A Versatile Synthesis of β‐Lactam‐Fused Oxacycles through the Palladium‐Catalyzed Chemo‐, Regio‐, and Diastereoselective Cyclization of Allenic Diols

Chemo‐, regio‐ and stereocontrolled palladium‐catalyzed preparations of enantiopure morpholines, oxocines, and dioxonines have been developed starting from 2‐azetidinone‐tethered γ,δ‐, δ,ε‐, and ε,ζ‐allendiols. The palladium‐catalyzed cyclizative coupling reaction of γ,δ‐allendiols 2 with allyl bromide or lithium bromide was effective as 8‐endo cyclization by attack of the primary hydroxy group to the terminal allene carbon to afford enantiopure functionalized oxocines; whereas the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered ε,ζ‐allendiols 4 furnished dioxonines 16 through a totally chemo‐ and regioselective 9‐endo oxycyclization. By contrast, the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered δ,ε‐allendiols 3 with aryl and alkenyl halides exclusively generated six‐membered‐ring compounds 14 a and 15 a . These results could be explained through a 6‐exo cyclization by chemo‐ and regiospecific attack of the secondary hydroxy group to the internal allene carbon. Chemo‐ and regiocontrol issues are mainly influenced by the length of the tether rather than by the nature of the metal catalysts and substituents. This reactivity can be rationalized by means of density functional theory calculations.     

An Efficient New Route for the Synthesis of Some 3‐Hterocyclylquinolinones via Novel 3‐(1,2‐Dihydro‐4‐hydroxy‐1‐methyl‐2‐oxoquinolin‐3‐yl)‐3‐oxopropanal and Their Antioxidant Screening

3‐(4‐hydroxy‐1‐methylquinoline‐3‐yl)‐3‐oxoproponal ( 5 ) was synthesized from 3‐[(E)‐3‐(dimethylamino)‐2‐propenoyl]‐4‐hydroxy‐1‐methyl‐2(1H )‐quinolinone ( 3 ) and was utilized as a starting precursor material. A convenient new route to functionalized 3‐heterocyclyl 4‐hydroxy‐2(1H )‐quinolinones such as pyrazolyl, isoxazolyl, pyrimidinyl, azepineyl , pyridonyl, and pyranyl heterocycles was described via cyclization of compound 5 with some N and C ‐nucleophiles. The newly synthesized aldehyde 5 showed only one ring closure possibility with maximum yield instead of using compound 3 that exhibited different regioselective ring closure routes with minimum yields. All newly synthesized products were structurally elucidated on the basis of their relevant spectroscopic data and elemental microanalyses. The antioxidant activity of the products was screened in a series of in vitro tests.     

Synthesis of Novel Pyrazole–sucrose Derivatives by 1,3‐dipolar Cycloaddition

The syntheses of an important class of enantiopure five‐membered glyconjucates containing furan unit are described. The regioselective synthesis of a series of sugar‐fused pyrazole heterocycles was achieved by the Huisgen cyclization of aryl diazomethanes with propargyl O‐glycoside derivatives in good yields. The cycloaddition regioselectivity was confirmed by NMR.     

Enantiodivergent Synthesis of (+)‐ and (−)‐Pyrrolidine 197B: Synthesis of trans‐2,5‐Disubstituted Pyrrolidines by Intramolecular Hydroamination

A highly efficient, diastereoselective, iron(III)‐catalyzed intramolecular hydroamination/cyclization reaction involving α‐substituted amino alkenes is described. Thus, enantiopure trans‐2,5‐disubstituted pyrrolidines and trans‐5‐substituted proline derivatives were synthesized by means of a combination of enantiopure starting materials, easily available from l ‐α‐amino acids, with sustainable metal catalysts such as iron(III) salts. The scope of this methodology is highlighted in an enantiodivergent approach to the synthesis of both (+)‐ and (?)‐pyrrolidine 197B alkaloids from l ‐glutamic acid. In addition, a computational study was carried out to gain insight into the complete diastereoselectivity of the transformation.     

