fluoride‐Based Fluorination Reagent

A new strategy for the synthesis of fluorovinyl acetates and β,β‐difluoro carboxylates using a hypervalent iodine and hydrogen fluoride‐based fluorination reagent is established through a silver‐catalyzed one‐pot reaction involving formation of carbon‐oxygen and carbon‐nitrogen bonds. The generated fluoroalkenes substituted with the carbon‐oxygen and carbon‐nitrogen bond on the β‐position have the potential to be transformed into various products which would be difficult to obtain via direct fluorination.

     

The Synthesis of trans‐Perhydroindolic Acids and their Application in Asymmetric Domino Reactions of Aldehyde Esters with β,γ‐Unsaturated α‐Keto Esters

(2S,3aR,7aS)‐Perhydroindolic acid, the key intermediate in the synthesis of trandolapril, and its trans‐isomers, were readily prepared. These proline‐like molecules are unique in that they contain a rigid bicyclic structure, with two hydrogen atoms trans to each other at the bridgehead carbon atoms. These molecules were used successfully as chiral organocatalysts in asymmetric domino Michael addition/cyclization reactions of aldehyde esters with β,γ‐unsaturated α‐keto esters. They proved to have excellent catalytic behavior, allowing for the synthesis of multi‐substituted, enantiomerically enriched hemiacetal esters. Under optimal conditions (using 10 mol% catalyst loading), a series of β,γ‐unsaturated α‐keto esters was examined with up to 99% de, ee and yield, respectively. Additionally, the enantiomerically enriched hemiacetal esters could be readily transformed into their corresponding bioactive pyrano[2,3‐b]pyrans (possessing a multi‐substituted bicyclic backbone).     

Organocatalytic Asymmetric Synthesis of Protected α,β‐Diamino Acids

In the presence of the readily available quinine‐derived catalyst 4d , highly diastereo‐ and enantioselective Mannich reactions of tosyl‐protected imines and α‐isothiocyanato imides proceeded to afford the protected α,β‐diamino acids, useful building blocks for natural products and biologically active compounds, in good to excellent yields.     

Direct Decarboxylative Alkynylation of α,α‐Difluoroarylacetic Acids under Transition Metal‐Free Conditions

An efficient and generally applicable protocol for decarboxylative coupling of α,α‐difluoroarylacetic acids with ethynylbenziodoxolone (EBX) reagents has been developed, affording α,α‐difluoromethylated alkynes bearing various functional groups in moderate to excellent yields. Remarkably, this potassium persulfate (K₂S₂O₈)‐promoted reaction employs water as solvent under transition metal‐free conditions, thus providing a green synthetic approach to α,α‐difluoromethylated alkynes.

     

Asymmetric Synthesis of 3,4‐Dihydrocoumarins Bearing an α,α‐Disubstituted Amino Acid Moiety

An organocatalytic approach for the stereoselective synthesis of 3,4‐dihydrocoumarins with an α,α‐disubstituted amino acid moiety incorporated is presented. The developed methodology is based on the cascade reaction between α‐substituted azlactones and 2‐hydroxychalcones. It is initiated by a chiral Brønsted base‐catalyzed enantio‐ and diastereoselective Michael reaction followed by the azlactone ring opening to construct a 3,4‐dihydrocoumarin framework. Products bearing two adjacent stereogenic centers, one being quaternary, were formed with high enantioselectivities and excellent diastereoselectivities. Furthermore, the complete regioselectivity of the new cascade reactivity is worthy of notice.

     

A Convenient Synthesis of 2,2′,6,6′‐Tetramethoxy‐ 4,4′‐bis(dicyclohexylphosphino)‐3,3′‐bipyridine (Cy‐P‐Phos): Application in Rh‐Catalyzed Asymmetric Hydrogenation of α‐(Acylamino)acrylates

The first example of the synthesis of an axially chiral bis(aryldicyclohexylphosphine) dioxide via catalytic hydrogenation of the optically resolved parent bis(aryldiphenylphosphine) dioxide was reported. The procedure for the synthesis of Cy‐P‐Phos ( 4d ) has thus successfully avoided the need for an otherwise lengthy synthetic route owing to the π‐excessive nature of one of the aryl groups in the latter. The use of Cy‐P‐Phos in the Rh(I)‐catalyzed asymmetric hydrogenation of the derivatives of methyl (Z)‐2‐acetamidocinnamate gave significantly higher rates of reaction as compared to the use of the previously reported optimal ligand Xyl‐P‐Phos ( 4c ) whilst the level of enantioselectivity was essentially maintained.     

Regio‐ and Enantioselective Copper‐Catalyzed 1,4‐Conjugate Addition of Trimethylaluminium to Linear α,β,γ,δ‐Unsaturated Alkyl Ketones

A regio‐ and enantioselective copper‐catalyzed 1,4‐conjugate addition of trimethylaluminium to linear δ‐aryl‐substituted α,β,γ,δ‐unsaturated alkyl ketones was developed. A series of γ,δ‐unsaturated alkyl ketones were obtained in good yields with high regio‐ and enantioselectivity (up to 88% ee and 96:4 dr). Expansion of the reaction scope to substrates containing aromatic heterocycles also afforded good yields and enantioselectivities (up to 91% ee) with very high regioselectivities, exclusively providing the single 1,4‐products.

     

Highly Enantioselective Michael Addition of Cyclic 1,3‐Dicarbonyl Compounds to β,γ‐Unsaturated α‐Keto Esters

A highly enantioselective Michael addition of cyclic 1,3‐dicarbonyl compounds to β,γ‐unsaturated α‐keto esters catalyzed by amino acid‐derived thiourea‐tertiary‐amine catalysts is presented. Using 5 mol% of a novel tyrosine‐derived thiourea catalyst, a series of chiral coumarin derivatives were obtained in excellent yields (up to 99%) and with up to 96% ee under very mild conditions within a short reaction time.