ZnII‐ and AuI‐Catalyzed Regioselective Hydrative Oxidations of 3‐En‐1‐ynes with Selectfluor: Realization of 1,4‐Dioxo and 1,4‐Oxohydroxy Functionalizations

Catalytic 1,4‐dioxo functionalizations of 3‐en‐1‐ynes to (Z)‐ and (E)‐2‐en‐1,4‐dicarbonyl compounds are described. This regioselective difunctionalization was achieved in one‐pot operation through initial alkyne hydration followed by in situ Selectfluor oxidation. The presence of pyridine alters the reaction chemoselectivity to give 4‐hydroxy‐2‐en‐1‐carbonyl products instead. A cooperative action of pyridine and Zn^II assists the hydrolysis of key oxonium intermediate.     

Efficient Method for the Elongation of the N‐Acetylglucosamine Unit by Combined Use of Chitinase and β‐Galactosidase

A novel strategy for the regio‐ and stereoselective synthesis by two enzymatic steps of oligosaccharides having an N‐acetylglucosamine unit at the nonreducing end was developed. The first step involves a chitinase‐catalyzed highly selective β‐N‐acetyllactosamination of an oligosaccharide acceptor with a 4,5‐dihydrooxazole derivative of N‐acetyllactosamine as the glycosyl donor. The usage of a transition‐state‐analogue substrate for the chitinase under basic conditions allows the reaction to proceed only in the synthetic direction while suppressing hydrolysis of the product in aqueous media. Several chitinase mutants also catalyzed the glycosylation efficiently under neutral conditions. The second step is a regioselective cleavage of the glycosidic bond between the terminal galactose unit and the adjacent N‐acetylglucosamine unit by the action of a β‐galactosidase. This constitutes a very useful method to add an N‐acetylglucosamine unit to the nonreducing end of chito‐ and cello‐oligosaccharide derivatives in a regio‐ and stereoselective manner.     

Asymmetric Synthesis of β2‐homo‐tert‐Leucine via Radical Addition to Enantiopure N‐Fumaroylhexahydrobenzooxazolidin‐2‐one

β‐Amino acids are key structural elements in unnatural peptides, peptidomimetics, and many other physiologically active compounds. In view of their importance, we have developed an efficient synthetic route that provides highly enantiomerically enriched (R)‐ and (S)‐H‐β²‐h^tLeu‐OH via highly diastereo‐ and regioselective addition of tert‐butyl radical to enantiomerically pure N‐fumaroyloxazolidinones, followed by removal of the chiral auxiliary, Curtius rearrangement, ester hydrolysis, and catalytic hydrogenolysis.     

Unexpected Spiroproducts from the Reaction of N‐Benzoylglycine with Ortho‐Formylbenzoic Acids −3,5′‐Dioxo‐2′‐Phenyl‐1,3‐Dihydrospiro[Indene‐2,4′‐[1,3]Oxazol]‐1‐yl Acetates: Establishments of Their Structure

This paper describes a method of preparation of new 3,5′‐dioxo‐2′‐phenyl‐1,3‐dihydrospiro[indene‐2,4′‐[1,3]oxazol]‐1‐yl acetate and its 5‐chloro‐ and bromoderivatives as products of interaction of N‐benzoylglycine (hippuric acid) with corresponding ortho‐formylbenzoic acids. The reaction carried out in acetic anhydride media in the presence of piperidine as catalyst. The novel spirocompounds were purified by column chromatography from multicomponent reaction mixtures. The composition of the spiro‐products was confirmed by C, H, N element analysis. The structure was established by IR, MS, ¹H‐ and ¹³C‐NMR analysis including COSY ¹H‐¹³C experiments.     

