Complexes of the Triolide from (R)-3-Hydroxybutanoic Acid with Sodium,Potassium, and Barium Salts: Crystal Structures,Ester Chelates and Ester Crowns,Crystal Packing,Bonding, and Electron-Localization Functions

The triolide of (R)-3-hydroxybutanoic acid ((R,R,R,))-3,7,11-trimethyl-2,6,10-trioxadodecane-1,5,9-trione; ( 1 ), readily available from the corresponding biopolymer P(3-HB) in one step, forms crystalline complexes with alkali and alkaline earth salts. The X-ray crystal structures of three such complexes, (3 NaSCN)·4 1 ( 2 ), (2 KSCN)·2 1 · H₂O ( 3 ), and (2) Ba(SCN)₂ · 2 1 · 2 H₂O · THF ( 4 ), have been determined and are compared. The triolide is found in these structures (i) as a free molecule, making no contacts with a cation (clathrate-type inclusion), (ii) as a monodentate ligand coordinated to a single ion with one carbonyl O-atom only, (iii) as a chelator, forming an eight-membered ring, with two carbonyl O-atoms attached to the same ion, (iv) as a linker, using two carbonyl O-atoms to bind to the two metals of an ion-X-ion unit (ten-membered ring), and (v), in a crown-ester complex, in which an ion is sitting on the three unidirectional C?O groups of a triolide molecule (Figs. 1–3). The crystal packing is such that there are columns along certain axes in the centers of which the cations are surrounded by counterions and triolide molecules, with the non-polar parts of 1 on the outside (Fig. 4). In the complexes 2–4 , the triolide assumes conformations which are slightly distorted, with the carbonyl O-atoms moved closer together, as compared to the ‘free’ triolide 1 (Fig. 5). These observed features are compatible with the view that oligo (3-HB) may be involved in the formation of Ca polyphosphate ion channels through cell membranes. A comparison is also made between the triolide structure in 1–4 and in enterobactin, a super Fe chelator (Fig. 5). To better understand the binding between the Na ion and the triolide carbonyl O-atoms in the crown-ester complex, we have applied electron-localization function (ELF) calculations with the data set of structure 2 , and we have produced ELF representations of ethane, ethene, and methyl acetate (Figs. 6–9). It turns out that this theoretical method leads to electron-localization patterns which are in astounding agreement with qualitative bonding models of organic chemists, such as the ‘double bond character of the CO? OR single bond’ or the ‘hyperconjugative n → σ* interactions between lone pairs on the O-atoms and neighbouring σ-bonds’ in ester groups (Fig. 8). The noncovalent, dipole/pole-type character of bonding between Na⁺ and the triolide carbonyl O-atoms in the crown-ester complex (the Na? O?C plane is roughly perpendicular to the O? C?O plane) is confirmed by the ELF calculation; other bonding features such as the C?N bond in the NaSCN complex 2 are also included in the discussion (Fig. 9).     

Poly(hydroxyalkanoates): A Fifth Class of Physiologically Important Organic Biopolymers?

Along with polyisoprenoids, polypeptides, polysaccharides, and polynucleotides, Nature contains a further group of biopolymers, the poly(hydroxyalkanoates). The commonest member of this group, poly[(R)-3-hydroxybutyrate] P(3-HB), had been identified by Lemoigne as early as the 1920s, as a storage substance in the microorganism Bacillus megaterium made up of more than 12000 (3-HB) units. However, the widespread distribution and significance of these biopolymers has only become clear recently. The work of Reusch, in particular, has shown that low molecular weight P(3-HB) (100–200 3-HB units) occurs in the cell membranes of prokaryotic and eukaryotic organisms. The function of P(3-HB) in the latter sources is largely unknown; it has been proposed that a complex of P(3-HB) and calcium polyphosphate acts as an ion channel through the membrane. Indeed, it has even been speculated that P(3-HB) plays a role in transport of DNA through the cell wall. In the present article, the following subjects will be discussed: metabolism of P(3-HB) and analogous polyesters in the synthesis and degradation of storage materials; P(3-HB) as a starting material for chiral synthetic building blocks; synthesis of cyclic oligomers (oligolides) of up to ten 3-HB units, and their crystal structure; high molecular weight bio-copolymers of hydroxybutyrate and hydroxyvalerate (BIOPOL) as biologically degradable plastics; nonbiological production of polyhydroxyalkanoates from 3-hydroxy carboxylic acids and the corresponding β-lactones; specific synthesis of linear oligomers with a narrow molecular weight distribution, consisting of about 100 (R)-3-hydroxybutyrate units, by using an exponential coupling procedure; structure of the polyesters, and a comparison with other polymers; the experimental results which led to the postulation of a P(3-HB) ion channel through the cell wall; modeling of P(3-HB) helices of various diameters, by using the parameters obtained from the crystal structures of oligolides; formation of a crown ester complex and ion transport experiments with the triolide of 3-HB. The article describes one example of the contributions that synthetic organic chemists can make to important biological problems in an interdisciplinary framework.     

