Degree Of Stereoselectivity Research Articles

Modulating stereoselectivity in allylic C(sp3)-H bond arylations via nickel and photoredox catalysis

While significant progress has been made in developing selective C-H bond cross-couplings in the field of radical chemistry, the site and stereoselectivity remain a long-standing challenge. Here, we present the successful development of stereodivergent allylic C(sp3)-H bond arylations through a systematic investigation of the direction and degree of stereoselectivity in the cross-coupling process. In contrast to the signature photosensitized geometrical isomerization of alkenes, the catalytic reaction demonstrates the feasibility of switching the C-C double bond stereoselectivity by means of ligand control as well as steric and electronic effects. Computational studies explain the stereochemical outcome and indicate that excitation of a Ni-allyl complex from singlet to a triplet state results in a spontaneous change of the allyl group coordination and that the subsequent isomerization can be directed by the choice of the ligand to achieve E/Z selectivity.

Chemoselective Flow Hydrogenation Approaches to Diversify the Cytotoxic Tetrahydroepoxyisoindole Carboxamide Scaffold

AbstractAn Intramolecular Diels‐Alder cycloaddition reaction between a furan diene and an alkynic dienophile was performed within a flow hydrogenator fitted with an inert titanium column at 150 °C, no H2, under 100 bar pressure. A single column pass (tR=1.6 min) afforded ≈55% conversion to the tetrahydroepoxyisoindole carboxamide scaffold with a product turnover of ≈0.035 g/h, a 95% improvement over batch procedures. The cycloaddition protocol is performed in water and ethanol, and does not require catalysts or other additives. Quantitative hydrogenation of the resulting dual π‐bonds within the oxabicyclo system was effected with either a 10% Pd/Al2O3 or 10% Pd/CaCO3 catalyst at 20 °C, 20 bar, with full H2 whereas utilisation of a Raney Ni catalyst under these conditions resulted in a quantitative mono‐olefin reduction of the C4‐C5 double‐bond. With regard to di‐olefin reduction, a degree of stereoselectivity was observed with the aforementioned palladium‐based catalysts yielding exclusive formation of (R) configuration at C7 while utilisation of a 5% Pt/C (sulfided) catalyst at temperatures below 60 °C promoted the formation of the (S)‐isomer at C7. Hence this work further highlights that flow‐hydrogenation provides unprecedented convenience for establishing robust protocols to effect chemoselective transformations.magnified image

Chiral Bistacrine Analogues: Synthesis, Cholinesterase Inhibitory Activity and a Molecular Modeling Approach

Cholinesterase enzymes are important targets for the therapy of Alzheimer’s disease. Tacrine-based dual binding site cholinesterases inhibitors are potential disease-modifying anti-Alzheimer drug candidates. In the present work, we described the synthesis of a series of chiral homo- and heterodimers of bis(7)-tacrine connected by a heptylene chain as a spacer with the methyl substituent at the C-3 position of the alicyclic region of tacrine nucleus and/or a chlorine atom attached to the C-6. Friedlander cyclocondensation between (R) or (S) 3-methylcyclohexanone prepared from monoterpene pulegone and o-aminobenzoic acids in the presence of POCl3 afford 9-chloroacridines as intermediates, which were used to the synthesis of homo- and heterodimers. All compounds demonstrated to be potent inhibitors of acetylcholinesterase (AChE) at low nanomolar concentration and showed selectivity for AChE over butyrylcholinesterase (BuChE). Furthermore, the affinity difference between enantiomeric bis(7)-tacrine analogues series indicated some degree of stereoselectivity in the active site of AChE for chiral bis-cognitin compounds.

ChemInform Abstract: Lithium Borohydride for Achiral and Stereospecific Reductive Boronation at Phosphorus: Lack of Electronic Effects on Stereoselective Formation of Alkoxyphosphonium Salts.