Access to the Enantiopure Axially Chiral Cyclophane Isoplagiochin D through Atropo‐diastereoselective Heck Coupling

Macrocyclization is typically the key step in the syntheses of cyclophane‐type natural products. Considering cyclophanes with axially chiral biaryl moieties, the control of atroposelectivity is essential with biological activity and is synthetically challenging. We report an atroposelective approach involving Heck cyclization, which for the first time enables the total synthesis of an enantiopure macrocyclic bis(bibenzyl), namely isoplagiochin D. An enantiopure sulfinyl auxiliary in the ortho position of a biaryl axis (still flexible) was used to induce an atropo‐diastereoselective Heck coupling (up to 98 % de). The traceless character of the sulfinyl auxiliary enables the introduction of a hydroxy group to give the target molecule with 98 % ee as well.     

Diastereoselective synthesis of linear‐fused tricyclic nitrogen heterocycles by a tandem reduction‐reductive amination reaction

A two‐step diastereoselective synthesis of linear‐fused tricyclic nitrogen heterocycles has been developed from cyclic β‐ketoesters. The cyclization substrates are readily prepared by alkylation of the methyl 2‐oxo‐cycloalkanecarboxylates with 2‐nitrobenzyl bromide. Hydrogenation of these substrates initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the resulting hydroxyl‐amine or aniline nitrogen with the cycloalkanone and (3) reduction of the imine. The products are isolated in high yield as single diastereomers having the trans‐fused ring junction. The observed selectivity is rationalized in terms of a steric effect imposed by the ester group in the final reductive amination step which directs the incoming hydrogen to the opposite face of the molecule. By comparison, reductive cyclizations of substrates lacking the stereodirecting ester group give mixtures of cis and trans products with a preference for the cis‐fused heterocycle.     

Synthesis and antimicrobial activity of 3‐(N‐arylamino)‐2‐phenyl‐naphtho[1,3‐d]‐1,2‐oxaphosphole 2‐oxides

The efficient preparation of cis‐3‐(N‐arylamino)‐2‐phenylnaphtho[1,3‐d]‐1,2‐oxaphosphole 2‐oxides 4 and 5 is described by a three‐component reaction involving phenyldichlorophosphine ( 2 ) 1‐hydroxy‐2‐naph‐thaldehyde/1‐hydroxy‐2‐acetonaphthone ( 1 ) and different substituted amines ( 3 ) in anhydrous benzene. The stereo structure, of the products ( 4 and 5 ), as well as the reaction mechanism of the cyclization is discussed. The title compounds ( 4 and 5 ) were fully characterized by NMR and mass spectral data. Their anti microbial activity was evaluated     

Gold(I)‐Catalyzed 1,4‐ and/or 1,5‐Heteroaryl Migration Reactions through Regiocontrolled Cyclizations

Gold(I)‐catalyzed regioselective cycloisomerizations of furan‐ynes have been described. The reaction provides a concise access to stereodefined trisubstituted alkenes by endo cyclization with concomitant 1,5‐migration of the furanyl group in the presence of unactivated 3 Å molecular sieves. In the absence of molecular sieves, indene products are generated by exo cyclization, followed by 1,4‐furanyl migration/cyclization. The scope for 1,5‐migrations can be extended to other heterocycles, such as benzofurans, thiophenes, and pyrroles.     

First Total Synthesis of (±)‐Celaphanol A

The first total synthesis of (±)‐Celaphanol A was accomplished starting from α‐cyclocitral and 3,4‐dimethoxy benzyl chloride in six steps. The intramolecular cyclization with BF₃·Et₂O and enolization in t‐BuOK/t‐BuOH were the key steps. The process of intramolecular cyclization afforded an all‐cis isomer intermediate for synthesis of aromatic tricyclic diterpenes.     