Preparation,Structure, and Properties of All Possible Cyclic Dimers (Diolides) of 3-Hydroxybutanoic Acid

In connection with the proposed structure of a trans-membrane cellular ion channel consisting of a complex between poly[(R)-3-hydroxy butanoate] (P(3-HB)) and calcium polyphosphate, CaPP_i (ca. 150 units each), which is supposed to contain s-cis-bonds or even more highly strained ester conformations, we have prepared and studied the properties of the cyclic dimer of 3-HB, the diolide 1 . All possible forms of 1 , the rac-, the meso-, and the enantiomerically pure (R,R)- and (S,S)-compounds were prepared, purified, and characterized. The synthesis (Scheme 1) started from dimethyl succinate with the key step being the Baeyer-Villiger oxidation of the rac- and meso-2,5-dimethylcyclohexane-1,4-diones 5 . The rac-diolide 1 was resolved by preparative chromatography on a Chiralcel OD column (Fig.1). The crystal structures of rac- 1 (Fig.3) and of meso- 1 (Fig.5) were determined by X-ray diffraction: the diolides 1 contain s-cis-ester bonds and an ester group with a conformation half way to the transition state of rotation (Fig.2). Strain energies for the diolides 1 of up to 17.8 kcal/mol are suggested. Accordingly, these compounds show reactivities similar to those of carboxylic-acid anhydrides or even acid chlorides. They cannot be chromatographed on silica gel, and they react with primary, secondary, and tertiary alcohols, and with amines to form derivatives of open chain 3-HB ‘dimers’, hydroxy acids 6 , esters 7 , and amides 8 (Scheme 2). The rate of acid-catalyzed ring opening of the diolides 1 with alcohols has been measured (Fig.6 and 7). From the results described, we conclude that it is unlikely for strained and reactive ester conformations to occur as part of ion channels through phospholipid bilayers of cells.     

Preparation,Structure, and Reactivity of Thioxo and Imino Derivatives of the Triolide (and Pentolide) from (R)-3-Hydroxybutanoic Acid

Reaction of the triolide 1 from (R)-3-hydroxybutanoic acid with Lawesson's reagent 5 leads to the mono-, di-, and trithio derivatives 6–8 which can be isolated in pure form (20–40% yields), and which have crystal structures very similar to the parent triolide 1 (Fig. 1). Similarly, pentolide 3 is converted to mixtures of various thio derivatives, three of which are separated ( 10–12 ) by HPLC and fully characterized. The X-ray structures of the mono- and of one of the dithiopentolides ( 10, 12 ) differ remarkably from each other (Fig. 3). Reduction of the thiotriolides 6–8 (NaBH₄, R₃SnH, Cl₃SiH, Raney-Ni) gives 12-membered rings containing up to three ether groups (chiral crown ethers, 15, 17–19 ) in poor yields. The thiotriolides react spontaneously and in yields of up to 96% with ammonia, certain primary amines, and hydroxylamine to give imine and oxime derivatives with intact 12-membered-ring backbones ( 20, 22–24, 30 , see crystal structures in Figs. 4–7). The rigid structure of all the derivatives of triolide 1 puts the C?O, C?S, and C?NR O-, S-, and N-atoms in juxtaposition (a feature reminiscent of the side chains in the iron-binder enterobactin, Fig. 6). Imines containing PPh₂ groups are prepared ( 30, 33, 35 ) from the thiotriolides and tested as chiral ligands for Pd^II-catalyzed 1,3-diphenyallylations (→ 37 , enantiomer ratio up to 77:23). The reactions described demonstrate that multiple reactions of the triolide 1 from (R)-3-hydroxybutanoic acid which proceed through tetrahedral intermediates are possible without ring opening – the skeleton is remarkably stable, and this might be exploited as a template for bringing up to three pendent substituents into close proximity to allow a study of their interactions and cooperative properties. Also, the di- and trithio derivatives 7 and 8 could be used for cross-linking in molecules containing primary NH₂ groups.     