A Facile Synthesis of Enantiomerically Pure (R)‐6‐Arylbinols

This work reported a convenient method for the preparation of enantiomerically pure 6‐aryl‐2,2′‐dihydroxy‐1,1′‐binaphthyl derivatives starting from the commercially available (R)‐2,2′‐hydroxy‐1,1′‐binaphthyl [(R)‐ 1 ] via bromination, hydrolysis and Suzuki cross coupling reaction. This novel synthetic method was characterized with high regioselectivity, simple operation, mild reaction conditions, and excellent yield (up to 73%). On the other hand, we synthesized the target unknown compounds, which were confirmed by IR, ¹H NMR, ¹³C NMR, MS and elementary analysis.     

Insights into the Synthesis of Steroidal A‐Ring Olefins

The classical synthesis, followed by purification of the steroidal A‐ring Δ¹‐olefin, 5α‐androst‐1‐en‐17‐one ( 5 ), from the Δ¹‐3‐keto enone, (5α,17β)‐3‐oxo‐5‐androst‐1‐en‐17‐yl acetate ( 1 ), through a strategy involving the reaction of Δ¹‐3‐hydroxy allylic alcohol, 3β‐hydroxy‐5α‐androst‐1‐en‐17β‐yl acetate ( 2 ), with SOCl₂, was revisited in order to prepare and biologically evaluate 5 as aromatase inhibitor for breast cancer treatment. Surprisingly, the followed strategy also afforded the isomeric Δ²‐olefin 6 as a by‐product, which could only be detected on the basis of NMR analysis. Optimization of the purification and detection procedures allowed us to reach 96% purity required for biological assays of compound 5 . The same synthetic strategy was applied, using the Δ⁴‐3‐keto enone, 3‐oxoandrost‐4‐en‐17β‐yl acetate ( 8 ), as starting material, to prepare the potent aromatase inhibitor Δ⁴‐olefin, androst‐4‐en‐17‐one ( 15 ). Unexpectedly, a different aromatase inhibitor, the Δ^3,5‐diene, androst‐3,5‐dien‐17‐one ( 12 ), was formed. To overcome this drawback, another strategy was developed for the preparation of 15 from 8 . The data now presented show the unequal reactivity of the two steroidal A‐ring Δ¹‐ and Δ⁴‐3‐hydroxy allylic alcohol intermediates, 3β‐hydroxy‐5α‐androst‐1‐en‐17β‐yl acetate ( 2 ) and 3β‐hydroxyandrost‐4‐en‐17β‐yl acetate ( 9 ), towards SOCl₂, and provides a new strategy for the preparation of the aromatase inhibitor 12 . Additionally, a new pathway to prepare compound 15 was achieved, which avoids the formation of undesirable by‐products.     

The Stereoselective Synthesis of 2‐Aryl‐2‐hydroxybutanoic Acid via Menthyl Chiral Auxiliaries

In the presence of titanium(IV) tetraethoxide ((EtO)₄Ti), menthyl arylglyoxylates are prepared by transesterification of ethyl arylglyoxylates and natural (−)‐(1R,2S,5R)‐menthol. Using menthyl as a chiral auxiliary, the corresponding novel (R)‐menthyl 2‐aryl‐2‐hydroxybutanoates are synthesized by the addition of Et₂Zn with menthyl arylglyoxylates. The structures of the products are characterized by IR and ¹H‐ and ¹³C‐NMR spectroscopy, mass spectrometry, and elemental analysis. The diastereoselectivities are analyzed by HPLC. The addition reactions are completed with good yields and high diastereoisomeric excess (de up to 95%), and, after hydrolysis, the (R)‐2‐aryl‐2‐hydroxybutanoic acids are obtained with high optical purities.     

