Ring Enlargement and Sulfur‐Transfer Processes in SiO2‐Catalyzed Reactions of Thiocarbonyl Compounds with Optically Active Oxiranes

The reactions of 1,3‐dioxolane‐2‐thione ( 3 ) with (S)‐2‐methyloxirane ((S)‐ 1 ) and with (R)‐2‐phenyloxirane ((R)‐ 2 ) in the presence of SiO₂ in anhydrous dichloroalkanes led to the optically active spirocyclic 1,3‐oxathiolanes 8 with Me at C(7) and 9 with Ph at C(8), respectively (Schemes 2 and 3). The analogous reaction of 1,3‐dimethylimidazolidine‐2‐thione ( 4a ) with (R)‐ 2 yielded stereoselectively (S)‐2‐phenylthiirane ((S)‐ 10 ) in 83% yield and 97% ee together with 1,3‐dimethylimidazolidin‐2‐one ( 11a ). In the cases of 3‐phenyloxazolidine‐2‐thione ( 4b ) and 3‐phenylthiazolidine‐2‐thione ( 4c ), the reaction with (RS)‐ 2 yielded the racemic thiirane (RS)‐ 10 , and the corresponding carbonyl compounds 11b and 11c (Scheme 4 and Table 1). The analogous reaction of 4a with 1,2‐epoxycyclohexane (= 7‐oxabicyclo[4.1.0]heptane; 7 ) afforded thiirane 12 and the corresponding carbonyl compound 11a (Scheme 5). On the other hand, the BF₃‐catalyzed reaction of imidazolidine‐2‐thione ( 5 ) with (RS)‐ 2 yielded the imidazolidine‐2‐thione derivative 13 almost quantitatively (Scheme 6). In a refluxing xylene solution, 1,3‐diacetylimidazolidine‐2‐thione ( 6 ) and (RS)‐ 2 reacted to give two imidazolidine‐2‐thione derivatives, 13 and 14 (Scheme 7). The structures of 13 and 14 were established by X‐ray crystallography (Fig.).     

Supramolecular Fullerene Chemistry: A Comprehensive Study of Cyclophane‐Type Mono‐ and Bis‐Crown Ether Conjugates of C70