New Approaches to 6‐Oxoisoaporphine and Tetrahydroisoquinoline Derivatives

2,3‐Dihydro‐6‐hydroxy‐5‐methoxy‐7H‐dibenzo[de,h]quinolin‐7‐one, 6‐hydroxy‐5‐methoxy‐7H‐dibenzo[de,h]quinolin‐7‐one, and 2‐(6,7‐dimethoxy‐3,4‐dihydroisoquinolin‐1‐yl)benzyl benzoate, easily available by a Bischler–Napieralski cyclization, were used as starting materials to afford 6‐oxoisoaporphine and 2,3‐dimethoxy‐5,6,8,12b‐tetrahydroisoindolo[1,2‐a]isoquinoline as the main products. However, the catalytic hydrogenation of the benzyl benzoate derivative afforded, under mild conditions, 1,2,3,4‐tetrahydro‐6,7‐dimethoxy‐1‐(2‐methylphenyl)isoquinoline.     

Fused‐ring nitrogen and sulfur heterocycles by a tandem SN2‐michael addition reaction

A tandem S_N2‐Michael addition reaction has been developed for the synthesis of cis‐ and trans‐fused nitrogen and sulfur heterocycles from the cis and trans isomers of ethyl (±)‐(2E)‐3‐[2‐(iodomethyl)cyclo‐hexyl]‐2‐propenoate. Octahydro‐1H‐isoindole‐1‐acetic acid and octahydrobenzo[c]thiophene‐1‐acetic acid derivatives have been prepared and their stereochemistries elucidated using NMR and X‐ray crystallo‐graphic methods. Cyclization substrates for both the cis‐ and the trans‐fused rings are readily available in four steps from known compounds. Yields for the cyclization range from 80‐85% and stereochemical selec‐tivities with respect to the side chain vary from 12.5‐16:1 for the cis‐fused structures to 6‐7.5:1 for the trans‐fused structures. Steric interactions in the transition states for ring closure are proposed to rationalize the observed preferences.     

1,5‐Dipolar Electrocyclizations of Thiocarbonyl Ylides Bearing CN Groups: Reactions of N‐[(Dimethylamino)methylene]thiobenzamide and 2‐(Dimethylhydrazono)‐1‐phenylethane‐1‐thione with Diazo Compounds

The reactions of thiobenzamide 8 with diazo compounds proceeded via reactive thiocarbonyl ylides as intermediates, which underwent either a 1,5‐dipolar electrocyclization to give the corresponding five membered heterocycles, i.e., 4‐amino‐4,5‐dihydro‐1,3‐thiazole derivatives (i.e., 10a, 10b, 10c , cis‐ 10d , and trans‐ 10d ) or a 1,3‐dipolar electrocyclization to give the corresponding thiiranes as intermediates, which underwent a S_Ni′‐like ring opening and subsequent 5‐exo‐trig cyclization to yield the isomeric 2‐amino‐2,5‐dihydro‐1,3‐thiazole derivatives (i.e., 11a, 11b, 11c , cis‐ 11d , and trans‐ 11d ). In general, isomer 10 was formed in higher yield than isomer 11 . In the case of the reaction of 8 with diazo(phenyl)methane ( 3d ), a mixture of two pairs of diastereoisomers was formed, of which two, namely cis‐ 10d and trans‐ 10d , could be isolated as pure compounds. The isomers cis‐ 11d and trans‐ 11d remained as a mixture. In the reactions of the thioxohydrazone 9 with diazo compounds 3b and 3d , the main products were the alkenes 18 and 23 , respectively. Their formation was rationalized by a 1,3‐dipolar electrocyclization of the corresponding thiocarbonyl ylide and subsequent desulfurization of the intermediate thiiran. As minor products, 2,5‐dihydro‐1,3‐thiazol‐5‐amines 21 and 24 were obtained, which have been formed by 1,5‐dipolar electrocyclization of the thiocarbonyl ylide, followed by a 1,3‐shift of the dimethylamino group.     