Multiple Pentafluorophenylation of 2,2,3,3,5,6,6‐Heptafluoro‐3,6‐dihydro‐2H‐1,4‐oxazine with an Organosilicon Reagent: NMR and DFT Structural Analysis of Oligo(perfluoroaryl) Compounds

The reagent Me₃Si(C₆F₅) was used for the preparation of a series of perfluorinated, pentafluorophenyl‐substituted 3,6‐dihydro‐2H‐1,4‐oxazines ( 2 – 8 ), which, otherwise, would be very difficult to synthesize. Multiple pentafluorophenylation occurred not only on the heterocyclic ring of the starting compound 1 (Scheme), but also in para position of the introduced C₆F₅ substituent(s) leading to compounds with one to three nonafluorobiphenyl (C₁₂F₉) substituents. While the tris(pentafluorophenyl)‐substituted compound 3 could be isolated as the sole product by stoichiometric control of the reagent, the higher‐substituted compounds 5 – 8 could only be obtained as mixtures. The structures of the oligo(perfluoroaryl) compounds were confirmed by ¹⁹F‐ and ¹³C‐NMR, MS, and/or X‐ray crystallography. DFT simulations of the ¹⁹F‐ and ¹³C‐NMR chemical shifts were performed at the B3LYP‐GIAO/6‐31++G(d,p) level for geometries optimized by the B3LYP/6‐31G(d) level, a technique that proved to be very useful to accomplish full NMR assignment of these complex products.     

One‐Pot Regioselective Synthesis of Novel Oximino Ester‐Containing 1‐Aryl‐4‐chloro‐3‐oxypyrazoles as Potential Fungicides

A novel, functional‐group‐tolerant, and highly regioselective one‐pot synthesis of six 4‐chloro‐1‐aryl‐3‐oxypyrazoles, 8a – 8f , containing an oximino ester moiety has been developed. Their structures were characterized by ¹H‐ and ¹³C‐NMR, IR, MS, and elemental analyses. The regioselectivity of the reaction was also determined by single‐crystal X‐ray diffraction analysis of product 8d . The reaction pathway, proposed with the aid of DFT calculations, likely proceeds via a DMF‐catalyzed mechanism, which involves an electrophilic attack by SOCl₂ and two nucleophilic substitutions by benzyl bromide (BnBr) and Cl^?, respectively, as the key steps. A preliminary in vitro bioassay indicated that most compounds exhibited good fungicidal activities against Sclerotinia sclerotiorum and Gibberella zeae. Especially, 8d and 8e displayed higher or similar fungicidal activities compared with pyraclostrobin at the concentration of 10 μg/ml.     

Highly Convergent One‐Pot Four‐Component Regioselective Synthesis of Spiro‐pyranopyrazoles and Oxa‐aza‐[3.3.3]propellanes

A concise and efficient route for the synthesis of spiro‐pyranopyrazoles and oxa‐aza‐[3.3.3]propellanes by simple regioselective multicomponent reaction of ninhydrin, malononitrile, hydrazine derivatives, and β‐keto esters or dimethyl acetylenedicarboxylate was developed. This protocol provides an alternative method for combinatorial and parallel syntheses in drug discovery. The value of this method lies in its simplicity, regioselectivity, and good yields. The structures of 3 and 4 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS). A plausible mechanism for this type of reaction is proposed (Schemes 2 and 3).     

Synthesis of 2‐Oxopyridine‐Fused 1,3‐Diazaheterocyclic Compounds via a Three‐Component Reaction

An efficient and simple route for the preparation of 2‐oxopyridine‐fused 1,3‐diazaheterocyclic compounds via a three component reaction is described. It involves the reaction between alkylenediamines 1 , 1,1‐bis(methylsulfanyl)‐2‐nitroethene, and alkyl prop‐2‐ynoates 2 in refluxing THF (Table). The structures were corroborated by spectroscopic (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and elemental analyses. A plausible mechanism for this type of cyclization is proposed (Scheme).     

Regio‐ and Enantio‐selective Chemo‐enzymatic C−H‐Lactonization of Decanoic Acid to (S)‐δ‐Decalactone

The conversion of saturated fatty acids to high value chiral hydroxy‐acids and lactones poses a number of synthetic challenges: the activation of unreactive C?H bonds and the need for regio‐ and stereoselectivity. Here the first example of a wild‐type cytochrome P450 monooxygenase (CYP116B46 from Tepidiphilus thermophilus) capable of enantio‐ and regioselective C5 hydroxylation of decanoic acid 1 to (S)‐5‐hydroxydecanoic acid 2 is reported. Subsequent lactonization yields (S)‐δ‐decalactone 3 , a high value fragrance compound, with greater than 90 % ee. Docking studies provide a rationale for the high regio‐ and enantioselectivity of the reaction.     