The covalently templated bis‐functionalization of C₇₀, employing bis‐malonate 5 tethered by an anti‐disubstituted dibenzo[18]crown‐6 (DB18C6) ether, proceeds with complete regiospecificity and provides two diastereoisomeric pairs of enantiomeric C₇₀ crown ether conjugates, (±)‐ 7a and (±)‐ 7b , featuring a five o'clock bis‐addition pattern that is disfavored in sequential transformations (Scheme 1). The identity of (±)‐ 7a was revealed by X‐ray crystal‐structure analysis (Fig. 6). With bis‐malonate 6 containing a syn‐disubstituted DB18C6 tether, the regioselectivity of the macrocylization via double Bingel cyclopropanation changed completely, affording two constitutionally isomeric C₇₀ crown ether conjugates in a ca. 1 : 1 ratio featuring the twelve ( 16 ) and two o'clock ((±)‐ 15 ) addition patterns, respectively (Scheme 3). The X‐ray crystal‐structure analysis of the twelve o'clock bis‐adduct 16 revealed that a H₂O molecule was included in the crown ether cavity (Figs. 7 and 8). Two sequential Bingel macrocyclizations, first with anti‐DB18C6‐tethered ( 5 ) and subsequently with syn‐DB18C6‐tethered ( 6 ) bis‐malonates, provided access to the first fullerene bis‐crown ether conjugates. The two diastereoisomeric pairs of enantiomers (±)‐ 28a and (±)‐ 28b were formed in high yield and with complete regioselectivity (Scheme 9). The cation‐binding properties of all C₇₀ crown‐ether conjugates were determined with the help of ion‐selective electrodes (ISEs). Mono‐crown ether conjugates form stable 1 : 1 complexes with alkali‐metal ions, whereas the tetrakis‐adducts of C₇₀, featuring two covalently attached crown ethers, form stable 1 : 1 and 1 : 2 host‐guest complexes (Table 2). Comparative studies showed that the conformation of the DB18C6 ionophore imposed by the macrocyclic bridging to the fullerene is not particularly favorable for strong association. Reference compound (±)‐ 22 (Scheme 4), in which the DB18C6 moiety is attached to the C₇₀ sphere by a single bridge only and, therefore, possesses higher conformational flexibility, binds K⁺ and Na⁺ ions better by factors of 2 and 20, respectively. Electrochemical studies demonstrate that cation complexation at the crown ether site causes significant anodic shifts of the first reduction potential of the appended fullerene (Table 3). In case of the C₇₀ mono‐crown ether conjugates featuring a five o'clock functionalization pattern, addition of 1 equiv. of KPF₆ caused an anodic shift of the first reduction wave in the cyclic voltammogram (CV) by 70 to 80 mV, which is the result of the electrostatic effect of the K⁺ ion bound closely to the fullerene core (Fig. 14). Addition of 2 equiv. of K⁺ ions to C₇₀ bis‐crown ether conjugates resulted in the observation of only one redox couple, whose potential is anodically shifted by 170 mV with respect to the corresponding wave in the absence of the salt (Fig. 16). The synthesis and characterization of novel tris‐ and tetrakis‐adducts of C₇₀ are reported (Schemes 5 and 6). Attempts to prepare even more highly functionalized derivatives resulted in the formation of novel pentakis‐ and hexakis‐adducts and a single heptakis‐adduct (Scheme 7), which were characterized by ¹H‐ and ¹³C‐NMR spectroscopy (Fig. 10), as well as matrix‐assisted laser‐desorption‐ionization mass spectrometry (MALDI‐TOF‐MS). Based on predictions from density‐functional‐theory (DFT) calculations (Figs. 12 and 13), structures are proposed for the tris‐, tetrakis‐, and pentakis‐adducts.     

An Approach to the Synthesis of 7‐Amino‐6‐imino‐9‐phenyl‐6H‐benzo[c]chromene‐8‐carbonitrile Derivatives via a Three‐Component Reaction under Ultrasonic Irradiation

An efficient synthesis of 7‐amino‐6‐imino‐9‐phenyl‐6H‐benzo[c]chromene‐8‐carbonitrile derivatives 3 by a three‐component reaction of salicylaldehydes (=2‐hydroxybenzaldehydes) 1 , malononitrile (=propanedinitrile), and 2‐(1‐arylethylidene)malononitrile 2 under ultrasonic irradiation in EtOH is reported. Good yields, short reaction times, and easy purification are the main advantages of the present method. The structures were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

Preparation of C3‐Symmetric Homochiral syn‐Trisnorbornabenzenes through Regioselective Cyclotrimerization of Enantiopure Iodonorbornenes

C₃‐symmetric homochiral (?)‐syn‐trisoxonorbornabenzene 1 possessing a rigid cup‐shaped structure was synthesized through a novel regioselective cyclotrimerization of enantiopure iodonorbornenes catalyzed by palladium nanoclusters. The yield of the cyclotrimerization was dependent on the stability of the palladium clusters, which was ascertained from the appearance and TEM images of the reaction mixtures. The efficient preparation of (?)‐syn‐ 1 was established in short steps, including the newly developed cyclotrimerization reaction. The thus‐prepared homochiral (?)‐syn‐ 1 can serve as a key intermediate for the synthesis of C₃‐symmetric homochiral cup‐shaped molecules with a helical arrangement of substituents. Introduction of several types of substituents was well demonstrated through palladium‐catalyzed coupling reactions with the corresponding phosphate and triflate of (?)‐syn‐ 1 .     