Preparation and Structure of Oligolides from (R)-3-Hydroxypentanoic Acid and comparison with the hydroxybutanoic-acid derivatives: A small change with large consequences

Cyclic oligomers of (R)-3-hydroxyvaleric acid (3-HV) are prepared from the monomer by three different methods, giving various ratios of the oligomers. The macrocycles containing three to twelve 3-HV units (12- to 48-membered rings) are isolated in pure form by chromatography. The triolide 3 can be separated by distillation and isolated on large scale. Biopol, the copolymer of (R)-3-hydroxybutanoic acid (3-HB) and (R)-3-hydroxyvaleric acid (3-HV), is degraded to mixtures of Me- and Et-substituted triolides (‘mixolides’) with high crystallization tendency. The X-ray crystal structures of the tetrolide 4 , pentolide 5 , hexolide 6 , heptolide 7 , and of two ‘mixolides’ (with inclusions of solvent) have been determined (Figs. 3–7, 10, and 11) and are compared with those of the corresponding 3-HB derivatives reported previously. From the structural data, a 3₁ and a 2₁ helix of 3-HV can be modelled, and the latter one compared with helix structures of P9(3-HB) and P(3-HV) derived from stretch-fibre X-ray scattering. Crystals of a water-containing NaSCN complex of the triethyl triolide 3 were obtained in good quality for X-ray analysis. The structure (Figs. 12, 13, and Table 6) contains an interesting array of C?O and H₂O O-atoms around the Na⁺ ions along a channel-type tube (a-axis of the crystal) which may be relevant to the role of P(3-HB) and P(3-HV) as components of cellular ion channels.     

Synthese monodisperser linearer und cyclischer Oligomere der (R)-3-Hydroxybuttersäure mit bis zu 128 Einheiten

Monodisperse Linear and Cyclic Oligo[(R)-3-hydroxybutanoates] Containing up to 128 Monomeric Units Using benzyl ester/(tert-butyl)diphenylsilyl ether protection, (COCl)₂/pyridine esterification conditions, and a fragment-coupling strategy (with H₂/Pd-C debenzylation and HF · pyridine desilylation), linear oligomers of (R)-3-hydroxybutanoic acid (3-HB) containing up to 128 3-HB building blocks (mol. weight > 11 000 Da) are assembled (Schemes 1,2,5, and 6). In contrast to the previously employed protecting-group combination, and due to the low-temperature esterifying conditions, this procedure leads to monodisperse oligomers: all steps occur without loss of single 3-HB units. The product oligomers with two, one, and no terminal protecting groups (mostly prepared in multi-gram amounts) are characterized by all standard spectroscopic methods, especially by mass spectroscopy (Figs. 2 and 3), by their optical activity, and by elemental analyses. Cyclization of the oligo[(R)-3-hydroxybutanoic acids] with up to 32 3-HB units, using thiopyridine activation and CuBr₂ for the ring closure, produces oligolides consisting of up to 128 ring atoms (Scheme 7). Mixed oligolides containing 3-HB and (R)-3-hydroxypentanoic units are prepared from the corresponding linear trimers, using Yamaguchi's method for the ring closure (Scheme 8 and Fig.4 (X-ray crystal structures of two folded conformers)). Comparisons of melting points (Table 1), of [α] values (Tables 2 and 3), of ¹H-NMR coupling constants (Table 3), and of molecular volume/hydroxyalkanoate unit (Table 4) of linear and cyclic oligomer derivatives and of the high-molecular-weigh polymer show that the monodisperse oligomers appear to be surprisingly good models for the polymer. Besides this insight, our synthesis is supplying the samples to further test the role of P(3-HB) (ca. 140 units) as a component of complexes forming channels through cell-wall phospholipid bilayers.     