Synthesis and Biological Evaluation of Some Heterocyclic Compounds from Salicylic Acid Hydrazide

Different heterocyclic compounds were prepared starting from 2‐hydroxy benzohydrazide; for example, cyclization of hydrazide hydrazone 3 derived from 2‐hydroxybenzohydrazide 2 with acetic anhydride or concentrated sulfuric acid gave 1,3,4‐oxadiazole derivatives 4 – 5 . On the other hand, direct cyclization of 2‐hydroxy benzohydrazide 2 with one carbon cyclizing agent gave a new derivative of 1,3,4‐oxadiazole 7 , 8 , 9 , 10 , 11 . Heating of hydrazide hydrazone 3 with thioglycolic acid in pyridine gave thiazolidinone 12 . When 2‐hydroxy benzohydrazide 2 reacted with aliphatic carboxylic acids such as formic acid or acetic acid, it gave the corresponding N‐formyl or N‐acetyl derivatives 6 . Subsequent cyclization of 6 using phosphorous pentasulphide in pyridine gave 1,3,4‐thiadiazoles 13 . Cyclization of 2‐hydroxy benzohydrazide with ethyl acetoacetate gives pyrazolone derivative 14 . Finally, when an ethanolic solution of acid hydrazide 2 was treated with ammonium thiocyanate in 35% HCl, it gave the thiosemicarbazide 15 . Subsequent treatment of 15 with concentrated sulfuric acid or 10% sodium hydroxide gave 5‐amino‐1,3,4‐thiadiazole 16 and 1,2,4‐triazole 17 , respectively. The structures of all newly isolated compounds were confirmed using ¹H NMR, IR spectra, and elemental analyses. The antimicrobial activities for all isolated compounds were examined against different microorganisms.     

Total syntheses of (±)‐cis‐ and trans‐11‐methoxydeethyleburnamonine

The total syntheses of 11‐methoxydeethyleburnamonines ( 4 ) and ( 13 ) were carried out with use of 6‐methoxytryptophyl bromide ( 5 ) as starting material. Compound 5 was converted in three steps to trans‐ester 8 . Acid‐catalysed epimerization of 8 , lithium aluminum hydride reduction of the ester group, tosylation and substitution with cyanide gave the cis‐nitrile 12 . Acid‐induced cyclization of 12 yielded mainly (±)‐trans‐11‐methoxydeethyleburnamonine ( 13 ), whereas base‐induced cyclization gave (±)‐cis‐11‐methoxydeethyleburnamonine ( 4 ).     

Absolute Asymmetric Synthesis of Enantiopure Organozinc Reagents,Followed by Highly Enantioselective Chlorination

We report the absolute asymmetric synthesis (AAS) of indenylzinc reagents by using total spontaneous resolution followed by enantiospecific conversion into 1‐chloroindene. The chiral complex [Zn(dcp)(ind)(tmeda)] (dcp=2,6‐dichlorophenoxy and tmeda=N,N,N′,N′‐tetramethylethylenediamine) ( 3 ) was prepared from the achiral starting materials indene, potassium, zinc chloride, TMEDA, and 2,6‐dichlorophenol. The reagent resolved spontaneously on crystallization, and single crystals of 3 react with N‐chlorosuccinimide in the presence of benzoquinone in 2‐propanol to give 1‐chloroindene in >98 % enantiomeric excess. It was found that (R)‐ 3 gave (R)‐1‐chloroindene upon reaction, indicating an S_E2′‐mechanism. Since bulk samples of 3 gave optically active product upon chlorination, total spontaneous resolution must have occurred. This demonstrates that enantiopure products can be obtained through the absolute asymmetric synthesis of organometallic reagents starting from achiral materials. The general absolute asymmetric synthesis (AAS) method offers easy access to both enantiomers and an almost limitless variation in the design of the product.     

Experimental and Theoretical Study of an Intramolecular CF3‐Group Shift in the Reactions of α‐Bromoenones with 1,2‐Diamines

The reactions of trifluoromethylated 2‐bromoenones and N,N′‐dialkyl‐1,2‐diamines have been studied. Depending on the structures of the starting compounds, the formation of 2‐trifluoroacetylpiperazine or 3‐trifluoromethylpiperazine‐2‐ones was observed. The mechanism of the reaction is discussed in terms of multistep processes involving sequential substitution of bromine in the starting α‐bromoenones and intramolecular cyclization of the captodative aminoenones as key intermediates to form the target heterocycles. The results of theoretical calculations are in perfect agreement with the experimental data. The unique role of the trifluoromethyl group in this reaction is demonstrated.     