Reaction of Optically Active Oxiranes with Thiofenchone and 1‐Methylpyrrolidine‐2‐thione: Formation of 1,3‐Oxathiolanes and Thiiranes

The SnCl₄‐catalyzed reaction of (?)‐thiofenchone (=1,3,3‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 10 ) with (R)‐2‐phenyloxirane ((R)‐ 11 ) in anhydrous CH₂Cl₂ at ?60° led to two spirocyclic, stereoisomeric 4‐phenyl‐1,3‐oxathiolanes 12 and 13 via a regioselective ring enlargement, in accordance with previously reported reactions of oxiranes with thioketones (Scheme 3). The structure and configuration of the major isomer 12 were determined by X‐ray crystallography. On the other hand, the reaction of 1‐methylpyrrolidine‐2‐thione ( 14a ) with (R)‐ 11 yielded stereoselectively (S)‐2‐phenylthiirane ((S)‐ 15 ) in 56% yield and 87–93% ee, together with 1‐methylpyrrolidin‐2‐one ( 14b ). This transformation occurs via an S_N2‐type attack of the S‐atom at C(2) of the aryl‐substituted oxirane and, therefore, with inversion of the configuration (Scheme 4). The analogous reaction of 14a with (R)‐2‐{[(triphenylmethyl)oxy]methyl}oxirane ((R)‐ 16b ) led to the corresponding (R)‐configured thiirane (R)‐ 17b (Scheme 5); its structure and configuration were also determined by X‐ray crystallography. A mechanism via initial ring opening by attack at C(3) of the alkyl‐substituted oxirane, with retention of the configuration, and subsequent decomposition of the formed 1,3‐oxathiolane with inversion of the configuration is proposed (Scheme 5).     

Synthesis of 1‐Methyl‐6,10‐diphenylheptalene Derivatives

The reduction of heptalene diester 1 with diisobutylaluminium hydride (DIBAH) in THF gave a mixture of heptalene‐1,2‐dimethanol 2a and its double‐bond‐shift (DBS) isomer 2b (Scheme 3). Both products can be isolated by column chromatography on silica gel. The subsequent chlorination of 2a or 2b with PCl₅ in CH₂Cl₂ led to a mixture of 1,2‐bis(chloromethyl)heptalene 3a and its DBS isomer 3b . After a prolonged chromatographic separation, both products 3a and 3b were obtained in pure form. They crystallized smoothly from hexane/Et₂O 7 : 1 at low temperature, and their structures were determined by X‐ray crystal‐structure analysis (Figs. 1 and 2). The nucleophilic exchange of the Cl substituents of 3a or 3b by diphenylphosphino groups was easily achieved with excess of (diphenylphospino)lithium (=lithium diphenylphosphanide) in THF at 0° (Scheme 4). However, the purification of 4a / 4b was very difficult since these bis‐phosphines decomposed on column chromatography on silica gel and were converted mostly by oxidation by air to bis(phosphine oxides) 5a and 5b . Both 5a and 5b were also obtained in pure form by reaction of 3a or 3b with (diphenylphosphinyl)lithium (=lithium oxidodiphenylphospanide) in THF, followed by column chromatography on silica gel with Et₂O. Carboxaldehydes 7a and 7b were synthesized by a disproportionation reaction of the dimethanol mixture 2a / 2b with catalytic amounts of TsOH. The subsequent decarbonylation of both carboxaldehydes with tris(triphenylphosphine)rhodium(1+) chloride yielded heptalene 8 in a quantitative yield. The reaction of a thermal‐equilibrium mixture 3a / 3b with the borane adduct of (diphenylphosphino)lithium in THF at 0° gave 6a and 6b in yields of 5 and 15%, respectively (Scheme 4). However, heating 6a or 6b in the presence of 1,4‐diazabicyclo[2.2.2]octane (DABCO) in toluene, generated both bis‐phosphine 4a and its DBS isomer 4b which could not be separated. The attempt at a conversion of 3a or 3b into bis‐phosphines 4a or 4b by treatment with t‐BuLi and Ph₂PCl also failed completely. Thus, we returned to investigate the antipodes of the dimethanols 2a, 2b , and of 8 that can be separated on an HPLC Chiralcel‐OD column. The CD spectra of optically pure (M)‐ and (P)‐configurated heptalenes 2a, 2b , and 8 were measured (Figs. 4, 5, and 9).     

