New Optically Active tert-Butylarylthiophosphinic Acids and Their Selenium Analogues as the Potential Synthons of Supramolecular Organometallic Complexes: Syntheses and Crystallographic Structure Determination.

The aim of the research described in this publication is two-fold. The first is a detailed description of the synthesis of a series of compounds containing a stereogenic heteroatom, namely the optically active P-stereogenic derivatives of tert-butylarylphoshinic acids bearing sulfur or selenium. The second is a detailed discussion dedicated to the determination of their structures by an X-ray analysis. Such a determination is needed when considering optically active hetero-oxophosphoric acids as new chiral solvating agents, precursors of new chiral ionic liquids, or ligands in complexes serving as novel organometallic catalysts.

Non-Invasive Assessment of Vascular Circulation Based on Flow Mediated Skin Fluorescence (FMSF).

Flow Mediated Skin Fluorescence (FMSF) is a new non-invasive method for assessing vascular circulation and/or metabolic regulation. It enables assessment of both vasoconstriction and vasodilation. The method measures stimulation of the circulation in response to post-occlusive reactive hyperemia (PORH). It analyzes the dynamical changes in the emission of NADH fluorescence from skin tissue, providing the information on mitochondrial metabolic status and intracellular oxygen delivery through the circulatory system. Assessment of the vascular state using the FMSF technique is based on three parameters: reactive hyperemia response (RHR), hypoxia sensitivity (HS), and normoxia oscillatory index (NOI). The RHR and HS parameters determine the risk of vascular circulatory disorders and are the main diagnostic parameters. The NOI parameter is an auxiliary parameter for evaluating the state of microcirculation under stress of various origins (e.g., emotional stress, physical exhaustion, or post-infection stress). The clinical data show that the risk of vascular complications is limited among people whose RHR, log(HS), and NOI parameters are not significantly below the mean values determined by the FMSF technique, especially if they simultaneously meet the conditions RHR > 30% and log(HS) > 1.5 (HS > 30), and NOI > 60%.

Enantioselective, Decarboxylative (3+2)-Cycloaddition of Azomethine Ylides and Chromone-3-Carboxylic Acids.

Herein, we describe the synthesis of a variety of chiral hybrid pyrrolidine-chromanone polycyclic derivatives. A convenient (3+2)-annulation of azomethine ylides with chromone-3-carboxylic acid realized under Brønsted base catalysis produced highly functionalized products in high yields with good stereoselectivities through asymmetric, intermolecular, and decarboxylative (3+2)-cyclization.

5-Substituted-furan-2(3H)-ones in [8 + 2]-Cycloaddition with 8,8-Dicyanoheptafulvene.

This study demonstrates the use of organocatalytic Brønsted base activation of 5-substituted-furan-2(3H)-ones to generate 2π-components for the diastereoselective [8 + 2]-cycloaddition involving 8,8-dicyanoheptafulvene as an 8π-component. The use of dienolates in a higher-order cycloaddition reaction leads to the formation of biologically relevant polycyclic products bearing a γ-butyrolactone structural motif, thus broadening the synthetic potential of Brønsted base activated higher-order cycloadditions.

Dearomative Michael addition involving enals and 2-nitrobenzofurans realized under NHC-catalysis.

In this manuscript, the first enantioselective dearomative Michael addition between α,ß-unsaturated aldehydes and 2-nitrobenzofurans realized under N-heterocyclic carbene activation has been described. The reaction proceeds via addition of homoenolate to Michael acceptors leading to the formation of biologically important heterocycles with high yields and stereoselectivities. Their functionalization potential has been confirmed in selected, diastereoselective transformations.

Enzymatic Approach to the Synthesis of Enantiomerically Pure Hydroxy Derivatives of 1,3,5-Triaza-7-phosphaadamantane.

A series of enantiomerically pure derivatives of 6-(1-hydroxyalkyl)-1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane 5 were successfully synthesized for the first time. A series of hydrolytic enzymes was applied in a stereoselective acetylation performed under kinetic resolution conditions. Although the secondary alcohols: α-aryl-hydroxymethyl-PTA (phosphines) 5b-d', PTA-oxides 8b-d', and PTA-sulfides 9b-d' were found to be totally unreactive in the presence of all the enzymes and various conditions applied, the primary alcohols, i.e., the hydroxymethyl derivatives PTA oxide 8a and PTA sulfide 9a, were successfully resolved into enantiomers with moderate to good enantioselectivity (up to 95%). The absolute configurations of the products were determined by an X-ray analysis and chemical correlation.