Synthesis and Structure of Linear and Cyclic Oligomers of 3-Hydroxybutanoic Acid with Specific Sequences of (R)- and (S)-Configurations

To study the stereoselectivity of enzymatic cleavage of poly(3-hydroxybutyrates) (PHB) in a well-defined system (purified depolymerase and monodisperse substrate of specific relative configuration), linear and cyclic oligomers of HB (OHBs) containing (R)- and (S)-3-hydroxybutanoate residues were synthesized. The starting material (R)-HB was prepared from natural sPHB, and (S)-HB by enantioselective reduction of 3-oxobutanoate with yeast or with H₂/Noyori-Taber catalyst (Scheme 2). The HB building blocks were then protected (O-benzyl/tert-butyl ester; Scheme 3) and coupled to give dimers 3 , 4 , tetramers 5 – 9 , and octamers 10 – 18 ; for analytical comparison, a 3mer, 5mer, 6mer, and 7mer ( 19 – 22 ) were also prepared. Two of the tetramers were subjected to macrolactonization conditions (Yamaguchi) to give the cyclic tetramers 23 and 25 and octamers 24 and 26 . All new compounds were fully characterized (m.p., [α]_D, CD, IR, ¹H- and ¹³C-NMR, MS, elemental analysis). Single-crystal X-ray structure analyses were performed with oligolides 24 and 25 (Figs. 2 and 4), and the structures, as well as the crystal packing, were compared with those of analogs containing only (R)-HB units or consisting of 3-amino- instead of 3-hydroxybutanoic-acid moieties.     

On the Macrolactonization of β-Hydroxy Acids. Crystal structures of the pentolide and the hexolide from (R)-3-hydroxybutanoic acid. Molecular modeling studies of the tetrolide

The temperature and concentration dependence of the previously reported formation of oligolides from (R)- or (S)-3-hydroxybutanoic acid under Yamaguchi's macrolactonization conditions (2,4,6-trichlorobenzoyl chloride/base) was studied. While the content of hexolide 2 in the product mixture is almost invariably ca. 35%, the amounts of pentolide 1 and of the larger rings strongly depend upon the temperature employed (Fig.1). Cyclic oligomers ( 5,6 ) are also obtained from 3-hydroxypentanoic acid. Enantiomerically pure β-butyrolactone can be used for the preparation of pento-, hexo-, and heptolide under Shanzer's macrolactonization conditions (tetra-oxadistannacyclodecane ‘template’). The X-ray crystal structures of the pentolide 1 and of two modifications (space groups C 2 and P 2₁) of the hexolide 2 were determined (Figs. 2–6 and Tables 1 and 5). No close contacts between substituent atoms and atoms in the rings or between ring atoms are observed in these structures. The hexolide C 2 modification is ‘just a large ring’, while the crystals of the P 2₁ modification contain folded rings the backbones of which resemble the seam of a tennis ball. A comparison of the torsion angles in the folded hexolide ring of the P 2₁ modification with those in the helical poly-(R)-3-hydroxybutanoate ( PHB ) suggests (Table 2) that the same interactions might be responsible for folding in the first and helix formation in the second case. Molecular modeling with force-field energy minimization of the tetrolide from four homochiral β-hydroxybutanoic acid units was undertaken, in order to find possible reasons for the fact that we failed to detect the tetrolide in the reaction mixtures. The calculated conformational energies (per monomer) for some of the tetrolide models (Figs. 7–9 and Tables 3 and 4) are not significantly higher than for the pentolide and hexolide crystal structures. We conclude that thermodynamic instability is an unlikely reason for the lack of tetrolide isolation. This result and failure to observe equilibration of pentolide 1 to a mixture of oligomers under the reaction conditions suggest that product distribution is governed by kinetic control.     