Selenium‐Containing Heterocycles from Isoselenocyanates: Synthesis of 5‐Amino‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐selones

The reaction of S‐methylisothiosemicarbazide hydroiodide (=S‐methyl hydrazinecarboximidothioate hydroiodide; 1 ), prepared from thiosemicarbazide by treatment with MeI in EtOH, and aryl isoselenocyanates 5 in CH₂Cl₂ affords 3H‐1,2,4‐triazole‐3‐selone derivatives 7 in good yield (Scheme 2, Table 1). During attempted crystallization, these products undergo an oxidative dimerization to give the corresponding bis(4H‐1,2,4‐triazol‐3‐yl) diselenides 11 (Scheme 3). The structure of 11a was established by X‐ray crystallography.     

A One‐Pot Biginelli Synthesis of 6‐Unsubstituted 5‐Aroylpyrimidin‐2(1H)‐ones and 6‐Acetyl‐1,2,4‐triazin‐3(2H)‐ones

The three‐component Biginelli‐like cyclocondensation reaction of enamines 1 , urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6‐unsubstituted 3,4‐dihydropyrimidin‐2(1H)‐ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (=hydrazone) 7 with benzaldehyde and urea afforded 6‐acetyl‐1,2,4‐triazin‐3(2H)‐ones in good yields (Scheme 3).     

One‐Pot Synthesis of Functionalized 2H‐Chromene (=2H‐1‐Benzopyran) Derivatives via a Three‐Component Reaction between a CH‐Acid,a Dialkyl Acetylenedicarboxylate,and Methyl Chloroglyoxylate or Benzyl Carbonochloridate Mediated by Triphenylphosphine

An effective route to functionalized 2H‐chromene (=2H‐1‐benzopyran) derivatives 4 is described (Scheme 1). This involves the reaction of a 1,1‐diactivated alkene, resulting from the reaction of dimedone (=5,5‐dimethylcyclohexane‐1,3‐dione; 1a ) with methyl chloroglyoxylate (ClC(O)COOMe), benzyl carbonochloridate (ClC(O)OCH₂Ph) or 3,5‐dinitrobenzoyl chloride (3,5‐(NO₂)₂C₆H₃C(O)Cl), and a dialkyl acetylenedicarboxylate (=dialkyl but‐2‐ynedioate) in the presence of Ph₃P which undergo intramolecular Wittig reaction to produce 2H‐chromene derivatives (Scheme 1).     

Convenient Synthesis of Various Substituted Homotaurines from Alk‐2‐enamides

Various substituted homotaurines (=3‐aminopropane‐1‐sulfonic acids) 6 were readily synthesized in satisfactory to good yields via the Michael addition of thioacetic acid to alk‐2‐enamides 3 (→ 4 ), followed by LiAlH₄ reduction (→ 5 ) and performic acid oxidation (Scheme 1). The configuration of ‘anti’‐disubstituted homotaurine ‘anti’‐ 6h was deduced from the 3‐(acetylthio)alkanamide (=S‐(3‐amino‐1,2‐dimethyl‐3‐oxopropyl) ethanethioate)‘anti’‐ 4h formed in the Michael addition, which was identified via the Karplus equation analysis, and confirmed by X‐ray diffraction analysis. The current route is an efficient method to synthesize diverse substituted homotaurines, including 1‐, 2‐, and N‐monosubstituted, as well as 1,2‐, 1,N‐, 2,N‐, and N,N‐disubstituted homotaurines (Table).     