We report LiBH4 as a preferred, simple and effective reagent for reductive boronation of achiral and racemic chlorophosphonium salts (CPS) and for diastereomeric alkoxyphosphonium salts (DAPS), both of which are, in turn, easily generated from either the corresponding phosphane or, more conveniently, the phosphane oxide. Further, we have shown that the DAPS reduction/boronation could be achieved with complete stereocontrol to give scalemic phosphane–borane directly in excellent yield and enantiomeric excess (ee). This new methodology was employed to investigate the effects of aryl substitution on the outcome of dynamic kinetic resolution of arylmethylphenylphosphanes and phosphane oxides via DAPS. It was found that substitution at the ortho position strongly affects the degree of stereoselection. However, surprisingly, we confirmed that there was no variation of stereoselectivity seen with the electronic effect of substituents on the para position.

ChemInform Abstract: Organocatalyzed Cascade Reactions of Carbohydrates — A Direct Access to C‐Glycosides.

AbstractAn organocatalytic transformation to elongate carbohydrates is reported.

Indirect N-vinylation of indoles via isomerisation of N-allyl derivatives: synthesis of (±)-debromoarborescidine B

Abstract Double bond migration in N -allylindoles has been investigated as a method to access N -vinyl derivatives of this heterocycle. The optimal reaction conditions employed t -BuOK or NaH in DMSO as the solvent at room temperature to afford the products in yields ranging from 51 to 99%. Although in some cases a high degree of stereoselectivity was observed, preferential formation of either the Z - or E -isomer was not predictable. The developed methodology was employed in the synthesis of (±)-debromoarborescidine B.

Synthesis, characterization and X-ray structures of enatiopure-diamine zinc(II) complexes as pre-catalysts for stereoselective production of poly(rac-lactide)

Two novel dichlorozinc complexes, (peeda)ZnCl2 and (pepda)ZnCl2, where peeda is N1,N2-bis{(R)-1-phenylethyl}ethane-1,2-diamine and pepda is N1,N3-bis{(R)-1-phenylethyl}propane-1,3-diamine, were synthesised and characterised by X-ray diffraction. Dialkyl derivatives of these compounds, generated in situ, efficiently initiated the ring-opening polymerisation (ROP) of rac-lactide (rac-LA). The backbone links, composed of diamine units, had a significant influence on the degree of stereoselectivity in the resulting heterotactic polylactide (PLA). Increased flexibility of the diamine backbone resulted in enhanced heterotacticity. (pepda)ZnMe2 produced heterotactic PLA with a Pr of 0.78 at −25°C.

High Carbon Ash from Stoker Fired Boiler of a Thermal Power Station as Support in the Reduction of Ketones: A Novel Application

Reduction of a few substituted cyclohexanones adsorbed on size classified high carbon ash fractions from a stoker fired boiler of a thermal power station using NaBH4 as the reducing agent with ethanol as the medium resulted in the formation of two epimeric alcohols. However, trans-4-t-butyl and trans-4-methylcyclohexanols are exclusively formed when the corresponding ketones adsorbed on one particular size classified ash fraction are reduced with NaBH4. In all other cases, a fairly high degree of stereoselectivity has been obtained. It has been observed that low carbon ash does not activate the ketones towards similar stereoselectivity, clearly establishing that the high carbon ash has a definite role to play. The stereochemical outcome of the reductions has been rationalized on the basis of a probable transition state involving Lewis/Br⊘nsted acid sites present in the ash. Mesopores and macropores present in the ash are most likely to act as pockets for adsorption of ketones. Product analysis has been carried out using 1HNMR and 13CNMR.

Synthesis of methyl 9-(benzo[d][1,3]dioxol-5-yl)-12-aryl(heteryl, cyclohexenyl)-11-oxo-7,8,9,10,11,12-hexahydrobenzo[b][4,7]phenanthroline-10-carboxylates

By condensation of 6-aminoquinoline with methyl 2-(benzo[d][1,3]dioxol-5-yl)-4,6-dioxocyclohexanecarboxylate and aldehydes of aromatic, heteroaromatic, and cyclohexene series new 4,7-phenanthroline derivatives were synthesized. The reaction performed in 1-butanol proceeded regiospecifically and with a moderate degree of stereoselectivity resulting in a mixture of cis- and trans-methyl 9-(benzo-[d][1,3] dioxol-5-yl)-12-aryl(heteryl, cyclohexenyl)-11-oxo-7,8,9,10,11,12-hexahydrobenzo-[b][4,7]-phenanthroline-10-carboxylates (∼30: 70).