Solid-State CP/MAS 13C-NMR Spectra of Oligolides derived from 3-hydroxybutanoic acid

The solid-state CP/MAS ¹³C-NMR spectra (cross-polarization/magic-angle spinning ¹³C-NMR) of eight lower cyclic and one linear oligomers and several polymers of (R)-3-hydroxybutanoic acid (3-HB) are reported. The polymeric samples of different origin and molecular weight give remarkably similar and well resolved spectra, indicating considerable similarity in the conformations of the molecules and homegeneity in the solid-state environment. The crystalline cyclic oligomers 1 – 8 containing 3–9 units of 3-HB give very well resolved spectra. The number of nonequivalent positions in the solid state can be identified and is in accord with structures from X-ray diffraction where these were determined. The spectra of the oligolides become increasingly similar to those of the polymer as the ring size increases. This spectral evidence supports the view of a homogeneous and well defined conformation for the polymeric material (as proposed previously, based on other experiments).     

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.     

Synthesis of Highly Fluorinated Di-O-alk(en)yl-glycerophospholipids and Evaluation of Their Biological Tolerance

The syntheses of various fluorocarbon/fluorocarbon and fluorocarbon/hydrocarbon rac-1,2- and 1,3-di-O-alk(en)ylglycerophosphocholines and rac-1,2-di-O-alkylglycerophosphoethanolamines (see Fig.2), which may be used as components for drug-carrier and delivery systems, are described together with some results concerning their biological tolerance. They were obtained by phosphorylation of perfluoroalkylated rac-di-O-alk(en)ylgly-cerols using POCl₃, then condensation with choline tosylate or N-Boc-ethanolamine (2-[(tert-butoxy)carbonyl-amino]ethanol) followed by Boc-deportection (Schemes 6–8). The fluorcarbon/fluorocarbon 1,2-di-O-alkylgly-cerols were prepared by O-alkylation of rac-1-O-benzylglycerol using perfluoroalkylated mesylates, then hydrogenolysis for benzyl deprotection (Scheme 1). The two different hydrophobic chains in the mixed fluorocarbon/fluorocarbon and fluorocarbon/hydrocarbon 1,2-di-O-alk(en)ylglycerols were introduced starting from 1,2-O-iso-propylidene- then O-trityl-protected glycerols or from 1,3-O-benzylidene-glycerol (Schemes 3 and 4). The perfluoroalkylated O-alkenylglycerols were obtained by O-alkylation of a glycerol derivative using an ω-unsaturated alkenyl reagent, the perfluoroalkyl segment being connected onto the double bond in a subsequent step (Schemes 1) and 3. The perfluoroalkylated symmetrical and mixed 1,3-di-O-alkylglycerols were synthesized by displacement of the Cl-atom in epichlorohydrin by perfluoroalkylated alcohols, then catalytic (SnCl₄) opening of the oxirane ring of the resulting alkyl glycidyl ethers in neat alcohols (Scheme 5). When injected intravenously into mice, acute maximum tolerated doses higher than 1500 and 2000 mg/kg body weight were observed for the fluorinated glycerophosphocholines, indicating a very promising in vivo tolerance.     

On the Mechanisms of Enantioselective Reactions Using α,α,α′,α′ -Tetraaryl-1,3-dioxolane-4,5-dimethanol(TADDOL)-Derived Titanates: Differences between C2- and C1-symmetrical TADDOLs – facts,implications and generalizations