Iodine‐Catalyzed Synthesis of Spiro[1,3,4‐benzotriazepine‐2,3′‐indole]‐2′,5(1H,1′H)‐diones under Mild Conditions

The I₂‐catalyzed preparation of spiro[1,3,4‐benzotriazepine‐2,3′‐indole]‐2′,5(1H,1′H)‐diones from 2‐aminobenzohydrazide and isatins in MeCN at room temperature in good‐to‐excellent yields is described. The structure of 3 was corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS data). A plausible mechanism for this type of reaction is proposed (Scheme 2).     

Isolation and purification of arctigenin from Fructus Arctii by enzymatic hydrolysis combined with high‐speed counter‐current chromatography

Enzymatic hydrolysis pretreatment combined with high‐speed counter‐current chromatography for the transformation and isolation of arctigenin from Fructus Arctii was successfully developed. In the first step, the extract solution of Fructus Arctii was enzymatic hydrolyzed by β‐glucosidase. The optimal hydrolysis conditions were 40°C, pH 5.0, 24 h of hydrolysis time, and 1.25 mg/mL β‐glucosidase concentration. Under these conditions, the content of arctigenin was transformed from 2.60 to 12.59 mg/g. In the second step, arctigenin in the hydrolysis products was separated and purified by high‐speed counter‐current chromatography with a two‐phase solvent system composed of petroleum ether/ethyl acetate/methanol/water (10:25:15:20, v/v), and the fraction was analyzed by HPLC, ESI‐MS, and ¹H NMR spectroscopy. Finally, 102 mg of arctigenin with a purity of 98.9% was obtained in a one‐step separation from 200 mg of hydrolyzed sample.     

O‐2′,3′‐Ketal‐Nucleolipids of the Cytostatic 5‐Fluorouridine: Synthesis,Lipophilicity, and Acidic Stability

The synthesis of a series of cyclic and acyclic O‐2′,3′‐ketal derivatives of the cancerostatic 5‐fluorouridine ( 2a ) is described. The novel compounds were characterized by ¹H‐ and ¹³C‐NMR, and UV spectroscopy, as well as by elemental analyses. The lipophilicity values (log P, retention times in RP‐18 HPLC) of the cyclic ketals were determined and related to the ring tensions as well as the acid stability of the spiro‐linked ketal rings.     

Synthesis of 5‐Aryl‐3‐(methylsulfanyl)‐1H‐pyrazoles via Three‐Component Reaction of 1,1‐Bis(methylsulfanyl)‐2‐nitroethene,Aromatic Aldehydes,and Hydrazine

An efficient approach for the preparation of functionalized 5‐aryl‐3‐(methylsulfanyl)‐1H‐pyrazoles 2 is described. This three‐component reaction between benzaldehydes 1 , NH₂NH₂?H₂O, and 1,1‐bis(methylsulfanyl)‐2‐nitroethene proceeds in EtOH under reflux conditions in good‐to‐excellent yields. The structures of 2 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS). A plausible mechanism for this type of reaction is proposed (Scheme 2).     

Synthesis of 2‐Aryl‐5‐oxo‐4‐[2‐(phenylmethylidene)hydrazino]‐2,5‐dihydro‐1H‐pyrrole‐3‐carboxylates by the Reaction between Hydrazones,Acetylenedicarboxylates, and 1‐Aryl‐N,N′‐bis(arylmethylidene)methanediamines

An efficient approach for the preparation of functionalized 2‐aryl‐2,5‐dihydro‐5‐oxo‐4‐[2‐(phenylmethylidene)hydrazino]‐1H‐pyrroles is described. The four‐component reaction between aldehydes, NH₂NH₂?H₂O, dialkyl acetylenedicarboxylates, and 1‐aryl‐N,N′‐bis(arylmethylidene)methanediamines proceeds in EtOH under reflux in good‐to‐excellent yields (Scheme 1). The structures of 4 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS, and, in the case of 4f , by X‐ray crystallography). A plausible mechanism for this type of reaction is proposed (Scheme 2).     

