Synthese von (Methylthio)penam-Derivaten durch Keten-Addition an 4,5-Dihydro-5-(methylthio)-1,3-thiazole

Synthesis of (Methylthio)penam Derivatives via Keten Addition onto 4,5-Dihydro-5-(methylthio)-1,3-thiazoles The 4,5-dihydro-5-(methylthio)-2-phenyl-1,3-thiazoles 3a and 3b , easily prepared from the corresponding 1,3-thiazol-5(4H)-thiones and MeLi, react with dichloroacetyl chloride ( 5a ) and acidoacetyl chloride ( 5b ) in the presence of Et₃N to give (methylthio)penam derivatives 6 (Table 1). The reaction mechanism is either a [2 + 2] cycloaddition of in situ generated ketene or a two-step reaction (Scheme 2). The structure of 6f has been confirmed by X-ray crystallography (Fig. 2). The relative configuration of 6a-e follow from comparison of their ¹H-NMR spectra with those of 6f (Fig. 1). The 6-azidopenams 6d and 6f have been reduced to aminopenams 8a and 8b , respectively. Acylation of 8a with phenacetyl chloride yields 9 (Scheme 4).     

Crystal Structure of Akuammigine Picrate Hydrate

The single‐crystal X‐ray data of akuammigine picrate hydrate ( 1 ?Picr?H₂O) confirm the relative configuration of the indole alkaloid akuammigine ( 1 ) as epiallo (Fig. 1). With reference to the known (15S)‐configuration due to biosynthesis, the absolute configuration of the other stereogenic centers is thus given by (3R,19S,20S). Four crystallographically independent molecules are observed in the asymmetric unit (Fig. 2). Each of the alkaloid cations forms H‐bonds to a H₂O and a picrate anion (Fig. 3). The H₂O molecules are further associated by a H‐bond as indicated by the short O???O distance (Table 2). The conformation in the solid state of the picrate hydrate is now firmly established, and a cute H‐bonding motif is observed.     

Nonreductive Enantioselective Ring Opening of N-(Methylsulfonyl)dicarboximides with Diisopropoxytitanium α,α,α′,α′-Tetraaryl-1,3-dioxolane-4,5-dimethanolate

The bicyclic and tricyclic meso-N-(methylsulfonyl)dicarboximides 1a–f are converted enantioselectively to isopropyl [(sulfonamido)carbonyl]-carboxylates 2a–f by diisopropoxytitanium TADDOLate (75–92% yield; see Scheme 3). The enantiomer ratios of the products are between 86:14 and 97:3, and recrystallization from CH₂Cl₂/hexane leads to enantiomerically pure sulfonamido esters 2 (Scheme 3). The enantioselectivity shows a linear relationship with the enantiomer excess of the TADDOL employed (Fig.3). Reduction of the ester and carboxamide groups (LiAlH₄) and additional reductive cleavage of the sulfonamido group (Red-Al) in the products 2 of imide-ring opening gives hydroxy-sulfonamides 3 and amino alcohols 4 , respectively (Scheme 4). The absolute configuration of the sulfonamido esters 2 is determined by chemical correlation (with 2a,b ; Scheme 6), by the X-ray analysis of the camphanate of 3e (Fig. 1), and by comparative ¹⁹F-NMR analysis of the Mosher esters of the hydroxy-sulfonamides 3 (Table 1). A general proposal for the assignment of the absolute configuration of primary alcohols and amines of Formula HXCH₂CHR¹R², X = O, NH, is suggested (see 11 in Table 1). It follows from the assignment of configuration of 2 that the Re carbonyl group of the original imide 1 is converted to an isopropyl ester group. This result is compatible with a rule previously put forward for the stereochemical course of reactions involving titanium TADDOLate activated chelating electrophiles ( 12 in Scheme 7). A tentative mechanistic model is proposed ( 13 and 14 in Scheme 7).     

Conformational Features of 7,8,13β,14α-Tetrahydro-N7-methylcorysaminium,a biosynthetic intermediate to the protopine-type alkaloid corycavine

The crystal structure of (±)-7,8,13β,14α-tetrahydro-N⁷-(¹³C)methylcorysaminium iodide (¹³C- 3a ·I) was investigated by X-ray analysis and thus the relative configuration (7S*,13S*,14S*) established (Fig. 1). The conformation of 3a was shown to have a cis-junction of the B/C rings and the rings A and D in an antiperiplanar position relative to the C(13)? C(14) bond (‘anti-cis’), a twisted half-chair for ring B, and a half-chair for ring C (Figs. 2 and 3). Conformation analysis by ¹H-NMR data indicated that the crystal conformation of 3a is also the preferred one in MeOH solution.     