Synthesis of Fusion‐Isomeric Imidazopyridines and Their Evaluation as Inhibitors of syn‐ and anti‐Protonating Glycosidases

The galacto‐ and gluco‐configured imidazopyridines 4 and 5 were synthesised as potential inhibitors of syn‐protonating β‐glycosidases. Methyl α‐D ‐lyxopyranoside ( 9 ) was transformed into the 3,4‐anhydro‐β‐L ‐riboside 16 , which, upon treatment with Et₂AlCN, gave the nitrile 17 (76–85%). Reaction of 17 with the dimethyl aluminate of aminoacetaldehyde dimethyl acetal led directly to the branched chain lyxo‐configured imidazole 27 (53%) that was hydrolysed to an equilibrating mixture of 4 and 28 – 30 . Oxido reduction of 27 provided the arabino‐configured imidazole 42 (ca. 48% from 27 ). Hydrolysis of 42 led to the mixture 5 / 45 (63–90%). anti‐Protonating β‐galactosidases and β‐glucosidases (families 1 and 2) were only weakly inhibited by 4 / 28 – 30 and 5 / 45 , respectively. Also the syn‐protonating cellulase (Cel7A) was weakly inhibited by the monosaccharide mimics 5 / 45 , suggesting either that monosaccharide mimics are too small to inhibit Cel7A, or that fusion isomeric tetrahydroimidazo[1,2‐a]pyridines are not a suitable scaffold for the inhibition of syn‐protonating glycosidases.     

A One‐Pot Synthesis of 1,2‐Dihydroisoquinoline Derivatives from Isoquinoline via a Four‐Component Reaction

A four‐component reaction for the synthesis of 1,2‐dihydroisoquinoline derivatives is described. The Huisgen 1,4‐dipolar intermediate, which is produced from isoquinoline and an electron‐deficient acetylene compound 1 , reacts with H₂O in the presence of diketene to produce 1,2‐dihydroisoquinoline derivatives 2 (Scheme 1). In addition, reaction of isoquinoline, dibenzoylacetylene (=1,4‐diphenylbut‐2‐yne‐1,4‐dione), and diketene in the presence of H₂O leads to pyrroloisoquinoline derivative 7 . The structures of the compounds 2a – f and 7 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, EI‐MS) and by elemental analyses. A plausible mechanism for the reaction is proposed (Schemes 2 and 3).     

Photo‐Cross‐Linking of Polymethacrylates with Stilbene Chromophores in the Side Chains

Methacrylates (=2‐methylpropenoates) 5 with (E)‐stilbene (=(E)‐1,2‐diphenylethene) building blocks on tethers of variable length were prepared (Scheme 2) and polymerized (i.e., 5 → 6 ; Scheme 3) in the presence of AIBN (=2,2′‐azobis(2‐methylpropanenitrile). 4‐[(E)‐2‐Phenylethenyl]phenyl acetate ( 7 ) as model compound established the cyclodimerization as a single irreversible photoreaction. i.e., ( 7 → 8 – 11 ; Scheme 4) in the absence of oxygen. The solution photolysis of the polymers 6 provided a similar result, whereby [2π+2π] cycloadditions of stilbene units of neighboring tethers predominated. On the contrary, the desired photo‐cross‐linking of chaines occurred in the irradiation of polymer films.     

Synthesis of Bis‐Heterocyclic 1H‐Imidazole 3‐Oxides from 3‐Oxido‐1H‐imidazole‐4‐carbohydrazides

The reaction of 1H‐imidazole‐4‐carbohydrazides 1 , which are conveniently accessible by treatment of the corresponding esters with NH₂NH₂?H₂O, with isothiocyanates in refluxing EtOH led to thiosemicarbazides (=hydrazinecarbothioamides) 4 in high yields (Scheme 2). Whereas 4 in boiling aqueous NaOH yielded 2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones 5 , the reaction in concentrated H₂SO₄ at room temperature gave 1,3,4‐thiadiazol‐2‐amines 6 . Similarly, the reaction of 1 with butyl isocyanate led to semicarbazides 7 , which, under basic conditions, undergo cyclization to give 2,4‐dihydro‐3H‐1,2,4‐triazol‐3‐ones 8 (Scheme 3). Treatment of 1 with Ac₂O yielded the diacylhydrazine derivatives 9 exclusively, and the alternative isomerization of 1 to imidazol‐2‐ones was not observed (Scheme 4). It is important to note that, in all these transformations, the imidazole N‐oxide residue is retained. Furthermore, it was shown that imidazole N‐oxides bearing a 1,2,4‐triazole‐3‐thione or 1,3,4‐thiadiazol‐2‐amine moiety undergo the S‐transfer reaction to give bis‐heterocyclic 1H‐imidazole‐2‐thiones 11 by treatment with 2,2,4,4‐tetramethylcyclobutane‐1,3‐dithione (Scheme 5).     