The titanates derived from α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs, prepared from tartrate) act as catalysts for enantioselective additions of dialkylzinc compounds to aldehydes. For the standard reaction chosen for this investigation of the mechanism, the addition of diethylzinc to benzaldehyde, there is very little change of selectivity with different aryl substituents on the TADDOLate ligands (Tables 2–4, examples). With 0.02 to 0.2 equiv. of the chiral titanates, selectivities above 90% are observed only in the presence of excess tetraisopropyl titanate! According to NMR measurements (Fig. 2), the chiral bicyclic titanate and the achiral titanate do not react to give new species under these conditions. From experiments with different stoichiometries of the components, and with different achiral or chiral OR groups on the Ti-atom of the seven-membered ring titanate, it is concluded (i) that a single chiral titanate is involved in the product-forming step, (ii) that the bulky TADDOLate ligand renders the Ti-center catalytically more active than that of (i-PrO)₄Ti, due to fast dynamics of ligand exchange on the sterically hindered Ti-center (Table 5, Fig. 3), and (iii) that the role of excess (i-PrO)₄Ti is to remove – by ligand exchange – the product alkoxides (R*O) from the catalytically active Ti-center (Scheme 4, Table 6). Three new crystal structures of TADDOL derivatives (two clathrates with secondary amines, and a dimethyl ether) have been determined by X-ray diffraction (Figs. 5–7), and are compared with those previously reported. The distances between the C(aryl)₂O oxygen atoms in the C₂- and C₁-symmetrical structures vary from 2.58 to 2.94 Å, depending upon the conformation of their dioxolane rings and the presence or absence of an intramolecular H-bond (Fig. 8). A single-crystal X-ray structure of a spiro-titanate, with two TADDOLate ligands on the Ti-atom, is described (Fig. 9); it contains six different seven-membered titanate-ring conformations in the asymmetric unit (Fig. 10), which suggests a highly flexible solution structure. The structures of Ti TADDOLate complexes are compared with those of C₂-symmetrical Ru, Rh, and Pd disphosphine chelates (Table 7). A common topological model is presented for all nucleophilic additions to aldehydes involving Ti TADDOLates (Si attack with (R,R)-derivatives, relative topicity unlike; Fig. 11). Possible structures of complexes containing bidentate substrates for Ti TADDOLate-mediated ene reactions and cycloadditions are proposed (Fig. 12). A simple six-membered ring chair-type arrangement of the atoms involved can be used to describe the result of TADDOLate-mediated nucleophilic additions to aldehydes and ketones, with Ti, Zr, Mg, or Al bearing the chiral ligand (Scheme 6). A proposal is also made for the geometry of the intermediate responsible for enantioselective hydrogenation of N-(acetylamino)cinnamate catalyzed by Rh complexes containing C₂-symmetrical diphosphines (Fig. 13).     

Crystal Structures – A Manifesto for the Superiority of the Valine‐Derived 5,5‐Diphenyloxazolidinone as an Auxiliary in Enantioselective Organic Synthesis

The crystal structures of 32 derivatives of 4‐isopropyl‐5,5‐diphenyl‐1,3‐oxazolidin‐2‐one ( A and 1 – 31 ) are presented (Fig. 2 and Tables 1–3). In all but four structures, the Me₂CH group is in a disposition that mimick a Me₃C group (Figs. 3–5). The five‐membered ring shows conformations from an envelope form with the Ph₂C group out of the plane containing the other four atoms to the twist form with the twofold axis through the CO group (Fig. 6, and Table 2). In the entire series, the Me₂CH and the neighboring trans Ph group are approximately antiperiplanar (average torsion angle 155°). The structural features are used to interpret the previously observed reactivity behavior of the diphenyl‐oxazolidinone derivatives. The practical advantages of the title compound over classical Evans auxiliaries are outlined (Figs. 1 and 7, and Scheme 2): high crystallinity of all derivatives, steric protection of the CO group in the ring, excellent stereoselectivities in reactions of its derivatives, and safe preparation and easy recovery of the auxiliary.     

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).     