Asymmetrische Micheal-Additionen. Praktisch vollständigdiastereo- und enantioselektive Alkylierungen des Enamins aus Cyclohexanon und Prolinylmethyläther.durch ω-Nitrostyrole zu u-2-(l′-Aryl-2′-nitroäthyl)cyclohexanonen

Asymmetric Michael-Additions Practically Completely Diastereo- and Enantloselective Alkylations of the Enamine from Cyclohexanone and Prolinyl Methyl Ether by ω-Nitrostyrenes to Give u2-(1′-Aryl-2′-nitroethyl)cyclohexanones When the enamine (S)-N-(1′cyclohexenyl)-2-methoxymethyl-pyrrolidine is added to 2-aryl-l-nitroethylenes, only one of the four possible enantiomerically pure diastereomers is formed. Hydrolysis of the crude primary products furnishes α-alkylated cyclohexanones of > 90% e. e. ( 3 , Scheme 3). Their (2S,1′R)-configuration was deduced by chemical correlation with l-cyclohexyl-l-phenyl-ethane and from an X-ray crystal structure analysis of (?)-(2R,3S,6′R1,l″S′)-3-methyl-N-[6′-(2″-nitro-l″-phenylethyl)-l′-cyclohexenyl]-2-phenylmorpholine ( lla , Scheme 5 and Fig. 2). - The relative topicity of reactant approach with the prolinol derivative (see II ) is specified as lkul-l,4. The steric course and the mechanism of the reaction are discussed.     

Macrotricyclic Steroid Receptors by Pd°-Catalyzed Cross-Coupling Reactions: Dissolution of cholesterol in aqueous solution and investigations of the principles governing selective molecular recognition of steroidal substrates

Three double-decker cyclophane receptors, (±)- 2 , (±)- 3 , and (±)- 4 with 11–13-Å deep hydrophobic cavities were prepared and their steroid-binding properties investigated in aqueous and methanolic solutions. Pd°-Catalyzed cross-coupling reactions were key steps in the construction of these novel macrotricyclic structures. In the synthesis of D₂-symmetrical (±)- 2 , the double-decker precursor (±)- 7 was obtained in 14% yield by fourfold Stille coupling of equimolar amounts of bis(tributylstannyl)acetylene with dibromocyclophane 5 (Scheme 1). For the preparation of the macrotricyclic precursor (±)- 15 of D₂-symmetrical (±)- 3 , diiodocylophane 12 was dialkynylated with Me₃SiC?CH to give 13 using the Sonogashira cross-coupling reaction; subsequent alkyne deprotection yielded the diethynylated cyclophane 14 , which was transformed in 42% yield into (±)- 15 by Glaser-Hay macrocyclization (Scheme 2). The synthesis of the C₂-symmetrical conical receptor (±)- 4 was achieved via the macrotricyclic precursor (±)- 25 , which was prepared in 20% yield by the Hiyama cross-coupling reaction between the diiodo[6.1.6.1]paracyclophane 19 and the larger, dialkynylated cyclophane 17 (Scheme 4). Solid cholesterol was efficiently dissolved in water through complexation by (±)- 2 and (±)- 3 , and the association constants of the formed 1:1 inclusion complexes were determined by solid-liquid extraction as K_a = 1.1 × 10⁶ and 1.5 × 10⁵ l mol^?1, respectively (295 K) (Table 1). The steroid-binding properties of the three receptors were analyzed in detail by ¹H-NMR binding titrations in CD₃OD. Observed steroid-binding selectivities between the two structurally closely related cylindrical receptors (±)- 2 and (±)- 3 (Table 2) were explained by differences in cavity width and depth, which were revealed by computer modeling (Fig. 4). Receptor (±)- 2 , with two ethynediyl tethers linking the two cyclophanes, possesses a shallower cavity and, therefore, is specific for flatter steroids with a C(5)?C(6) bond, such as cholesterol. In contrast, receptor (±)- 3 , constructed with longer buta-1,3-diynediyl linkers, has a deeper and wider hydrophobic cavity and prefers fully saturated steroids with an aliphatic side chain, such as 5α-cholestane (Fig. 7). In the 1:1 inclusion complexes formed by the conical receptor (±)- 4 (Table 3), testosterone or progesterone penetrate the binding site from the wider cavity side, and their flat A ring becomes incorporated into the narrower [6.1.6.1]paracyclophane moiety. In contrast, cholesterol penetrates (±)- 4 with its hydrophobic side chain from the wider rim of the binding side. This way, the side chain is included into the narrower cavity section shaped by the smaller [6.1.6.1]paracyclophane, While the A ring protrudes with the OH group at C(3) into the solvent on the wider cavity side (Fig. 8). The molecular-recognition studies with the synthetic receptors (±)- 2 , (±)- 3 , and (±)- 4 complement the X-ray investigations on biological steroid complexes in enhancing the understanding of the principles governing selective molecular recognition of steroids.     