Formation of 6‐Methyl‐7,11‐diphenylheptaleno[1,2‐c]furanones

The dehydrogenation reaction of a mixture of heptalene‐1,2‐ and heptalene‐4,5‐dimethanols 4a and 4b with basic MnO₂ in AcOEt at room temperature led to the formation of the corresponding heptaleno[1,2‐c]furan‐1‐one 6a and heptaleno[1,2‐c]furan‐3‐one 7a (Scheme 2). Both products can be isolated by chromatography on silica gel. The methylenation of the furan‐3‐one 7a with 1 mol‐equiv. of Tebbe's reagent at ?25 to ?30° afforded the 2‐isopropenyl‐5‐methylheptalene‐1‐methanol 9a , instead of the expected 3,6‐dimethylheptaleno[1,2‐c]furan 8 (Scheme 3). Also, the treatment of 7a with Takai's reagent did not lead to the formation of 8 . On standing in solution at room temperature, or more rapidly on heating at 60°, heptalene 9a undergoes a reversible double‐bond shift (DBS) to 9b with an equilibrium ratio of 1 : 1.     

A Novel and Efficient Synthesis of 3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐ones (=3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐1‐benzopyran‐2‐ones)

An efficient one‐pot synthesis of 3‐[(4,5‐dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐one (=3‐[(4,5‐dihydro‐1H‐pyrrol‐3yl)carbonyl]‐2H‐1‐benzopyran‐2‐one) derivatives 4 by a four‐component reaction of a salicylaldehyde 1 , 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one, a benzylamine 2 , and a diaroylacetylene (=1,4‐diarylbut‐2‐yne‐1,4‐dione) 3 in EtOH is reported. This new protocol has the advantages of high yields (Table), and convenient operation. The structures of these coumarin (=2H‐1‐benzopyran‐2‐one) derivatives, which are important compounds in organic chemistry, were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

Formation of 6,10‐Diphenyl‐Substituted Heptalene‐4,5‐dicarboxylates

It is shown that 4,8‐diphenylazulene ( 1 ) can be easily prepared from azulene by two consecutive phenylation reactions with PhLi, followed by dehydrogenation with chloranil. Similarly, a Me group can subsequently be introduced with MeLi at C(6) of 1 (Scheme 2). This methylation led not only to the expected main product, azulene 2 , but also to small amounts of product 3 , the structure of which has been determined by X‐ray crystal‐structure analysis (cf. Fig. 1). As expected, the latter product reacts with chloranil at 40° in Et₂O to give 2 in quantitative yields. Vilsmeier formylation of 1 and 2 led to the formation of the corresponding azulene‐1‐carbaldehydes 4 and 5 . Reduction of 4 and 5 with NaBH₄/BF₃ ? OEt₂ in diglyme/Et₂O 1 : 1 and BF₃ ? OEt₂, gave the 1‐methylazulenes 6 and 7 , respectively. In the same way was azulene 9 available from 6 via Vilsmeier formylation, followed by reduction of azulene‐1‐carbaldehyde 8 (Scheme 3). The thermal reactions of azulenes 1, 6 , and 7 with excess dimethyl acetylenedicarboxylate (ADM) in MeCN at 100° during 72 h afforded the corresponding heptalene‐4,5‐dicarboxylates 11, 12 , and 13 , respectively (Scheme 4). On the other hand, the highly substituted azulene 9 gave hardly any heptalene‐4,5‐dicarboxylate.     

