(2S,3S)‐2,6‐Dimethylheptane‐1,3‐diol,the oxygenated side chain of 22(S)‐hydroxycholestrol,and its synthetic precursor (R)‐4‐benzyl‐3‐[(2R,3S)‐3‐hydroxy‐2,6‐dimethylheptanoyl]‐1,3‐oxazolidin‐2‐one

(2S,3S)‐2,6‐Dimethylheptane‐1,3‐diol, C₉H₂₀O₂, (I), was synthesized from the ketone (R)‐4‐benzyl‐3‐[(2R,3S)‐3‐hydroxy‐2,6‐dimethylheptanoyl]‐1,3‐oxazolidin‐2‐one, C₁₉H₂₇NO₄, (II), containing C atoms of known chirality. In both structures, strong hydrogen bonds between the hydroxy groups form tape motifs. The contribution from weaker C—H...O hydrogen bonds is much more evident in the structure of (II), which furthermore contains an example of a direct short Osp³...Csp² contact that represents a usually unrecognized type of intermolecular interaction.     

Tolterodinium (+)‐(2R,3R)‐hydrogen tartrate

In the crystal structure of (R)‐N,N‐diisopropyl‐3‐(2‐hydroxy‐5‐methyl­phenyl)‐3‐phenyl­propyl­aminium (2R,3R)‐hydrogen tartrate, C₂₂H₃₂NO⁺·C₄H₅O₆⁻, the hydrogen tartrate anions are linked by O—H⋯O hydrogen bonds to form helical chains built from (9) rings. These chains are linked by the tolterodine molecules via N—H⋯O and O—H⋯O hydrogen bonds to form separate sheets parallel to the (101) plane.     

Total Synthesis of (R,R,R)‐α‐Tocopherol Through Asymmetric Cu‐Catalyzed 1,4‐Addition

By introducing a disposable activating substituent at C‐3, the asymmetric 1,4‐addition to a notoriously unreactive 2‐substituted chromenone was achieved with high levels of (2R)‐stereoselectivity in the presence of a chiral Cu^I‐phosphoramidite complex as a catalyst. This paved the way for an efficient and conceptually novel synthesis of (R,R,R)‐α‐tocopherol from readily available starting materials.     

Synthesis of (−)‐Pinellic Acid and Its (9R,12S,13S)‐Diastereoisomer

The total synthesis of (?)‐pinellic acid with (9S,12S,13S)‐configuration and its (9R,12S,13S)‐diastereoisomer was achieved in high overall yields from a common intermediate derived from (+)‐L ‐diethyl tartrate.     

Stereoselective Total Synthesis of the Natural Oxylipin (6R,7E,9R,10S)‐6,9,10‐Trihydroxyoctadec‐7‐enoic Acid

The stereoselective total synthesis of the natural oxylipin, (6R,7E,9R,10S)‐6,9,10‐trihydroxyoctadec‐7‐enoic acid, has been accomplished using nonanal and hexane‐1,6‐diol as the starting materials. The synthesis involves Sharpless kinetic resolution, asymmetric epoxidation, and olefin cross‐metathesis as the key steps.     

The twinned crystal structure of rac‐(R,R)‐N,N′‐oxalyl­divalinol

The title compound, rac‐(R,R)‐N,N′‐bis(1‐hydroxy‐3‐methyl‐2‐butyl)oxalamide, C₁₂H₂₄N₂O₄, crystallizes as a non‐merohedral twin in the triclinic space group . The twin is generated by a twofold rotation about c*. The terminal hydroxy groups of molecules related by an inversion center form hydrogen‐bonded dimers. This hydrogen‐bonding pattern is further extended into a one‐dimensional chain by N—H⋯O hydrogen bonds.     

9(R)‐[6(R)‐Hydroxy­methyl‐1‐oxa‐4‐thia­cyclo­hexan‐2‐yl]hypoxanthine–water (4/3), a nucleoside analogue

The title compound, 9(R)‐[6(R)‐hydroxy­methyl‐1‐oxa‐4‐thia­cyclo­hexan‐2‐yl]‐1,9‐di­hydro‐6H‐purin‐6‐one–water (4/3), C₁₀H₁₂N₄O₃S·0.75H₂O, crystallizes in the triclinic space group P1 with four mol­ecules in the asymmetric unit and 0.75 waters of hydration per mol­ecule. The structure was refined to an R value of 0.072 for 3382 observed reflections. The four crystallographically independent mol­ecules are designated A, B, C and D. All four oxa­thia­ne rings adopt the chair conformation and the purine bases are in an anti orientation with respect to the sugar moieties. Molecules A and D and mol­ecules C and B are base paired by a single hydrogen bond of the type N—H?N. These base pairs are again hydrogen bonded to their translated pairs in the direction of a cell diagonal.     