Improved Synthesis of 2,2‐Arylmethylene Bis(3‐hydroxy‐5,5‐dimethyl‐2‐cyclohexene‐1‐one) and 1,8‐Dioxo‐octahydroxanthene Derivatives Catalyzed by Electrogenerated Base and Sulfuric Acid

An efficient method has been developed for the synthesis of 1,8‐dioxo‐octahydroxanthene derivatives in two‐step. In the first step, the electrogenerated base (EGB) catalyzed multicomponent transformation of dimedone and aromatic aldehydes in an undivided cell in the presence of sodium bromide as an electrolyte into 2,2′‐arylmethylene bis(3‐hydroxy‐5,5‐dimethyl‐2‐cyclohexene‐1‐one) at room temperature. In the second step, H₂SO₄ was employed as a dehydrating reagent for the cyclization process to give symmetrical heterocycles 1,8‐dioxo‐octahydroxanthene derivatives. Short reaction time, convenient work up, and using of inexpensive reagents, simple equipment, novel and eco‐friendly procedure make this strategy more useful for the preparation of xanthene derivatives.     

Enantioselective Copper‐Catalyzed Carboetherification of Unactivated Alkenes

Chiral saturated oxygen heterocycles are important components of bioactive compounds. Cyclization of alcohols onto pendant alkenes is a direct route to their synthesis, but few catalytic enantioselective methods enabling cyclization onto unactivated alkenes exist. Herein reported is a highly efficient copper‐catalyzed cyclization of γ‐unsaturated pentenols which terminates in C? C bond formation, a net alkene carboetherification. Both intra‐ and intermolecular C? C bond formations are demonstrated, thus yielding functionalized chiral tetrahydrofurans as well as fused‐ring and bridged‐ring oxabicyclic products. Transition‐state calculations support a cis‐oxycupration stereochemistry‐determining step.     

Prins Cyclization Catalyzed by a FeIII/Trimethylsilyl Halide System: The Oxocarbenium Ion Pathway versus the [2+2] Cycloaddition

The different factors that control the alkene Prins cyclization catalyzed by iron(III) salts have been explored by means of a joint experimental–computational study. The iron(III) salt/trimethylsilyl halide system has proved to be an excellent promoter in the synthesis of crossed all‐cis disubstituted tetrahydropyrans, minimizing the formation of products derived from side‐chain exchange. In this iron(III)‐catalyzed Prins cyclization reaction between homoallylic alcohols and non‐activated alkenes, two mechanistic pathways can be envisaged, namely the classical oxocarbenium route and the alternative [2+2] cycloaddition‐based pathway. It is found that the [2+2] pathway is disfavored for those alcohols having non‐activated and non‐substituted alkenes. In these cases, the classical pathway, via the key oxocarbenium ion, is preferred. In addition, the final product distribution strongly depends upon the nature of the substituent adjacent to the hydroxy group in the homoallylic alcohol, which can favor or hamper a side 2‐oxonia‐Cope rearrangement.     

Copper/P(tBu)3‐Mediated Regiospecific Synthesis of Fused Furans and Naphthofurans

A novel [3+2] cycloaddition between a variety of cyclic ketones and diverse olefins or alkynes can be effectively promoted by copper in combination with the tri‐tert ‐butylphosphine [P(t Bu)₃] ligand. This protocol exhibits excellent selectivity and provides an exemplary set of fused heterocycles in good to excellent yields. Present strategy also represents an extremely simple and atom‐economic way to construct substituted fused furans and naphthofurans from readily available starting materials under mild reaction conditions. The utility of the method is further demonstrated by the synthesis of chiral furans from (R )‐(−)‐carvone and (S )‐(+)‐carvone. A plausible mechanism involving the oxidative radical cyclization has been suggested based on experimental observations.