Stereoselective reduction of the active substance of the medicinal preparation dimeb n to the corresponding cis- and trans-1,2,3,4,4a,9b-hexahydro derivatives

Convenient preparative methods have been developed for the reduction of the active substance of the medicinal preparation Dimebon (2,8-dimethyl-5-[2-(6-methylpyrid-3-yl)ethyl]-1,2,3,4-tetrahydro-γ-carboline) to the corresponding racemic cis- and trans-1,2,3,4,4a,9b-hexahydro derivatives, distinguished by a high degree of stereoselectivity. The structures of the obtained diastereomeric hexahydro-γ-carbolines were confirmed by various physicochemical methods, including X-ray structural analysis.

Cyclopentanones Stereochemistry of the Lithium-Liquid Ammonia Reduction of 2, 3-Dialkyl-5-Hydroxy-2-Cyclopentenones

The stereochemistry of the lithium-liquid ammonia reduction of 2, 3-dimethyl-5-hydroxy-2-cyclopentenone (1) and 3-t.butyl-2-methyl-5-hydroxy-2-cyclopentenone (2) is studied in function of a set of proton donors. A high degree of stereoselectivity is observed as practically only two (predominantly one isomer) out of the eight diastereoisomeric 3, 4-dialkyl-1, 2-cyclopentane diols 3 or 4 are formed.

P‐Stereogenic Phosphorus Compounds: Effect of Aryl Substituents on the Oxidation of Arylmethylphenylphosphanes under Asymmetric Appel Conditions

AbstractThe effects of aryl ring substitution on the dynamic resolution of aryl(methyl)phenylphosphanes under asymmetric Appel reaction conditions have been studied. As expected, substitution at the ortho position strongly affects the degree ofstereoselection that can be achieved. Unexpectedly, however, there was no variation of stereoselectivity with the electronic nature of the para substituents, which suggests that there are two selection processes in operation. An unusual halogen‐exchange process was observed in the arylphenylphosphinous chlorides on route to the required tertiary phosphane substrates.

ChemInform Abstract: Enantiomers of the Muscarinic Antagonist 1-Cyclohexyl-1-(4- fluorophenyl)-4-piperidino-1-butanol (p-Fluoro-hexahydro-difenidol): Synthesis, Absolute Configuration, and Enantiomeric Purity.

The enantiomers of the antimuscarinic agent 1-cyclohexyl-1-(4-fluorophenyl)-4-piperidino-1-butanol [(R)- and (S)-p-fluorohexahydro-difenidol] [(R)- and (S)-2a] and their methiodides (R)-3 and (S)-3 were prepared with high enantiomeric purity. (R)-2a and (S)-2a (isolated as hydrochlorides) were obtained by catalytic hydrogenation (Pd/C contact) of the corresponding enantiomers of 1-cyclohexyl-1-(4-fluorophenyl)-4-piperidino-2-butyn-1-ol [(R)- and (S)-4]. Reaction of (R)-2a and (S)-2a with methyl iodide led to (R)-3 and (S)-3, respectively. The unsaturated precursors (R)- and (S)-4 (enantiomeric purity ⩾99.80 and ⩾99.94% e.e.; calorimetric analysis) were prepared by resolution of rac-4 [available from 4-FC6H4C(O)C6H11 by reaction with LiCCCH2NC5H10] using (R)- and (S)-mandelic acid as resolving agents. The absolute configurations of the (R) and (S) enantiomers of 2a, 3, and 4 were determined by an X-ray crystal-structure analysis of (S)-5, the methiodide of (S)-4. (R)-2a and (R)-3 exhibit a higher affinity for muscarinic M1, M2, M3, and M4 receptors (by up to two orders of magnitude) than their corresponding antipodes (S)-2a and (S)-3, the degree of stereoselectivity depending on the receptor subtype involved. (R)-2a represents a useful tool for muscarinic receptor research (affinity profile: M1 ≈ M3 ≈ M4 > M2).