(R)‐12‐Hydroxystearic Acid Hydrazides as Very Efficient Gelators: Diffusion,Partial Thixotropy,and Self‐Healing in Self‐Standing Gels

The gelation properties of derivatives of N‐alkylated (R)‐12‐hydroxystearic acid hydrazide (n‐HSAH, n=0, 2, 6, 10; n is the length of an n‐alkyl chain on the terminal nitrogen atom) in a wide variety of liquids is reported. The n‐HSAH compounds were derived from a naturally occurring alkanoic acid, (R)‐12‐hydroxystearic acid (R‐12HSA), and although they differ from the analogous N‐alkyl (R)‐12‐hydroxystearamides (n‐HSAA) only by the presence of one N?H group, their behavior as gelators is very different. For example, the parent molecule (0‐HSAH) is a supergelator in ethylene glycol, in which it forms self‐standing gels that are self‐healing, partially thixotropic, moldable, and load‐bearing; gels of 0‐HSAA are not self‐standing. 0‐HSAH is structurally the simplest molecular gelator of which we are aware that is capable of forming both self‐standing and partially thixotropic gels. Also, diffusion of the cationic dye erythrosine B and the anionic dye methylene blue in 0‐HSAH/ethylene glycol gel blocks is much slower than the self‐diffusion of ethylene glycol. Polarizing optical microscopy, X‐ray diffraction, and FTIR studies revealed that the self‐assembled fibrillar networks (SAFINs) of the gels are crystalline, and that 0‐HSAH molecules may be arranged in a triclinic subcell with bilayer stacking. The SAFINs are stabilized by strong hydrogen‐bonding interactions between the hydrazide groups of adjacent molecules and a perpendicular hydrogen‐bonding network between the pendent hydroxyl groups of 0‐HSAH. The other n‐HSAH (n=2, 6, 10) molecules appear to be arranged in orthorhombic subcells with monolayers and strong hydrogen‐bonding interactions between the hydrazide group of one gelator molecule and the hydroxyl group of a neighboring one. These results show how small structural modifications of structurally simple gelator molecules can be exploited to form gels with novel properties that can lead potentially to valuable applications, such as in drug delivery.     

A pair of diastereomeric 1:2 salts of (R)‐ and (S)‐2‐methylpiperazine with (2S,3S)‐tartaric acid

The crystal structures of a pair of diastereomeric 1:2 salts of (R)‐ and (S)‐2‐methylpiperazine with (2S,3S)‐tartaric acid, namely (R)‐2‐methylpiperazinediium bis[hydrogen (2S,3S)‐tartrate] monohydrate, (I), and (S)‐2‐methylpiperazinediium bis[hydrogen (2S,3S)‐tartrate] monohydrate, (II), both C₅H₁₄N₂²⁺·2C₄H₅O₆⁻·H₂O, each reveal the formation of well‐defined head‐to‐tail‐connected hydrogen tartrate chains; these chains are linked into a two‐dimensional sheet via intermolecular hydrogen bonds involving hydroxy groups and water molecules, resulting in a layer structure. The (R)‐2‐methylpiperazinediium ions lie between the hydrogen tartrate layers in the most stable equatorial conformation in (I), whereas in (II), these ions are in an unstable axial position inside the more interconnected layers and form a larger number of intermolecular hydrogen bonds than are observed in (I).     