Binuclear trans‐Bis(β‐iminoaryloxy)palladium(II) Complexes Doubly Linked with Pentamethylene Spacers: Structure‐Dependent Flapping Motion and Heterochiral Association Behavior of the Clothespin‐Shaped Molecules

The synthesis, structure, and solution‐state behavior of clothespin‐shaped binuclear trans‐bis(β‐iminoaryloxy)palladium(II) complexes doubly linked with pentamethylene spacers are described. Achiral syn and racemic anti isomers of complexes 1 – 3 were prepared by treating Pd(OAc)₂ with the corresponding N,N′‐bis(β‐hydroxyarylmethylene)‐1,5‐pentanediamine and then subjecting the mixture to chromatographic separation. Optically pure (100 % ee) complexes, (+)‐anti‐ 1 , (+)‐anti‐ 2 , and (+)‐anti‐ 3 , were obtained from the racemic mixture by employing a preparative HPLC system with a chiral column. The trans coordination and clothespin‐shaped structures with syn and anti conformations of these complexes have been unequivocally established by X‐ray diffraction studies. ¹H NMR analysis showed that (±)‐anti‐ 1 , (±)‐anti‐ 2 , syn‐ 2 , and (±)‐anti‐ 3 display a flapping motion by consecutive stacking association/dissociation between cofacial coordination planes in [D₈]toluene, whereas syn‐ 1 and syn‐ 3 are static under the same conditions. The activation parameters for the flapping motion (ΔH^≠ and ΔS^≠) were determined from variable‐temperature NMR analyses as 50.4 kJ mol^?1 and 60.1 J mol^?1 K^?1 for (±)‐anti‐ 1 , 31.0 kJ mol^?1 and ?22.7 J mol^?1 K^?1 for (±)‐anti‐ 2 , 29.6 kJ mol^?1 and ?57.7 J mol^?1 K^?1 for syn‐ 2 , and 35.0 kJ mol^?1 and 0.5 J mol^?1 K^?1 for (±)‐anti‐ 3 , respectively. The molecular structure and kinetic parameters demonstrate that all of the anti complexes flap with a twisting motion in [D₈]toluene, although (±)‐anti‐ 1 bearing dilated Z‐shaped blades moves more dynamically than I‐shaped (±)‐anti‐ 2 or the smaller (±)‐anti‐ 3 . Highly symmetrical syn‐ 2 displays a much more static flapping motion, that is, in a see‐saw‐like manner. In CDCl₃, (±)‐anti‐ 1 exhibits an extraordinary upfield shift of the ¹H NMR signals with increasing concentration, whereas solutions of (+)‐anti‐ 1 and the other syn/anti analogues 2 and 3 exhibit negligible or slight changes in the chemical shifts under the same conditions, which indicates that anti‐ 1 undergoes a specific heterochiral association in the solution state. Equilibrium constants for the dimerizations of (±)‐ and (+)‐anti‐ 1 in CDCl₃ at 293 K were estimated by curve‐fitting analysis of the ¹H NMR chemical shift dependences on concentration as 26 M ^?1 [K_D(racemic)] and 3.2 M ^?1 [K_D(homo)], respectively. The heterochiral association constant [K_D(hetero)] was estimated as 98 M ^?1, based on the relationship K_D(racemic)=1/2 K_D(homo)+1/4 K_D(hetero). An inward stacking motif of interpenetrative dimer association is postulated as the mechanistic rationale for this rare case of heterochiral association.     