Asymmetric vinylogous Michael addition of 5-substituted-furan-2(3H)-ones to an α,ß-unsaturated-γ-lactam.

The manuscript describes an utilization of 5-substituted-furan-2(3H)-ones as pronucleophiles in an asymmetric vinylogous Michael addition to an α,ß-unsaturated-γ-lactam, thus leading to hybrid molecules possessing γ-lactam and butenolide structural motifs. The transformation utilizes two potentially vinylogous pronucleophiles and has been realized by simultaneous activation of both substrates by a bifunctional organocatalyst derived from a cinchona alkaloid. Reaction occurs in a highly enantio- and diastereoselective manner and the synthetic potential of the target products has been confirmed in stereoselective transformations.

Flowmotion Monitored by Flow Mediated Skin Fluorescence (FMSF): A Tool for Characterization of Microcirculatory Status.

Oscillations in the microcirculation, known as flowmotion, are a well-recognized characteristic of cutaneous blood flow. Since flowmotion reflects the microcirculatory status of the vascular system, which is very often impaired in many diseases and disorders, a quantitative assessment of skin flowmotion could potentially be used to screen for early symptoms of such conditions. In this study, skin flowmotion was monitored using the Flow Mediated Skin Fluorescence (FMSF) technique. The flowmotion parameter was used for quantitative assessment of basal flowmotion both at rest (FM) and during reperfusion [FM(R)] following the post-occlusive reactive hyperemia (PORH). The study population was composed of healthy volunteers between the ages of 30 and 72 (n = 75). The FM parameter showed an inverse dependence relative to age, while the FM(R) parameter was inversely correlated to blood pressure. The FM(R) parameter reflects the strong effect of hypoxia on flowmotion, which is mainly due to increased myogenic activity in the vessels. The FMSF technique appears to be uniquely suited for the analysis of basal flowmotion and the hypoxia response, and may be used for the characterization of microcirculatory status.

Enantioselective Synthesis of Chromanones Bearing an α,α-Disubstituted α-Amino Acid Moiety via Decarboxylative Michael Reaction.

In this manuscript, a novel, decarboxylative Michael reaction between α-substituted azlactones and chromone-3-carboxylic acids is described. The reaction proceeds in a sequence Michael addition followed by decarboxylative deprotonation, and it results in the formation of chromanones bearing an azlactone structural unit. The possibility of transforming an azlactone moiety into a protected α,α-disubstituted α-amino acid derivative is also demonstrated.

Decarboxylative, trienamine mediated cycloaddition for the synthesis of 3,4-dihydrocoumarin derivatives.

In this Communication, a new approach for trienamine chemistry is described. It is based on the application of carboxylic-acid-activated dienophiles that undergo spontaneous decarboxylative protonation after the initial [4 + 2]-cycloaddition step. The utilization of such a novel cascade reaction for the synthesis of biologically relevant 3,4-dihydrocoumarins has been demonstrated. High levels of enantiocontrol and excellent yield of the cascade reaction have been achieved by the use of diphenylprolinol diphenylmethylsilyl ether.

Captopril and its dimer captopril disulfide: comparative structural and conformational studies.

The crystal structures of captopril {systematic name: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid}, C(9)H(15)NO(3)S, (1), and its dimer disulfide metabolite, 1,1'-{disulfanediylbis[(2S)-2-methyl-1-oxopropane-3,1-diyl]}bis-L-proline, C(18)H(28)N(2)O(6)S(2), (2), were determined by single-crystal X-ray diffraction analysis. Compound (1) crystallizes in the orthorhombic space group P2(1)2(1)2(1), while compound (2) crystallizes in the monoclinic space group P2(1), both with one molecule per asymmetric unit. The molecular geometries of (1) and (2) are quite similar, but certain differences appear in the conformations of the five-membered proline rings and the side chains containing the sulfhydryl group. The proline ring adopts an envelope conformation in (1), while in (2) it exists in envelope and slightly deformed half-chair conformations. The conformation adopted by the side chain is extended in (1) and folded in (2). A minimum-energy conformational search using Monte Carlo methods in the aqueous phase reveals that the optimized conformations of the title compounds differ from those determined crystallographically, which depend on their immediate environment. Intermolecular O-H...O and relatively weak C-H...O interactions seem to be effective in both structures and, together with S-H...O and C-H...S contacts, they create three-dimensional networks.