Conformational and crystal packing differences in (+)‐7,8‐Di‐tert‐butoxy‐1‐ phenyloctahydro‐1H‐pyrrolo(1,2‐b)‐1H‐phospholo(2,3‐d)isoxazole 1‐oxide diastereoisomers

The crystal and molecular structures of (1S,3aR,7S,8S,8aR,8bR)‐(+)‐7,8‐Di‐tert‐butoxy‐1‐ph‐ enyloctahydro‐1H‐pyrrolo(1,‐b)‐1H‐phospholo(2,‐ d)isoxazole 1‐oxide ( III , hereafter) and (1R,3aS,7S, 8S,8aS,8bS)‐(+)‐7,8‐Di‐tert‐butoxy‐1‐phenyloctahyd‐ ro‐1H‐pyrrolo(1,2‐b)‐1H‐phospholo(2,3‐d)isoxazole 1‐ oxide ( IV , hereafter) have been determined. III crystallizes in space group P2₁2₁2₁, and IV in P2₁ one. The conformational analysis of the puckered heteroatom three‐ring system shows the conformation of noticeable distorted envelope with puckering amplitude Q₂ = 0.397 Å, the intermediate conformation between twisted and envelope with Q₂ = 0.353 Å, and half‐chair conformation with Q₂ = 0.451 Å, for phospholane, oxazolidine, and pyrrolidine rings of III , respectively. Rings in molecule of IV adopt conformations of envelopes with Q₂ = 0.381 Å, Q₂ = 0.367 Å, and Q₂ = 0.363 Å, respectively, for the rings as described above. The molecules of III are assembled by intermolecular weak hydrogen bonds to the one‐dimensional chain along x‐axis. The structure of IV is built‐up of weak intermolecular hydrogen bonds to form a two‐dimensional hydrogen bond network. The differences in conformation between compounds III and IV cause changes in hydrogen bonding pattern, because in molecule IV there is no hydrogen cavern filled with three hydrogen bond donors, and one weak hydrogen bond has not enough strength to force such an arrangement as it is in III . © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:613–620, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20160     

Synthesis of N,N‐Dialkyl‐9‐oxoacridine‐10(9H)‐carbothioamides via the Reaction of (2‐Halophenyl)(2‐isothiocyanatophenyl)methanones with Secondary Amines,Followed by Cyclization with NaH

The first preparation of acridin‐9(10H)‐ones carrying a tertiary thiocarbamoyl group at C(10), i.e., N,N‐dialkyl‐9‐oxoacridine‐10(9H)‐carbothioamides 9 , is described. The method is based on the reaction of (2‐halophenyl)(2‐isothiocyanatophenyl)methanones 7 , prepared from (2‐aminophenyl)(2‐halophenyl)methanones 5 by a convenient three‐step sequence, with secondary amines in DMF at room temperature to generate the corresponding thiourea derivatives 8 in situ, which are treated with NaH at 100–120° to provide the desired products in one‐pot reactions in generally good yields.     

Helical self‐assembly of 2‐(1,4,7,10‐tetraazacyclododecan‐1‐yl)cyclohexan‐1‐ol (cycyclen)

The title macrocyclic amino alcohol compound, C₁₄H₃₀N₄O, is investigated as a solid‐state synthon for the design of a self‐assembled tubular structure. It crystallizes in a helical column constructed by stereospecific O—H...N and N—H...N interactions. The hydrogen‐bonding interactions, dependent upon macrocyclic ring helicity and molecular conformation, link R,R and S,S enantiomers in a head‐to‐tail fashion, forming a continuous hydrophilic inner core.     

(4,6‐Dimethyl‐2‐sulfanylidenepyrimidin‐1‐ium) trichlorido(thiourea‐κS)zinc(II)

The title compound, (C₆H₉N₂S)[ZnCl₃{SC(NH₂)₂}], exists as a zincate where the zinc(II) centre is coordinated by three chloride ligands and a thiourea ligand to form the anion. The organic cation adopts the protonated 4,6‐dimethyl‐2‐sulfanylidenepyrimidin‐1‐ium (L) form of 4,6‐dimethylpyrimidine‐2(1H)‐thione. Two short N—H...Cl hydrogen bonds involving the pyrimidine H atoms and the [ZnCl₃L]⁻ anion form a crystallographically centrosymmetric dimeric unit consisting of two anions and two cations. The packing structure is completed by longer‐range hydrogen bonds donated by the thiourea NH₂ groups to chloride ligand hydrogen‐bond acceptors.     