Diastereoselektive Alkylierung von 3-Aminobutansäure in der 2-Stellung

Diastereoselective Alkylation 3-Aminobutanoic Acid in the 2-Position The enantiomerically pure 3-aminobutanoic acids (R)- and (S)- 6 are readily available by preparative HPLC separation of the two diastereoisomers 5 obtained from addition of (S)-phenethylamine to methyl crotonate and subsequent hydrogenolysis (Scheme 2). (S)-Methyl 3-(benzoylamino) butanoate ((S)- 3 ) is also available by enzymatic kinetic resolution with pig-liver esterase. The N-benzyl- and N- benzyloxycarbonyl derivatives rac 3 , 8 , and 9 of 3-aminobutanoates are doubly deprotonated with LDA and alkylated or aminated in high selectivity (17 examples, relative topicity like; see Tables 1 and 2). The configuration of three of the products is assigned (Schemes 4–6), and in four cases, the free α-substituted β-amino acid is prepared by acidic hydrolysis (see Table 3). It is shown that the doubly lithiated β-amino-acid derivative is solubilized, and its reactivity may be strongly influenced by the presence of 3 equiv. of LiCl.     

Organic Reactions in the Solid State: Reactions of Enclathrated 3,4-Epoxycyclopentanone (=6-Oxobicyclo[3.1.0]hexan-3-one) in Tri-o-thymotide and Absolute Configuration of 4-Hydroxy- and 4-Chlorocyclopent-2-en-1-one

Several aspects of the heterogeneous actions of aqueous and gaseous HCl on the chemical behavior of 3,4-epoxycyclopentanone (=6-oxabicyclo[3.1.0]hexan-3-one; 1 ) included in the asymmetric cages of tri-o-thymotide (TOT) clathrates belonging to space groups P3₁21 are described, showing specific features strikingly at variance with those observed in liquid solutions. In a first step, the substrate underwent an acid-promoted allylic isomerization, as already observed in our previous investigations, to give optically active 4-hydroxycyclopent-2-en-1-one ( 2 ). In a consecutive step, a displacement of the OH group was accomplished by the Cl⁻ anion to afford the corresponding chloro compound 3 . Polymorphism was encountered in the preparation of TOT/ 1 clathrates. Recrystallization of TOT in the pure guest 1 yielded micro-twinned crystals belonging to the P3₁ space group (host/guest ratio 1 : 1), whereas the expected P3₁21 lattice grew from a mixture of TOT, 1 , and MeOH. The structural determination of TOT/ 1 was carried out by X-ray diffraction (Fig. 1). Kinetic measurements were achieved that shed light on some striking features of this type of heterogeneous reactions for solid-liquid and solid-gas systems. Several reactions of pure clathrate antipodes (+)-TOT/ 1 with gaseous HCl were carried out under various conditions; concentration and enantiomer-excess(ee) determinations of the products 2 and 3 allowed to establish a larger ee for 3 , thus demonstrating the influence of the host-guest diastereomeric association on the progression of the reaction. The correlation of optical activities of the host and products for the global reaction disclosed the sequence (+)-(M)-TOT/ 1 →(−)- 2 →(−)- 3 . A new way for the preparation of 2 was devised. It was further demonstrated that the X-ray structure analysis of the chiral clathrate (M)-TOT/(+)- 2 (Fig. 4) associated with chiroptical measurements was an efficient and straightforward method to determine the absolute (+)-(R)-configuration of the guest. The enantioselectivity of the TOT clathrate for 2 was established by two different methods which allowed the appraisal of an accurate revised value of the specific rotation of 2 . The enclathration of 3 occurred exclusively in the orthorhombic centrosymmetric host lattice Pbca, thus prohibiting the X-ray structural determination of the guest absolute configuration. The problem of finding a pathway to the intended enantiomer enrichment of 3 was worked out through the action of aqueous HCl on microcrystalline (+)-TOT/(−)-(S)- 2 that gave an optically active mixture of unreacted 2 with 3 as sole product. The pure optically active 3 was isolated by subsequent TLC. The resolution of 3 was achieved by GC over a chiral column and its (unknown) specific rotation measured. The absolute configuration of 3 was established by the measurement of the enantiomer purity of the optically active mixture 3 obtained after the total conversion of (−)-(S)- 2 in the presence of thionyl chloride in Et₂O, dioxane, and benzene. It was deduced that the (−)- 3 enantiomer had the (S)-configuration.     