ChemInform Abstract: Silicon-Mediated Isoquinoline Synthesis: Preparation and Stereochemical Characterization of 4-Hydroxy-3-phenylisoquinolines.

Abstract The silicon-mediated synthesis of 4-hydroxy-6,7-dimethoxy-3-phenylisoquinoline derivatives is reported. The described procedure implies synthetically useful yields and a high degree of stereoselectivity.

Transcription of Chirality in the Organogel Systems Dictates the Enantiodifferentiating Photodimerization of Substituted Anthracene

An organogelator (G) that contains 2-anthracenecarboxylic acid (2Ac) attached covalently to a gelator counterpart that consists of 3,4,5-tris(n-dodecan-1-yloxy)benzoic acid by means of a chiral amino alcohol linkage has been synthesized. G acts as an efficient gelator of organic solvents, including mixed solvents and chiral solvents. Photodimers isolated after the photoreaction of the gel samples display different degrees of stereoselectivity. In the gel state, the formation of head-to-head (h-h) photodimers is always favored over head-to-tail (h-t) photodimers. Enantiomeric excess (ee) values of the major h-h photodimers reached as high as -56% in the case of the gels with enantiomeric glycidyl methyl ethers. Here, the solvent chirality is outweighed by the intrinsic chirality of the gelator molecule. The packing of the chromophore in the gel state has been characterized by the absorption and the emission behaviors and their variations during the course of gel-to-sol phase transition. Whereas for the hexane gel, emission intensity increases with an increase in temperature, other systems show a decrease in emission intensity. Redshift of the lambda(max) in the gel spectra indicates the J-aggregate arrangement of the chromophores. Chiral transcription in the gel state has been investigated by CD spectroscopy, which shows a decrease in CD intensity during the gel-to-sol phase transition. The X-ray diffraction study clearly differentiates among the gels in terms of the order of molecular arrangements. The gel systems are categorized as strong, moderately strong, and weak, that originate from the cooperative or individual participations of intermolecular hydrogen-bonding and pi-pi interactions, fine-tuned by the solvent polarity and the gelation temperature. A simple model based on the experimental findings and the molecular preorientation as evidenced by the stereochemistry of the photodimers has been proposed.

Synthesis of (−)-conocarpan by two routes based on radical cyclization and establishment of its absolute configuration

Two independent routes for the total synthesis of the bioactive neolignan (-)-conocarpan are described. The first (98% ee) is based on formal radical cyclization onto a benzene ring, and involves a 5-exo-trigonal closure onto a double bond restrained within a 6-membered ring. The second route (88% ee), which is shorter, is based on 5-exo-trigonal cyclization of an aryl radical onto a pendant terminal double bond. The two routes differ in their degree of stereoselectivity. The absolute configuration originally assigned to (+)-conocarpan had previously been called into question on the basis of empirical chiroptical rules; the present chemical work confirms the need for revision, and the assigned absolute configurations of several compounds correlated with (+)-conocarpan must also be changed.

Synthetic approaches towards a new class of strained "lactenediynes"

The paper described two alternative synthetic approaches towards a new class of strained “lactenediynes”, compounds where a 10-membered enediyne ring is fused with a β-lactam. Although the two alternative syntheses were successful up to the last step, the cyclization to give the desired products failed in both cases, probably because of excessive steric strain in the products. In one of the two approaches (which was the most efficient one in terms of overall yield) a mixture of diastereoisomeric cyclodimers was isolated in moderate yield. A certain degree of stereoselectivity was observed. These compounds may be interesting as new supramolecular systems.

Study on Synthesis of Thebaine Derivatives

The reaction of 7α-acetyl-6,14-endoethano-6,7,8,14-tetrahydrothebaine with 2-(thien-2-yl)ethylmagnesium bromide was investigated. The tertiary alcohol derivative 7α-[R-1-hydroxyl-1-methyl-3-(thien-2-yl)propyl])-6,14-endoethano-6,7,8,14-tetrahydrothebaine (3) and a by-product 4 were isolated. The structure of 4 was elucidated by X-ray analysis. The Grignard reaction shows high degree of stereoselectivity according with Cram rule. The crystal structure of 4 indicates that dihydrofuran ring was opened to form a phenolic hydroxyl group and a three-membered ring structure. It maintains the main rigid structure of morphine and contains a C(6)-C(14) enthano bridge. The 1-hydroxyl-1-methyl-3-(thien-2-yl)propyl group at C(7) position adopted S-configuration.