Cyclopolymerization of Nonconjugated Dienes with a Tridentate Phenoxyamine Hafnium Complex Supported by an sp3‐C Donor: Isotactic Enchainment and Diastereoselective cis‐Ring Closure

Cyclopolymerization of nonconjugated dienes produces poly(methylene‐1,3‐cycloalkanes) and provides a pathway to a number of stereochemically complex polymers. Activation of a diastereomeric mixture of a six‐membered metallacycle complex (rac‐ 1 ) in the presence of 1,5‐hexadiene produced poly(methylene‐1,3‐cyclopentane) (PMCP) with >98% cyclization of the diene monomer. The catalyst was found to cyclopolymerize 1,5‐hexadiene with relatively high activity. The microstructure of the PMCP furnished by rac‐ 1 was found to contain a high proportion of cis‐cyclopentane rings (σ = 0.70–0.74) and a relatively high isotactic content (α = 0.93–0.96). These are the first cis‐enriched isotactic cyclopolymers of 1,5‐hexadiene. Cyclopolymerization of 1,6‐heptadiene with rac‐ 1 /B(C₆F₅)₃ produced poly(methylene‐1,3‐cyclohexane) containing 97% cis‐isotactic rings. This is the first report of this highly isotactic and diastereomerically‐pure microstructure.

     

Channel-Forming Activity of 3-Hydroxybutanoic-Acid Oligomers in Planar Lipid Bilayers

Monodisperse and polydisperse oligomers and polymers of 3-hydroxybutanoic acid (3-HB) containing 8, 16, ca. 28, 32, ca. 60, 64, 96, and ca. 3000 monomer units were incorporated into palmitoyl-oleoyl-phosphatidyl choline (POPC) planar bilayers. At concentrations of 0.1–5% of oligo(3-HB), the resulting phospholipid bilayers showed typical single-channel behavior for Rb⁺ and Ba²⁺ ions, using the patch clamp technique. Thus, channel-forming activity of a pure polyester has been demonstrated for the first time (Figs. 1, 3, and 6). Single-channel activity depends upon the following structural parameters of the 3-HB derivatives: unprotected OH and COOH groups on the chain ends; chain length ⩾ 16 monomer units; no high-molecular-weight as in P(3-HB). The results are discussed in view of the Ca²⁺-specific channel formed with the P(3-HP)/Ca · PPi complex from genetically competent Escherichia coli and in view of the ubiquitous occurrence of low-molecular-weight P(3-HB) in prokaryotic and eukaryotic organisms. A simple model for the channel-causing structure is proposed, based on the proven tendency of oligo- and poly(3-HB) to form ca. 50-Å thick lamellar crystallites.     

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.     

Preparative Resolution of Heterocyclic Acetals Derived from Glycine,Mercapto-acetic Acid, β-Alanine,and Formyl- or Acetylacetic Acid by Recycling Chromatography on Chiraspher and Temperature Dependence of Separation Factors

Chiraspher, a polymer of ethyl N-acryloylphenylalanine on spherical silica gel, is used for the preparative separation by recycling chromatography of the enantiomers of oxazolidinones rac- 5 , thioxolanone rac- 6 , per-hydropyrimidinone rac- 7 , and dioxinones rac- 9 and 10 derived from the acids listed in the title (Figs. 1–5). The oxazolidinones rac- 1a , -2 , and -4 show a peculiar peak of the separation efficiences upon lowering the Chiraspher-column temperature to 15° (Fig. 6). In some cases, multigram amounts of enantiomerically pure heterocycles could thus be prepared. The absolute configurations of most enantiomers are assigned. First applications of the tert-butyl 5-oxo-2-phenyloxazolidine-3-carboxylate ( 5 ) as a nucleophilic chiral glycine building block are described (products 13 – 16 , Scheme 2). A list of enantiomerically pure 1,3-dioxinones is presented (Table 1), showing a correlation between their absolute configuration, sense of optical rotation, and elution behavior on Chiraspher.     