Preparation by yeast reduction and determination of the sense of chirality of enantiomerically pure ethyl (−)-4,4,4-trichloro-3-hydroxy- and (+)-4,4,4-trifluoro-3-hydroxybutanoate

Reduction of ethyl 4,4,4-trichloro- and 4,4,4-trifluoro-3-oxobutanoate by fermenting baker's yeast (Saccharomyces cerevisiae) on a preparative scale (20–50 g in ca. 3 1 of H₂O) gave 70–80% yields of the trichloro- [(?)-(S)- 1a ] and trifluoro-hydroxyesters [(+)-(R) 2a ] of ca. 85 and 45% ee, respectively. Both, (?)- 1a and (+)- 2a could be obtained in > 98% ee by subsequent crystallization (of(?)- 1 , (+)- 2a or the 3,5-dinitrobenzoate (+)- 2b . The absolute configuration of both hydroxyesters was determined (a) by chemical correlation ((?)- 1a ), (b) from the melting diagrams and mixed melting points (differential-scanning calorimetry Fig. 1) of the dinitrobenzoates of the CF₃-derivative (+)- 2a and its CH₃-analogue 8 , and c) by X-ray analysis of the ester 2f from (+)- 2a and (?)-camphanoyl chloride (Fig. 2 and 3).     

Toward Creation of a Universal NMR Database for Stereochemical Assignment: The Case of 1,3,5‐Trisubstituted Acyclic Systems

Using the diastereoisomeric triols 1a – d (Fig. 1) and examples summarized in Fig. 2, the central C‐atom of acyclic 1,3,5‐triols is demonstrated to exhibit a distinctive chemical shift that is dependent on the 1,3‐ and 3,5‐relative configuration, but is independent of the functionalities present outside of this structural motif. These NMR characteristics are then used to predict the relative configuration of several natural products (Fig. 7). In addition, an example is given to show the possibility of assembling an NMR database for a larger array of functional groups from NMR databases of smaller arrays of functional groups.     

Achiral and Chiral Higher Adducts of C70 by Bingel Cyclopropanation

Five optically active isomeric C₇₀ bis-adducts with (R)-configured chiral malonate addends were prepared by Bingel cyclopropanation (Scheme 1) and their circular dichroism (CD) spectra investigated in comparison to those of the corresponding five bis-adducts with (S)-configured addends (Fig. 2). Pairs of diastereoisomers, in which the inherently chiral addition patterns on the fullerene surface have an enantiomeric relationship, display mirror-image shaped CD spectra that are nearly identical to those of the corresponding pairs of enantiomers (Fig. 3, b and c). This result demonstrates that the Cotton effects arising from the chiral malonate addends are negligible as compared to the chiroptical contribution of the chirally functionalized fullerene chromophore. A series of four stereoisomeric tetrakis-adducts (Fig. 4) was prepared by Bingel cyclopropanation starting from four stereoisomeric bis-adducts. A comparison of the CD spectra of both series of compounds showed that the magnitude of the Cotton effects does not decrease with increasing degree of functionalization (Fig. 5). Bingel cyclopropanations of C₇₀ in Me₂SO are dramatically faster than in apolar solvents such as CCl₄, and the reaction of bis-adducts (±)- 13 and 15 with large excesses of diethyl 2-bromomalonate and DBU generated, via the intermediacy of defined tetrakis-adducts (±)- 16 and 17 , respectively, a series of higher adducts including hexakis-, heptakis-, and octakis-adducts (Table 1). A high regioselectivity was observed up to the stage of the hexakis-adducts, whereas this selectivity became much reduced at higher stages of addition. The regioselectivity of the nucleophilic cyclopropanations of C₇₀ correlates with the coefficients of the LUMO (lowest unoccupied molecular orbital) and LUMO+1 at the positions of preferential attack calculated by restricted Hartree-Fock – self-consistent field (RHF-SCF) methods (Figs. 9 – 11). Based on predictions from molecular-orbital calculations (Fig. 11) and the analysis of experimental ¹³C-NMR data (Fig. 7, a), the structure of a unique hexakis-adduct ((±)- 22 , Fig. 12), prepared from (±)- 13 , was assigned. The C₂-symmetrical compound contains four 6−6-closed methanofullerene sub-structures in its polar regions (at the bonds C(1)−C(2), C(31)−C(32), C(54)−C(55), and C(59)−C(60)), and two 6−5-open methanofullerene sub-structures parallel to the equator (at C(22)−C(23) and C(26)−C(27)). The 6−5-open sub-structures are formed by malonate additions to near-equatorial 6−5 bonds with enhanced LUMO coefficients, followed by valence isomerization (Fig. 12).     