New enantiomeric fluorine-containing derivatives of sulforaphane: synthesis, absolute configurations and biological activity.

Three pairs of enantiomers of the unknown sulforaphane analogs bearing organofluorine substituents bonded to the sulfinyl sulfur atom and having different number of methylene groups in the central carbon chain were synthesized and fully characterized, including determination of their absolute configurations. All the new compounds were tested in vitro for their cytotoxicity against melanoma cells to show increased activity in comparison with the natural sulforaphane. The influence of the particular structural changes in the molecule on the cytotoxicity is discussed.

Three new olanzapine structures: the acetic acid monosolvate, and the propan-2-ol and propan-2-one hemisolvate monohydrates.

The crystal structures of three new solvates of olanzapine [systematic name: 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno[2,3-b][1,5]benzodiazepine], namely olanzapine acetic acid monosolvate, C17H20N4S·C2H4O2, (I), olanzapine propan-2-ol hemisolvate monohydrate, C17H20N4S·0.5C3H8O·H2O, (II), and olanzapine propan-2-one hemisolvate monohydrate, C17H20N4S·0.5C3H6O·H2O, (III), are presented and compared with other known olanzapine forms. There is a fairly close resemblance of the molecular conformation for all studied analogues. The crystal structures are built up through olanzapine dimers, which are characterized via C-H...π interactions between the aliphatic fragment (1-methylpiperazin-4-yl) and the aromatic fragment (benzene system). All solvent (guest) molecules participate in hydrogen-bonding networks. The crystal packing is sustained via intermolecular N(host)-H···O(guest), O(guest)-H···N(host), O(guest)-H···O(guest) and C(host)-H···O(guest) hydrogen bonds. It should be noted that the solvent propan-2-ol in (II) and propan-2-one in (III) show orientational disorder. The propan-2-ol molecule lies close to a twofold axis, while the propan-2-one molecule resides strictly on a twofold axis through the carbonyl C atom. In both cases, the water molecules present positional disorder of the H atoms.

An orthorhombic polymorph of a cyclization product of perindopril.

Low-temperature X-ray diffraction experiments were employed to investigate the crystal structures of an orthorhombic polymorph of the intramolecular cyclization product of perindopril, a popular angiotensive-converting enzyme (ACE) inhibitor, namely ethyl (2S)-2-[(3S,5aS,9aS,10aS)-3-methyl-1,4-dioxo-5a,6,7,8,9,9a,10,10a-octahydro-3H-pyrazino[1,2-a]indol-2-yl]pentanoate, C19H30N2O4, (Io), and its tetragonal equivalent, (It), which was previously reported at ambient temperature [Bojarska et al. (2013). J. Chil. Chem. Soc. 58, 1415-1417]. Polymorph (Io) crystallizes in the orthorhombic space group P2(1)2(1)2(1) with two molecules in the asymmetric unit, while tetragonal form (It) crystallizes in the space group P4(1)2(1)2 with one molecule in the asymmetric unit. The geometric parameters of (Io) are very similar to those of (It). The six-membered rings in both polymorphs adopt a slightly deformed chair conformation and the piperazinedione rings are in a boat conformation. However, the proline rings adopt an envelope conformation in (Io), while in (It) the ring exists in a slightly deformed half-chair conformation. The most significant difference between the two structures is the orientation of the ethyl pentanoate chain. Molecules associate in pairs in a head-to-tail manner forming infinite columns. In (Io), molecules are related by a twofold screw axis forming identical columns, while in (It), molecules in successive neighbouring columns are related by alternating twofold screw axes and fourfold screw axes. In both cases, the crystal packing is stabilized by weak intermolecular C-H···O interactions only.

Perindoprilat monohydrate.

