Stereogenic Carbon Atom Research Articles

Intramolecular Diastereoselective Cascade Cyclization Reaction of N,N′-Bis(Salicylidene)Cyclohexanediimine with Phosphoryltrichloride to a Bis(Chlorophosphorylated) Decahydro-2,4-DI (2-Hydroxyphenyl)Benzo[d][1,3,6]oxadiazepine

A new type of cascade cyclization was observed in the phosphorylation reaction of (R,R)- or (S,S)-N,N′-bis(salicylidene)cyclohexanediimine with phosphoryltrichloride, which resulted in the formation of bis(chlorophosphorylated) decahydro-2,4-di(2-hydroxyphenyl)benzo[d][1,3,6]oxadiazepine with two new stereogenic phosphorus atoms and two new stereogenic carbon atoms in the oxadiazepine ring in the β-position to phosphorus. During the synthesis, the N atom attacks the phosphorodichloridate group with the formation of the P–N bond to give an asymmetric phosphorus atom and an iminium ion. This compound with six stereogenic centers crystallizes in the monoclinic centrosymmetric space group P21/c and the crystal structure together with solution and solid-state MAS 13C and 31P NMR studies reveals a preferential formation of stereoisomers.

Reductive Labilization of a Cyclometalating Ligand Applied to Auxiliary-Mediated Asymmetric Coordination Chemistry

(4S)-4-Isopropyl-2-(3-nitrophenyl)-4,5-dihydrooxazole ((S)-Phox) is introduced as a novel chiral auxiliary for the asymmetric synthesis of ruthenium polypyridyl complexes. A simply accessible (S)-Phox-bearing precursor serves as the starting point for diastereoselective coordination chemistry: The stereogenic carbon atom of the cyclometalating auxiliary controls the spatial arrangement of incoming 1,10-phenanthrolines during ligand substitution reactions (ratio Λ:Δ up to 14:1), and further precipitation affords diastereopure compounds. In the following key step, the labilization of the auxiliary ligand is achieved by reduction, thus permitting its replacement against a third polypyridyl ligand with complete retention of the configuration at the metal center (er > 99:1) under mildly acidic conditions, in contrast with previously developed systems that require strong acid. On the basis of results of NMR experiments and X-ray analysis obtained for intermediate compounds, mechanistic considerations for the formation of diastereomeric complexes were made, revealing a Δ → Λ isomerization as the reason for the observed limitations in selectivity optimization. This work expands the pool of methods available for the asymmetric synthesis of tris-heteroleptic ruthenium polypyridyl complexes and additionally may serve as an inspiration for the synthesis of other nonracemic octahedral chiral-at-metal compounds.

Synthesis of cis-Octahydroindoles via Intramolecular 1,3-Dipolar Cycloaddition of 2-Acyl-5-aminooxazolium Salts

A concise method for the diastereoselective synthesis of octahydroindoles is presented. The products contain 2-amido and 7-hydroxyl substituents. A series of 2-acyl-5-aminooxazoles were prepared in one step. Upon methylation of the oxazole nitrogen atom, the substrates underwent rapid intramolecular 1,3-dipolar cycloaddition with a tethered alkene and, after reduction with excess hydride, produced octahydroindoles with excellent diastereoselectivity. The method allows for the installation of α-quaternary stereogenic carbon atoms.

Hydrolysis of Fatty Acid Esters by Candida Antarctica Lipase B (Novozym 435) Dissolved in Anhydrous Triethylamine

AbstractEnzyme‐catalyzed stereoselective esterification of OH groups in non‐aqueous media has been widely used for kinetic racemate resolution. However, rapid hydrolysis of the ester group was observed as a competing reaction if we attempted to resolve 3‐hydroxy octanoic acid methyl ester with Novozym 435 in a non‐aqueous medium with a catalytic amount of the base triethylamine. This hydrolysis away from the stereogenic carbon atom showed stereoselectivity, thus the preparative value of this reaction was inspected closer and it could be extended to higher homologues. 3‐Hydroxy decanoic acid methyl ester, 3‐hydroxy dodecanoic acid methyl ester and 3‐hydroxy tetradecanoic acid methyl ester were also hydrolyzed by Novozym 435 with enhanced reaction rates and moderate selectivities if dissolved in triethylamine. Ethyl mandelate and ethyl lactate were also converted under these conditions. The same phenomenon could also be observed with a 2 % DABCO solution in hexane, whereas secondary amines, for example piperidine, did not influence the reaction.

Rac-Methyl 3-(2-methoxyphenyl)-1-phenyl-3,3a,4,9b-tetrahydro-1H-chromeno[4,3-c]isoxazole-3a-carboxylate

The title compound, C25H23NO5, comprising two stereogenic carbon atoms of the same configuration, crystallizes in a centrosymmetric space group as a racemate. The six-membered pyran ring and the five-membered isoxazole ring adopt sofa and twisted conformations, respectively. The dihedral angle between the benzene ring and the mean plane through the near coplanar atoms of the pyran ring is 10.73 (7)°. The crystal structure features C—H⋯O hydrogen bonds.