Catalytic Dendrophanes as Enzyme Mimics: Synthesis,Binding Properties,Micropolarity Effect,and Catalytic Activity of Dendritic Thiazolio-cyclophanes

Catalytic dendrophanes 9 and 10 were prepared as functional mimics of the thiamine-diphosphate-dependent enzyme pyruvate oxidase, and studied as catalysts in the oxidation of naphthalene-2-carbaldehyde ( 4 ) to methyl naphthalene-2-carboxylate ( 8 ) (Scheme 1). They are composed of a thiazolio-cyclophane initiator core with four generation 2 (G-2) poly(etheramide) dendrons attached. The two dendrophanes were synthesized by a convergent growth strategy by coupling dendrons 11 and 12 , respectively (Scheme 2) with (chloromethyl)-cyclophane 42 (Scheme 5) and subsequent conversion with 4-methylthiazole (Scheme 7). The X-ray crystal structures of cyclophane precursors 30 (Scheme 3), 37 , and 38 (Scheme 5) on the way to dendrophanes were determined (Fig. 1). The crystal-structure analysis of the benzene clathrate of 37 revealed the formation of channel-like stacks by the cyclophane which incorporate its morpholinomethyl side chain and the enclathrated benzene molecule (Fig. 2). The interactions of the enclathrated benzene molecule with the phenyl rings of the two adjacent cyclophane molecules in the stack closely resemble those between neighboring benzene molecules in crystalline benzene (Fig. 3). The characterization by MALDI-TOF-MS (Fig. 4), and ¹H- and ¹³C-NMR spectroscopy (Fig. 5) proved the monodispersity of the G-2 dendrophanes 9 and 10 with molecular weights up to 11500 Da (for 10 ). ¹H-NMR and fluorescence binding titrations in H₂O and aqueous MeOH showed that 9 and 10 form stable 1 : 1 complexes with naphthalene-2-carbaldehyde ( 4 ) and 6-(p-toluidino)naphthalene-2-sulfonate ( 48 , TNS) (Tables 1 and 2). The evaluation of the fluorescence emission maxima of bound TNS revealed that the dendritic branching creates a microenvironment of distinctly reduced polarity at the cyclophane core by limiting its exposure to bulk solvent. Initial rate studies for the oxidation of naphthalene-2-carbaldehyde to methyl naphthalene-2-carboxylate in basic aqueous MeOH in the presence of flavin derivative 6 revealed only a weak catalytic activity of dendrophanes 9 and 10 (Table 3), despite the favorable micropolarity at the cyclophane active site. The low catalytic activity in the interior of the macromolecules was explained by steric hindrance of reaction transition states by the dendritic branches.     

Cyclische Oligomere von (R)-3-Hydroxybuttersäure: Herstellung und strukturelle Aspekte

Cyclic Oligomers of (R)-3-Hydroxybutanoic Acid: Preparation and Structural Aspects The oligolides containing three to ten (R)-3-hydroxybutanoate (3-HB) units (12-through 40-membered rings 1–8 ) are prepared from the hydroxy acid itself, its methyl ester, its lactone (‘monolide’), or its polymer (poly(3-HB), mol. wt. ca. 10⁶ Dalton) under three sets of conditions: (i) treatment of 3-HB ( 10 ) with 2,6-dichlorobenzoyl chloride/pyridine and macrolactonization under high dilution in toluene with 4-(dimethylamino)pyridine (Fig. 3); (ii) heating a solution (benzene, xylene) of the β-lactone 12 or of the methyl ester 13 from 3-HB with the tetraoxadistanna compound 11 as trans-esterification catalyst (Fig. 4); (iii) heating a mixture of poly(3-HB) and toluene-sulfonic acid in toluene/1,2-dichloroethane for prolonged periods of time at ca. 100° (Fig. 6). In all three cases, mixtures of oligolides are formed with the triolide 1 being the prevailing component (up to 50% yield) at higher temperatures and with longer reaction times (thermodynamic control, Figs. 3–6). Starting from rac-β-lactone rac- 12 , a separable 3:1 to 3:2 mixture of the l,u- and the l,l-triolide diasteroisomers rac- 14 and rac- 1 , respectively, is obtained. An alternative method for the synthesis of the octolide 6 is also described: starting from the appropriate esters 15 and 17 and the benzyl ether 16 of 3-HB, linear dimer, tetramer, and octamer derivatives 18–23 are prepared, and the octamer 23 with free OH and CO₂H group is cyclized (→ 6 ) under typical macrolactonization conditions (see Scheme). This ‘exponential fragment coupling protocol’ can be used to make higher linear oligomers as well. The oligolides 1–8 are isolated in pure form by vacuum distillation, chromatography, and crystallization, an important analytical tool for determining the composition of mixtures being ¹³C-NMR spectroscopy (each oligolide has a unique and characteristic chemical shift of the carbonyl C-atom, with the triolide 1 at lowest, the decolide 8 at highest field). The previously published X-ray crystal structures of triolide 1 , pentolide 3 , and hexolide 4 (two forms), as well as those of the l,u-triolide rac- 14 , of tetrolide ent- 2 , of heptolide 5 , and of two modifications of octolide 6 described herein for the first time are compared with each other (Figs. 7–10 and 12–15, Tables 2 and 5–7) and with recently modelled structures (Tables 3 and 4, Fig. 11). The preferred dihedral angles τ₁ to τ₄ found along the backbone of the nine oligolide structures (the hexamer and the larger ones all have folded rings!) are mapped and statistically evaluated (Fig. 16, Tables 5–7). Due to the occurrence of two conformational minima of the dihedral angle O? CO? CH₂? CH (τ₃ = + 151 or ?43°), it is possible to locate two types of building blocks for helices in the structures at hand: a right-handed 3₁ and a left-handed 2₁ helix; both have a ca. 6 Å pitch, but very different shapes and dispositions of the carbonyl groups (Fig. 17). The 2₁ helix thus constructed from the oligolide single-crystal data is essentially superimposable with the helix derived for the crystalline domains of poly(3-HB) from stretched-fiber X-ray diffraction studies. The absence of the unfavorable (E)-type arrangements around the OC? OR bond (‘cis-ester’) from all the structures of (3-HB) oligomers known so far suggests that the model proposed for a poly(3-HB)-containing ion channel (Fig. 2) must be modified.     