The title compound [systematic name: (1S)-2-((S)-{1-[(2S,3aS,7aS)-2-carboxyoctahydro-1H-indol-1-yl]-1-oxopropan-2-yl}azaniumyl)pentanoate monohydrate], C(17)H(28)N(2)O(5)·H(2)O, (I)·H(2)O, the active metabolite of the antihypertensive and cardiovascular drug perindopril, was obtained during polymorphism screening of perindoprilat. It crystallizes in the chiral orthorhombic space group P2(1)2(1)2(1), the same as the previously reported ethanol disolvate [Pascard, Guilhem, Vincent, Remond, Portevin & Laubie (1991). J. Med. Chem. 34, 663-669] and dimethyl sulfoxide hemisolvate [Bojarska, Maniukiewicz, Sieron, Fruzinski, Kopczacki, Walczynski & Remko (2012). Acta Cryst. C68, o341-o343]. The asymmetric unit of (I)·H(2)O contains one independent perindoprilat zwitterion and one water molecule. These interact via strong hydrogen bonds to give a cyclic R(2)(2)(7) synthon, which provides a rigid molecular conformation. The geometric parameters of all three forms are similar. The conformations of the perhydroindole group are almost identical, but the n-alkyl chain has conformational freedom. A three-dimensional hydrogen-bonding network of O-H···O and N-H···O interactions is observed in the crystal structure of (I)·H(2)O, similar to the other two solvates, but because of the presence of different solvents the three crystal structures have diverse packing motifs. All three solvatomorphs are additionally stabilized by nonclassical weak C-H···O contacts.

Novel pseudopolymorph of the active metabolite of perindopril.

The dimethyl sulfoxide hemisolvate of perindoprilat [systematic name: (1S)-2-((S)-{1-[(2S,3aS,7aS)-2-carboxyoctahydro-1H-indol-1-yl]-1-oxopropan-2-yl}azaniumyl)pentanoate dimethyl sulfoxide hemisolvate], C(17)H(28)N(2)O(5)·0.5C(2)H(6)OS, an active metabolite of perindopril, has been synthesized, structurally characterized by single-crystal X-ray diffraction and compared with its ethanol disolvate analogue [Pascard et al. (1991). J. Med. Chem. 34, 663-669]. Both compounds crystallize in the orthorhombic P2(1)2(1)2(1) space group in the same zwitterionic form, with a protonated alanine N atom and an anionic carboxylate group at the n-alkyl chain. The three structural units present in the unit cell (two zwitterions and the solvent molecule) are held together by a rich system of O-H···O, N-H···O and C-H···O hydrogen-bond contacts.

Four- and five-coordinate copper(II) complexes with N-(4,4-diphenyl-5-oxo-4,5-dihydro-1H-imidazol-2-yl)glycine.

The two title mononuclear compounds are four-coordinate bis[N-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazolidin-2-ylidene)glycinato]copper(II) dimethylformamide disolvate, [Cu(C(17)H(14)N(3)O(3))(2)].2C(3)H(7)NO, (I), and five-coordinate aquabis[N-(5-oxo-4,4-diphenyl-4,5-dihydro-1H-imidazolidin-2-ylidene)glycinato]copper(II) dimethylformamide disolvate, [Cu(C(17)H(14)N(3)O(3))(2)(H(2)O)].2C(3)H(7)NO, (II). In (I), the Cu(II) ion lies on an inversion centre with one-half of the complex molecule in the asymmetric unit, while in (II) there are two independent ligand molecules in the asymmetric unit, with the Cu(II) ion and coordinated water molecule located on a general position. In both crystal structures, the complex molecules assemble in ribbons via N-H...O hydrogen-bond networks.

tert-Butyl N-[(S)-3-isopropyl-2-oxo-oxetan-3-yl]carbamate.

The structure of the title compound, C(11)H(19)NO(4), contains two crystallographically independent mol-ecules in the asymmetric unit. Both adopt the same conformation and they form pseudosymmetric R(2) (2)(8) dimers via two N-H⋯O hydrogen bonds. The dimers are linked by weak C-H⋯O inter-actions and are stacked in columns along the a axis.

Bis(2-amino-2-thiazolinium) tetra-mu-formato-kappa8O:O'-bis[(formato-kappaO)copper(II)].

In the title dimeric compound, (C(3)H(7)N(2)S)2[Cu(2)(CHO(2))6], each Cu(II) atom has a square-pyramidal coordination, with the nonbridging formate ion at the apical position. The complex anion is located on a crystallographic inversion centre, with a Cu...Cu separation of 2.6566 (4) A. 2-Amino-2-thiazolinium cations connect complex anions via hydrogen bonds to form a ribbon running along the a axis.

Poly[bis-(µ(2)-formato-κO:O')(quinoxaline-κN)copper(II)].

In the polymeric title copper(II) compound, [Cu(CHO(2))(2)(C(8)H(6)N(2))](n), both formato ligands are O-bidentate anions and act as bridging ligands, creating a planar polymeric arrangement. The slightly distorted square-pyramidal coordination around Cu(II) comprises four O atoms from two different formate anions as the base and a quinoxaline mol-ecule in the apical position.