Thermal [2+3]‐Cycloadditions of trans‐1‐Methyl‐2,3‐diphenylaziridine with CS and CC Dipolarophiles: An Unexpected Course with Dimethyl Dicyanofumarate

The thermal reaction of trans‐1‐methyl‐2,3‐diphenylaziridine (trans‐ 1a ) with aromatic and cycloaliphatic thioketones 2 in boiling toluene yielded the corresponding cis‐2,4‐diphenyl‐1,3‐thiazolidines cis‐ 4 via conrotatory ring opening of trans‐ 1a and a concerted [2+3]‐cycloaddition of the intermediate (E,E)‐configured azomethine ylide 3a (Scheme 1). The analogous reaction of cis‐ 1a with dimethyl acetylenedicarboxylate ( 5 ) gave dimethyl trans‐2,5‐dihydro‐1‐methyl‐2,5‐diphenylpyrrole‐3,4‐dicarboxylate (trans‐ 6 ) in accord with orbital‐symmetry‐controlled reactions (Scheme 2). On the other hand, the reactions of cis‐ 1a and trans‐ 1a with dimethyl dicyanofumarate ( 7a ), as well as that of cis‐ 1a and dimethyl dicyanomaleate ( 7b ), led to mixtures of the same two stereoisomeric dimethyl 3,4‐dicyano‐1‐methyl‐2,5‐diphenylpyrrolidine‐3,4‐dicarboxylates 8a and 8b (Scheme 3). This result has to be explained via a stepwise reaction mechanism, in which the intermediate zwitterions 11a and 11b equilibrate (Scheme 6). In contrast, cis‐1,2,3‐triphenylaziridine (cis‐ 1b ) and 7a gave only one stereoisomeric pyrrolidine‐3,4‐dicarboxylate 10 , with the configuration expected on the basis of orbital‐symmetry control, i.e., via concerted reaction steps (Scheme 10). The configuration of 8a and 10 , as well as that of a derivative of 8b , were established by X‐ray crystallography.     

Chiral Heterospirocyclic 2H‐Azirin‐3‐amines as Synthons for 3‐Amino‐2,3,4,5‐tetrahydrofuran‐3‐carboxylic Acid and Their Use in Peptide Synthesis

The heterospirocyclic N‐methyl‐N‐phenyl‐5‐oxa‐1‐azaspiro[2.4]hept‐1‐e n‐2‐amine (6 ) and N‐(5‐oxa‐1‐azaspiro[2.4]hept‐1‐en‐2‐yl)‐(S)‐proline methyl ester ( 7 ) were synthesized from the corresponding heterocyclic thiocarboxamides 12 and 10 , respectively, by consecutive treatment with COCl₂, 1,4‐diazabicyclo[2.2.2]octane, and NaN₃ (Schemes 1 and 2). The reaction of these 2H‐azirin‐3‐amines with thiobenzoic and benzoic acid gave the racemic benzamides 13 and 14 , and the diastereoisomeric mixtures of the N‐benzoyl dipeptides 15 and 16 , respectively (Scheme 3). The latter were separated chromatographically. The configurations and solid‐state conformations of all six benzamides were determined by X‐ray crystallography. With the aim of examining the use of the new synthons in peptide synthesis, the reactions of 7 with Z‐Leu‐Aib‐OH to yield a tetrapeptide 17 (Scheme 4), and of 6 with Z‐Ala‐OH to give a dipeptide 18 (Scheme 5) were performed. The resulting diastereoisomers were separated by means of MPLC or HPLC. NMR Studies of the solvent dependence of the chemical shifts of the NH resonances indicate the presence of an intramolecular H‐bond in 17 . The dipeptides (S,R)‐ 18 and (S,S)‐ 18 were deprotected at the N‐terminus and were converted to the crystalline derivatives (S,R)‐ 19 and (S,S)‐ 19 , respectively, by reaction with 4‐bromobenzoyl chloride (Scheme 5). Selective hydrolysis of (S,R)‐ 18 and (S,S)‐ 18 gave the dipeptide acids (R,S)‐ 20 and (S,S)‐ 20 , respectively. Coupling of a diastereoisomeric mixture of 20 with H‐Phe‐O^tBu led to the tripeptides 21 (Scheme 5). X‐Ray crystal‐structure determinations of (S,R)‐ 19 and (S,S)‐ 19 allowed the determination of the absolute configurations of all diastereoisomers isolated in this series.