Organocatalyzed Michael Addition of Aldehydes to Nitro Alkenes – Generally Accepted Mechanism Revisited and Revised

The amine‐catalyzed enantioselective Michael addition of aldehydes to nitro alkenes (Scheme 1) is known to be acid‐catalyzed (Fig. 1). A mechanistic investigation of this reaction, catalyzed by diphenylprolinol trimethylsilyl ether is described. Of the 13 acids tested, 4‐NO₂? C₆H₄OH turned out to be the most effective additive, with which the amount of catalyst could be reduced to 1 mol‐% (Tables 2–5). Fast formation of an amino‐nitro‐cyclobutane 12 was discovered by in situ NMR analysis of a reaction mixture. Enamines, preformed from the prolinol ether and aldehydes (benzene/molecular sieves), and nitroolefins underwent a stoichiometric reaction to give single all‐trans‐isomers of cyclobutanes (Fig. 3) in a [2+2] cycloaddition. This reaction was shown, in one case, to be acid‐catalyzed (Fig. 4) and, in another case, to be thermally reversible (Fig. 5). Treatment of benzene solutions of the isolated amino‐nitro‐cyclobutanes with H₂O led to mixtures of 4‐nitro aldehydes (the products 7 of overall Michael addition) and enamines 13 derived thereof (Figs. 6–9). From the results obtained with specific examples, the following tentative, general conclusions are drawn for the mechanism of the reaction (Schemes 2 and 3): enamine and cyclobutane formation are fast, as compared to product formation; the zwitterionic primary product 5 of C,C‐bond formation is in equilibrium with the product of its collapse (the cyclobutane) and with its precursors (enamine and nitro alkene); when protonated at its nitronate anion moiety the zwitterion gives rise to an iminium ion 6 , which is hydrolyzed to the desired nitro aldehyde 7 or deprotonated to an enamine 13 . While the enantioselectivity of the reaction is generally very high (>97% ee), the diastereoselectivity depends upon the conditions, under which the reaction is carried out (Fig. 10 and Tables 1–5). Various acid‐catalyzed steps have been identified. The cyclobutanes 12 may be considered an off‐cycle ‘reservoir’ of catalyst, and the zwitterions 5 the ‘key players’ of the process (bottom part of Scheme 2 and Scheme 3).     

Synthesis and Optical Resolution of the Floral Odorant (±)‐2,3‐Dihydro‐2,5‐dimethyl‐1H‐indene‐2‐methanol,and Preparation of Analogues

The title compound (±)‐ 1 , a recently discovered, valuable, floral‐type odorant, has been synthesized by a straightforward procedure (Scheme 1). To determine the properties of the enantiomers of 1 , their separation by preparative HPLC and the determination of their absolute configuration by X‐ray crystallography were carried out (Figure). Furthermore, the analogues 2 – 6 were synthesized, either from differently methylated 2‐methylindan‐1‐ones (Schemes 2 and 3) or, in the case of the 2,4,6‐trimethylated homologue 6 , by a completely different synthetic approach (Scheme 4). An evaluation of (+)‐(S)‐ 1 , (−)‐(R)‐ 1 , and (±)‐ 1 showed only minor differences in terms of odor (Table).     