Green synthesis and crystal structure of 4,7‐diaryl‐2‐oxo(thio)‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐5‐one derivatives

A green and convenient approach to the synthesis of novel 4,7‐diaryl‐2‐oxo(thio)‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐5‐one derivatives from appropriate aromatic aldehydes and 5‐aryl‐1,3‐cyclohexanedione with urea or thiourea in the presence of dilute HCl as catalyst in water is described. This method provides several advantages such as environmental friendliness, low cost, high yields, and simple workup procedure. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H NMR. The crystal and molecular structure of 4‐(4′‐chlorophenyl)‐7‐(4′‐methoxyphenyl)‐1,2,3,4,5,6,7,8‐octahydroquinazoline‐2,5‐dione 5m have been determined by single crystal X‐ray diffraction analysis. The crystal of compound 5m belongs to monoclinic with space group P‐2₁/c, a = 1.4353 (4) nm, b = 1.4011 (4) nm, c = 0.9248 (3) nm, α = 90.00°, β = 101.242 (6)°, γ = 90.00°, Z = 4, V = 1.8241 (9) nm³, R₁ = 0.0448, and wR₂ = 0.1022. J. Heterocyclic Chem., (2011).     

Diastereomers (RC,SP)‐ and (RC,RP)‐S‐methyl P‐(3‐azidopropyl)‐N‐[(1R)‐1‐phenylethyl]phosphonamidothioate

Diastereoisomers of the title organophosphorus compound, C₁₂H₁₉N₄OPS, denoted R_CS_P, (I), and R_CR_P, (II), were structurally characterized and compared. Asymmetric phosphorus compounds are of interest with regard to the use of these systems as possible protein probes via the stereoselective delivery of an azide group tethered to the P atom into key protein regions. The diastereomers were produced in a 1:1 mixture and isolated by chromatography. Although both isomers crystallize in the same space group with superficially similar cell constants, conformational and packing differences are pronounced. Despite the conformational differences, strong intermolecular hydrogen bonding links both isomers into chains parallel to the a axis [N...O = 2.8609 (18) and 2.966 (3) Å in (I) and (II), respectively], with C—H...π interchain interactions of ca 3.5 Å.     

(1R,3R,4S)‐1‐Benzyl‐3‐(tert‐butyldimethylsilyloxy)‐4‐(hydroxymethyl)pyrrolidine–borane: novel B—H...H—O hydrogen bonding

The absolute configuration of the title cis‐(1R,3R,4S)‐pyrrolidine–borane complex, C₁₈H₃₄BNO₂Si, was confirmed. Together with the related trans isomers (3S,4S) and (3R,4R), it was obtained unexpectedly from the BH₃·SMe₂ reduction of the corresponding chiral (3R,4R)‐lactam precursor. The phenyl ring is disordered over two conformations in the ratio 0.65:0.35. The crystallographic packing is dominated by the rarely found donor–acceptor hydroxy–borane O—H...H—B hydrogen bonds.     

Synthesis and crystal structures of C24‐epimeric 20(R)‐ocotillol‐type saponins

Ocotillol‐type saponins have a wide spectrum of biological activities. Previous studies indicated that the configuration at the C24 position may be responsible for their stereoselectivity in pharmacological action and pharmacokinetics. Natural ocotillol‐type saponins share a 20(S)‐form but it has been found that the 20(R)‐stereoisomers have different pharmacological effects. The semisynthesis of 20(R)‐ocotillol‐type saponins has not been reported and it is therefore worthwhile clarifying their crystal structures. Two C24 epimeric 20(R)‐ocotillol‐type saponins, namely (20R,24S)‐20,24‐epoxydammarane‐3β,12β,25‐triol, C₃₀H₅₂O₄, (III), and (20R,24R)‐20,24‐epoxydammarane‐3β,12β,25‐triol monohydrate, C₃₀H₅₂O₄·H₂O, (IV), were synthesized, and their structures were elucidated by spectral studies and finally confirmed by single‐crystal X‐ray diffraction. The (Me)C—O—C—C(OH) torsion angle of (III) is 146.41 (14)°, whereas the corresponding torsion angle of (IV) is −146.4 (7)°, indicating a different conformation at the C24 position. The crystal stacking in (III) generates an R₄⁴(8) motif, through which the molecules are linked into a one‐dimensional double chain. The chains are linked via nonclassical C—H…O hydrogen bonds into a two‐dimensional network, and further stacked into a three‐dimensional structure. In contrast to (III), epimer (IV) crystallizes as a hydrate, in which the water molecules act as hydrogen‐bond donors linking one‐dimensional chains into a two‐dimensional network through intermolecular O—H…O hydrogen bonds. The hydrogen‐bonded chains extend helically along the crystallographic a axis and generate a C₄⁴(8) motif.     