Synthesis of 3,8‐Dichloro‐6‐ethyl‐1,2,5,7‐tetramethyl–BODIPY from an Asymmetric Dipyrroketone and Reactivity Studies at the 3,5,8‐Positions

The asymmetric BODIPY 1 a (BODIPY=4,4‐difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene), containing two chloro substituents at the 3,8‐positions and a reactive 5‐methyl group, was synthesized from the asymmetric dipyrroketone 3 , which was readily obtained from available pyrrole 2 a . The reactivity of 3,8‐dichloro‐6‐ethyl‐1,2,5,7‐tetramethyl‐BODIPY 1 a was investigated by using four types of reactions. This versatile BODIPY undergoes regioselective Pd⁰‐catalyzed Stille coupling reactions and/or regioselective nucleophilic addition/elimination reactions, first at the 8‐chloro and then at the 3‐chloro group, using a variety of organostannanes and N‐, O‐, and S‐centered nucleophiles. On the other hand, the more reactive 5‐methyl group undergoes regioselective Knoevenagel condensation with an aryl aldehyde to produce a monostyryl‐BODIPY, and oxidation with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) gives the corresponding 5‐formyl‐BODIPY. Investigation of the reactivity of asymmetric BODIPY 1 a led to the preparation of a variety of functionalized BODIPYs with λ_max of absorption and emission in the ranges 487–587 and 521–617 nm, respectively. The longest absorbing/emitting compound was the monostyryl‐BODIPY 16 , and the largest Stokes shift (49 nm) and fluorescence quantum yield (0.94) were measured for 5‐thienyl‐8‐phenoxy‐BODIPY 15 . The structural properties (including 16 X‐ray structures) of the new series of BODIPYs were investigated.     

Characterization of reduced iso‐α‐acids derived from hops (Humulus lupulus) by NMR

Reduced forms of iso‐α‐acids (isohumulones), used in modern beer brewing were separated and characterized by ¹H and ¹³C NMR spectroscopy. Components from mixtures of rho‐iso‐α‐acids, tetrahydro‐iso‐α‐acids, and hexahydro‐iso‐α‐acids were isolated using high‐performance liquid chromatography (HPLC) and analyzed by use of one‐ and two‐dimensional NMR experiments. The data presented assign the identities of the main peaks in the HPLC traces for the reduced iso‐α‐acids. Previous tentative assignments regarding the cis and trans configurations and the structures of the acyl residues of the reduced iso‐α‐acids were confirmed and extensive NMR assignments were made. Furthermore, the previously unknown stereochemistry in the C‐4 side‐chain of the rho‐ and hexahydro‐iso‐α‐acids was assigned. Copyright © 2003 John Wiley & Sons, Ltd.     

Stability studies of potent opioid analgesic,morphine‐6‐O‐sulfate in various buffers and biological matrices by HPLC‐DAD analysis

The 6‐O‐ sulfate ester of morphine (M6S) has previously been shown to be an analgesic with greater potency and fewer side effects than morphine. However, being a sulfate ester derivative of morphine, the question exists as to whether this compound is stable in biological fluids and tissues with regard to pH‐ and esterase‐mediated degradation. To date, no studies have focused on the stability profile of M6S across the physiologically relevant pH range of 1.2–7.4. In addition, the stability of M6S is not known in rat plasma and rat brain homogenate, or in simulated rat gastric and intestinal fluids. This study determines the stability profile of M6S (utilized as the sodium salt) and demonstrates that M6S is highly stable and resilient to either enzymatic‐ or pH‐dependent hydrolysis in vitro .