Identification of (6R)‐5,6,7,8‐Tetrahydro‐D‐monapterin (=(6R)‐2‐Amino‐5,6,7,8‐tetrahydro‐6‐[(1R,2R)‐1,2,3 ‐trihydroxypropyl]pteridin‐4(3H)‐one) as the Native Pteridine in Tetrahymena pyriformis

The structure of the native pteridine in Tetrahymena pyriformis was determined as (6R)‐5,6,7,8‐tetrahydro‐D ‐monapterin (=(6R)‐2‐amino‐5,6,7,8‐tetrahydro‐6‐[(1R,2R)‐1,2,3‐trihydroxypropyl]pteridin‐4(3H)‐one; 4 ). First, the configuration of the 1,2,3‐trihydroxypropyl side chain was confirmed as D ‐threo by the fluorescence‐detected circular dichroism (FDCD) spectrum of its aromatic pterin derivative 2 obtained by I₂ oxidation (Fig. 1). The configuration at the 6‐position of 4 was determined as (R) by comparison of its hexaacetyl derivative 6 with authentic (6R)‐ and (6S)‐hexaacetyl‐5,6,7,8‐tetrahydro‐D ‐monapterins 6 and 7 , respectively, in the HPLC, LC/MS, and LC‐MS/MS (Figs. 3 – 6). (6R)‐5,6,7,8‐Tetrahydro‐D ‐monapterin ( 4 ) is a newly discovered natural tetrahydropterin.     

Cyclophane-Type Fullerene-dibenzo[18]crown-6 Conjugates with trans-1, trans-2, and trans-3 Addition Patterns: Regioselective Templated Synthesis,X-Ray Crystal Structure,Ionophoric Properties,and Cation-Complexation-Dependent Redox Behavior

The fullerene-crown ether conjugates (±)- 1 to (±)- 3 with trans-1 ((±)- 1 ), trans-2 ((±)- 2 ), and trans-3 ((±)- 3 ) addition patterns on the C-sphere were prepared by Bingel macrocyclization. The trans-1 derivative (±)- 1 was obtained in 30% yield, together with a small amount of (±)- 2 by cyclization of the dibenzo[18]crown-6(DB18C6)-tethered bis-malonate 4 with C₆₀ (Scheme 1). When the crown-ether tether was further rigidified by K⁺-ion complexation, the yield and selectivity were greatly enhanced, and (±)- 1 was obtained as the only regioisomer in 50% yield. The macrocyclization, starting from a mixture of tethered bis-malonates with anti ( 4 ) and syn ( 10 ) bisfunctionalized DB18C6 moieties, afforded the trans-1 ((±)- 1 , 15%), trans-2 ((±)- 2 , 1.5%), and trans-3 ((±)- 3 , 20%) isomers (Scheme 2). Variable-temperature ¹H-NMR (VT-NMR) studies showed that the DB18C6 moiety in C₂-symmetrical (±)- 1 cannot rotate around the two arms fixing it to the C-sphere, even at 393 K. The planar chirality of (±)- 1 was confirmed in ¹H-NMR experiments using the potassium salts of (S)-1,1′-binaphthalene-2,2′-diyl phosphate ((+)-(S)- 19 ) or (+)-(1S)-camphor-10-sulfonic acid ((+)- 20 ) as chiral shift reagents (Fig. 1). The DB18C6 tether in (±)- 1 is a true covalent template: it is readily removed by hydrolysis or transesterification, which opens up new perspectives for molecular scaffolding using trans-1 fullerene derivatives. Characterization of the products 11 (Scheme 3) and 18 (Scheme 4) obtained by tether removal unambiguously confirmed the trans-1 addition pattern and the out-out geometry of (±)- 1 . VT-NMR Studies established that (±)- 2 is a C₂-symmetrical out-out trans-2 and (±)- 3 a C₁-symmetrical in-out trans-3 isomer. Upon changing from (±)- 1 to (±)- 3 , the distance between the DB18C6 moiety and the fullerene surface increases and, correspondingly, rotation of the ionophore becomes increasingly facile. The ionophoric properties of (±)- 1 were investigated with an ion-selective electrode membrane (Fig. 2 and Table 2), and K⁺ was found to form the most stable complex among the alkali-metal ions. The complex between (±)- 1 and KPF₆ was characterized by X-ray crystal-structure analysis (Figs. 3 and 4), which confirmed the close tangential orientation of the ionophore atop the fullerene surface. Addition of KPF₆ to a solution of (±)- 1 resulted in a large anodic shift (90 mV) of the first fullerene-centered reduction process, which is attributed to the electrostatic effect of the K⁺ ion bound in close proximity to the C-sphere (Fig. 5). Smaller anodic shifts were measured for the KPF₆ complexes of (±)- 2 (50 mV) and (±)- 3 (40 mV), in which the distance between ionophore and fullerene surface is increased (Table 3). The effects of different alkali- and alkaline-earth-metal ion salts on the redox properties of (±)- 1 were investigated (Table 4). These are the first-ever observed effects of cation complexation on the redox properties of the C-sphere in fullerene-crown ether conjugates.     