Synthesis and α‐Mannosidase Inhibitory Evaluation of (2R,3R,4S)‐ and (2S,3R,4S)‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol Derivatives

The synthesis of 46 derivatives of (2R,3R,4S)‐2‐(aminomethyl)pyrrolidine‐3,4‐diol is reported (Scheme 1 and Fig. 3), and their inhibitory activities toward α‐mannosidases from jack bean (B) and almonds (A) are evaluated (Table). The most‐potent inhibitors are (2R,3R,4S)‐2‐{[([1,1′‐biphenyl]‐4‐ylmethyl)amino]methyl}pyrrolidine‐3,4‐diol ( 3fs ; IC₅₀(B)=5 μM , K_i=2.5 μM ) and (2R,3R,4S)‐2‐{[(1R)‐2,3‐dihydro‐1H‐inden‐1‐ylamino]methyl}pyrrolidine‐3,4‐diol ( 3fu ; IC₅₀(B)=17 μM , K_i=2.3 μM ). (2S,3R,4S)‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol ( 6 , R?H) and the three 2‐(N‐alkylamino)methyl derivatives 6fh, 6fs , and 6f are prepared (Scheme 2) and found to inhibit also α‐mannosidases from jack bean and almonds (Table). The best inhibitor of these series is (2S,3R,4S)‐2‐{[(2‐thienylmethyl)amino]methyl}pyrrolidine‐3,4‐diol ( 6o ; IC₅₀(B)=105 μM , K_i=40 μM ). As expected (see Fig. 4), diamines 3 with the configuration of α‐D ‐mannosides are better inhibitors of α‐mannosidases than their stereoisomers 6 with the configuration of β‐D ‐mannosides. The results show that an aromatic ring (benzyl, [1,1′‐biphenyl]‐4‐yl, 2‐thienyl) is essential for good inhibitory activity. If the C‐chain that separates the aromatic system from the 2‐(aminomethyl) substituent is longer than a methano group, the inhibitory activity decreases significantly (see Fig. 7). This study shows also that α‐mannosidases from jack bean and from almonds do not recognize substrate mimics that are bulky around the O‐glycosidic bond of the corresponding α‐D ‐mannopyranosides. These observations should be very useful in the design of better α‐mannosidase inhibitors.     

Synthesis of N‐Substituted (3S,4S)‐ and (3R,4R)‐Pyrrolidine‐3,4‐diols: Search for New Glycosidase Inhibitors

N‐Substituted (3S,4S)‐ and (3R,4R)‐pyrrolidine‐3,4‐diols 9 and 10 , respectively, were derived from (+)‐L ‐ and (?)‐D ‐tartaric acid, respectively. Compounds 9k, 9l , and 9m with the N‐substituents, BnNH(CH₂)₂, 4‐PhC₆H₄CH₂NH(CH₂)₂ and 4‐ClC₆H₄CH₂NH(CH₂)₂, respectively, showed modest inhibitory activities toward α‐D ‐amyloglucosidases from Aspergillus niger and from Rhizopus mold (Table 1). Unexpectedly, several (3R,4R)‐pyrrolidine‐3,4‐diols 10 showed inhibitory activities toward α‐D ‐mannosidases from almonds and from jack bean (Table 3). N‐Substitution by the NH₂(CH₂)₂ group, i.e., 10g , led to the highest potency.     

(1R,2R)‐2‐(4‐Methylenecyclohex‐2‐enyl)propyl (1R,4S)‐camphanate

Esterification of a single diastereomer of 2‐(4‐methylene­cyclohex‐2‐enyl)propanol, (II), with (1R,4S)‐(+)‐camphanic acid [(1R,4S)‐4,7,7‐trimethyl‐3‐oxo‐2‐oxabicyclo[2.2.1]heptane‐1‐carboxylic acid] leads to the crystalline title compound, C₂₀H₂₈O₄. The relative configuration of the camphanate was determined by X‐ray diffraction analysis. The outcome clarifies the relative and absolute stereochemistry of the naturally occurring bisabolane sesquiterpenes β‐turmerone and β‐sesquiphellandrene, since we have converted (II) into both natural products via a stereospecific route.