Oxydative Aryl-Aryl-Verknüpfung von 6,6′,7,7′-Tetramethoxy-1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-biisochinolin-Derivaten

Oxidative Aryl-Aryl-Coupling of 6,6′,7,7′-Tetramethoxy-1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-biisoquinoline Derivatives We describe the synthesis of 2 by intramolecular oxidative coupling of 1, 1′-biisoquinoline derivatives 1 (Scheme 1). This heterocyclic system can be considered as a union of two apomorphine molecules and may thus exhibit dopaminergic activity. - The readily available tetrahydrobiisoquinoline 6 was methylated to 11 (Scheme 4) and reduced (with NaBH₃CN) to rac- 7 and (catalytically) to meso- 7 (Scheme 3). Reduction of 11 with NaBH₄ and of the biurethane rac- 9 with LiAlH₄/AlCl₃ afforded meso- and rac- 10 , respectively (Scheme 4). Demethylation of 6 , meso- 10 , meso- and rac- 7 led to 12 , meso- 14 , meso- and rac- 13 , respectively (Scheme 5). The latter two phenols were converted with chloroformic ester to the hexaethoxycarbonyl derivatives meso- and rac- 15 and subsequently saponified to the biurethanes meso- and rac- 16 , respectively (Scheme 5). - In order to assure proximity of the two aromatic rings, the ethano-bridged derivatives meso- and rac- 18 were prepared by condensing meso- and rac- 7 with oxalic ester and reducing the oxalyl derivatives meso- and rac- 17 with LiAlH₄/AlCl₃, respectively (Scheme 6). The ¹H-NMR, spectra at different temperatures showed that rac- 18 populated two conformers but rac- 17 only one, all with C₂-symmetry, and that meso- 17 as well as meso- 18 populated two enantiomeric conformers with C₁-symmetry. Whereas both oxalyl derivatives 17 were fairly rigid due to the two amide groupings, the ethano derivatives 18 exhibited coalescence temperatures of -20 and 30°. - The intramolecular coupling of the two aromatic rings was successful under ‘non-phenolic oxidative’ conditions with the tetramethoxy derivatives 7, 10 and 18 , the rac-isomers leading to the desired dibenzophenanthrolines, the meso-isomers, however, mostly to dienones (Scheme 9): With VOF₃ and FSO₃H in CF₃COOH/CH₂Cl₂ rac- 7 was converted to rac- 19 , rac- 18 to rac- 21 and rac- 10 to a mixture of rac- 20 and the dienone 23b of the morphinane type. Under the same conditions meso- 10 was transformed to the dienone 23a of the morphinane type, whereas meso- 18 yielded the dienone 24 of the neospirine type, both in lower yields. The analysis of the spectral data of the six coupling products offers evidence for their structures. With the demethylation of rac- 20 and rac- 21 to rac- 25 and rac- 26 , respectively, the synthetic goal of the work was reached, but only in the rac-series (Scheme 10). - In the course of this work two cleavages of octahydro-1,1′-biisoquinolines at the C(1), C(1′)-bond were observed: (1) The biurethanes 9 and 16 in both the meso- and rac-series reacted with oxygen in CF₃COOH solution to give the 3,4-dihydroisoquinolinium salts 27 and 28 ; the latter was deprotonated to the quinomethide 30 (Scheme 11). (2) Under the Clarke-Eschweiler reductive-methylation conditions meso- and rac- 7 were cleaved to the tetrahydroisoquinoline derivative 32 .     

Copolymerization of propene and 1-hexene using metallocene amide compounds

Copolymerization of propene and 1-hexene has been carried out at 30°C in toluene under atmospheric pressure by using three isospecific metallocene amide compounds, rac-(EBI)Zr(NMe₂₎₂ (EBI = ethylenebis(1-indenyl), rac- 1 ), rac-(EBI)Zr(NC₄H₈₎₂ (rac- 2 ), and rac-Me₂Si(1-C₅H₂-2-Me-4-t-Bu)₂Zr(NMe₂₎₂ (rac- 3 ), in the presence of methylaluminoxane (MAO) or [Ph₃C][B(C₆F₅)₄]. The rate enhancements in the presence of 1-hexene were recorded as a function of the catalytic systems. The incorporation of 1-hexene decreases in the following order: rac- 2 /MAO > rac- 3 /Al(i-Bu)₃/[Ph₃C][B(C₆F₅)₄] > rac- 1 /MAO. All copolymers investigated in this study have a nearly random sequence distribution.