Three-Component Reactions with Sterically Crowded 2,2,4,4-Tetramethyl-3-thioxocyclobutanone,Phenyl Azide,and Electron-Deficient C,C-Dipolarophiles

In order to trap ‘thiocarbonyl-aminides’ A , formed as intermediates in the reaction of thiocarbonyl compounds with phenyl azide, a mixture of 2,2,4,4-tetramethyl-3-thioxocyclobutanone ( 1 ), phenyl azide, and fumarodinitrile ( 8 ) was heated to 80° until evolution of N₂ ceased. Two interception products of the ‘thiocarbonylaminide’ A (Ar?Ph) were formed: the known 1,4,2-dithiazolidine 3 (cf. Scheme 1) and the new 1,2-thiazolidine 12 (Scheme 2). The structure of the latter was established by X-ray crystallography (Fig.1). The analogous ‘three-component reaction’ with dimethyl fumarate ( 9 ) yielded, instead of 8 , in addition to the known interception products 3 and 6 (Scheme 1), two unexpected products 15 and 16 (Scheme 3), of which the structures were elucidated by X-ray crystallography (Fig.2). Their formation is rationalized by a primary [2 + 3] cycloaddition of diazo compound 18 with 1 to give 19 , followed by a cascade of further reactions (Scheme 4).     

Formation of Unusual Products from the Acid-Catalyzed Reaction of Azulenes with Dimethyl Acetylenedicarboxylate

The reaction of guaiazulene ( 4 ) and dimethyl acetylenedicarboxylate (ADM) in tetralin or toluene, catalyzed by 5 mol-% of trifluoroacetic acid (TFA) at ambient temperature, leads to the formation of the corresponding heptalene-4,5-dicarboxylate 6 and a guaiazulenyl-substituted 2,2a,4a,8b-tetrahydrocyclopent[cd]azulene derivative 7 beside the expected guaiazulenyl-substituted ethenedicarboxylates (E)- 5 and (Z)- 5 as main products (Scheme 2). The structure of 7 was unequivocally established by an X-ray crystal-structure analysis (Fig. 1). Precursor of 7 must be the 2a,4a-dihydrocyclopent[cd]azulene-3,4-dicarboxylate 9 which reacts, under TFA catalysis, with a second molecule of 4 (Scheme 3). No formation of products of type 7 has been observed in the TFA-catalyzed reaction of 4,6,8-trimethyl- and 1,4,6,8-tetramethylazulene ( 13 and 16 , respectively) and ADM (Scheme 4). On the other hand, the TFA-catalyzed reaction of azulene ( 18 ) itself and ADM at ambient temperature gives rise to a whole variety of new products (Scheme 5), the major part of which is derived from dimethyl 2a,4a-dihydrocyclopent[cd]azulene-3,4-dicarboxylate ( 25 ) as the main intermediate (Scheme 6). Nevertheless, for the formation of the 2a,4a,6,8b-tetrahydrocyclobut[a]azulene derivatives (E)- 24a and (E)- 24b , a corresponding 2a,8b-dihydro precursor 29 has to be postulated as crucial intermediate (Scheme 8).     

Chiral Lithiated Phosphoric Triamides: Structure,Reactivity, and Salt Effects

The theoretical structure of a cyclic phosphoric triamide 3 and of its monolithiated isomers 4 – 6 was calculated by ab initio methods (Fig. 1, Tables 1 and 2). The global minimum in 4 consists of a five-membered Li−C−N−P−O chelate. The intermediates 5 and 6 are, relative to 4 , energetically unfavorable by 15 and 18 kcal mol⁻¹, respectively, due to distortion in order to accommodate the N-complexation of the Li⁺ ions. NMR Investigations (¹H, ¹³C, ³¹P, and ⁷Li) of the lithiated bicyclic phosphoric triamide 1 were performed (Tables 3 – 5). The lithium aminomethanide 2 is characterized by a sp³-hybridized anion supporting Li−C contacts. The anions exist in a monomer-dimer equilibrium in solution (Scheme 2). Trapping reactions of rac- 2 with carbonyl compounds generated the corresponding amino-alcohol derivatives with high diastereoselectivities (Scheme 3, Table 6). A rational for the stereochemical outcome is given (Fig. 4). In the presence of LiBr, a P−N bond cleavage occurred on reaction of rac- 2 with aldehydes, which allowed the synthesis of (1-hydroxylalkyl)phosphonic diamides (Scheme 5, Table 7).