Novel Multichiral Diols and Diamines by Highly Stereoselective Pinacol Coupling of Planar Chiral [2.2]Paracyclophane Derivatives

The TiCl4/Zn-mediated intermolecular pinacol coupling of the planar chiral carbonyl compounds [2.2]paracyclophane-4-carbaldehyde, 4-acetyl[2.2]paracyclophane (ketone) and the four regioisomeric 5-, 7-, 12- and 13-methoxy[2.2]paracyclophane-4-carbaldehydes as well as the pTosOH-Zn/Cu-promoted coupling of their N-substituted imines is described. Coupling of the enantiomerically pure substrates (most of carbonyl compounds and all imines) occurs stereoselectively giving rise to diastereomerically pure 1,2-diols and 1,2-diamines. Racemic aldehydes and ketone react with different degrees of stereoselectivity (depending on the substituents in certain positions) and produce one to three diastereomers. 7-methoxy[2.2]paracyclophane-4-carbaldehyde undergoes a tandem pinacol coupling-pinacol rearrangement to yield bis-(7-methoxy[2.2]paracyclophane-4-yl)acetaldehyde. Coupling of the racemic imines produces a mixture of single racemic D,L-diamine and single meso-diamine in each case. The stereoselective formation of the asymmetric centres is governed by the planar chiral [2.2]paracyclophanyl moiety. The techniques elaborated are extended to the intramolecular coupling of [2.2]paracyclophane-4,13-dicarbaldehyde and its bis-N-phenylimine, resulting in stereoselective formation of the chiral triply-bridged diol and exclusive formation of the meso-diamine. X-Ray investigations of several diols and diamines have been carried out and the structural features of these derivatives are discussed.

Molecular Mechanisms Underlying Ketamine-mediated Inhibition of Sarcolemmal Adenosine Triphosphate-sensitive Potassium Channels

Ketamine inhibits adenosine triphosphate-sensitive potassium (KATP) channels, which results in the blocking of ischemic preconditioning in the heart and inhibition of vasorelaxation induced by KATP channel openers. In the current study, the authors investigated the molecular mechanisms of ketamine's actions on sarcolemmal KATP channels that are reassociated by expressed subunits, inwardly rectifying potassium channels (Kir6.1 or Kir6.2) and sulfonylurea receptors (SUR1, SUR2A, or SUR2B). The authors used inside-out patch clamp configurations to investigate the effects of ketamine on the activities of reassociated Kir6.0/SUR channels containing wild-type, mutant, or chimeric SURs expressed in COS-7 cells. Ketamine racemate inhibited the activities of the reassociated KATP channels in a SUR subtype-dependent manner: SUR2A/Kir6.2 (IC50 = 83 microM), SUR2B/Kir6.1 (IC50 = 77 microM), SUR2B/Kir6.2 (IC50 = 89 microM), and SUR1/Kir6.2 (IC50 = 1487 microM). S-(+)-ketamine was significantly less potent than ketamine racemate in blocking all types of reassociated KATP channels. The ketamine racemate and S-(+)-ketamine both inhibited channel currents of the truncated isoform of Kir6.2 (Kir6.2DeltaC36) with very low affinity. Application of 100 mum magnesium adenosine diphosphate significantly enhanced the inhibitory potency of ketamine racemate. The last transmembrane domain of SUR2 was essential for the full inhibitory effect of ketamine racemate. These results suggest that ketamine-induced inhibition of sarcolemmal KATP channels is mediated by the SUR subunit. These inhibitory effects of ketamine exhibit specificity for cardiovascular KATP channels, at least some degree of stereoselectivity, and interaction with intracellular magnesium adenosine diphosphate.