The optical activity of carvone: A theoretical and experimental investigation

The optical rotatory dispersion (ORD) and circular dichroism of the conformationally flexible carvone molecule has been investigated in 17 solvents and compared with results from calculations for the "free" (gas phase) molecule. The G3 method was used to determine the relative energies of the six conformers. The optical rotation of (R)-(-)-carvone at 589 nm was calculated using coupled cluster and density functional methods, including temperature-dependent vibrational corrections. Vibrational corrections are significant and are primarily associated with normal modes involving the stereogenic carbon atom and the carbonyl group, whose n → π∗ excitation plays a significant role in the chiroptical response of carvone. Without the inclusion of vibrational corrections the optical rotation calculated with CCSD and DFT has the opposite sign of experimental data. Calculations of optical rotation performed in solution using the polarizable continuum model were also opposite in sign when compared to that of the experiment.

Vibrational Circular Dichroism: A Valuable Tool for Conformational Analysis and Absolute Configuration Assignment of Chiral 1‐Aryl‐2,2,2‐Trifluoroethanols

Vibrational circular dichroism spectra allow one to assign the absolute configuration and to monitor the conformational equilibria related to CF3⋅⋅⋅OH hydrogen bonding of [2.2]paracyclophane with an external stereogenic carbon atom bearing CF3, OH and H (see picture). Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

(8aRS)-8,8a-Dihydrofuro[3,2-f]indolizine-6,9(4H,7H)-dione

The title compound, C10H9NO3, is a chiral mol­ecule with one stereogenic carbon atom, but which crystallizes as a racemate in the centrosymmetric space group P21/n. The central six-membered ring of the indolizine moiety adopts a definite envelope conformation, while the conformation of the oxopyrrolidine ring is close to that of a flat-envelope with a maximum deviation of 0.352 (1) Å for the flap atom.

Stabilizing Effect of Propionic Acid Derivative of Anthraquinone–Polyamine Conjugate Incorporated into α–β Chimeric Oligonucleotides on the Alternate-Stranded Triple Helix

Two types of anthraquinone conjugates were synthesized as non-nucleosidic oligonucleotide components. These include an anthraquinone derivative conjugated with 2,2-bis(hydroxymethyl)propionic acid and an anthraquinone--polyamine derivative conjugated with 2,2-bis(hydroxymethyl)propionic acid. The conjugates were successfully incorporated into the "linking-region" of the α-β chimeric oligonucleotides via phosphoramidite method as non-nucleosidic backbone units. The resultant novel α-β chimeric oligonucleotides possessed two diastereomers that were generated by the introduction of the anthraquinone conjugate with a stereogenic carbon atom. The isomers were successfully separated by a reversed-phase HPLC. UV-melting experiments revealed that both stereoisomers formed a substantially stable alternate-strand triple helix, irrespective of the stereochemistry of the incorporated non-nucleosidic backbone unit. However, the enhancing effect on thermal stability depended on the length of the alkyl linker connecting anthraquinone moiety and the propionic acid moiety. The sequence discrimination ability of the chimeric oligonucleotides toward mismatch target duplex was also examined. The T(m) values of the triplexes containing the mismatch target were substantially lower than the T(m) values of those containing the full-match target. The thermodynamic parameters (ΔH°, ΔS°, and ΔG°) required for the dissociation of the triplexes into the third strand and target duplex were also measured.

6-[Bis(ethoxycarbonyl)methyl]-6-deoxy-1,2;3,4-di-O-isopropylidene-D-galactopyranose

The title compound, C19H30O9, was prepared by substitution at the C6 position in 1,2;3,4-di-O-isopropyl­idene-6-O-trifluoro­methane­sulfonyl-d-galactose using sodium eth­oxy­malonate in dimethyl­formamide. The conformation is skew-boat 0 S 2, slightly distorted towards boat B 2,5. The inflexible pyran­ose structure makes the title compound a suitable inter­mediate for further synthetic work by keeping stereogenic carbon atoms safe from inversion. Several short intra­molecular C—H⋯ O contacts may stabilize the conformation of the mol­ecule. Inter­molecular C—H⋯O inter­actions also occur.

ChemInform Abstract: Chiral Ammonium Betaines as Ionic Nucleophilic Catalysts.

AbstractChiral betaine NAB is a highly enantioselective catalyst for the Steglich rearrangement of oxazolyl trichloroethyl carbonates (I) providing oxazolones bearing a quaternary stereogenic carbon atom.

Esterase-mediated synthesis of optically active GABA analogues containing a stereogenic all-carbon quaternary carbon atom

Esterase from Horse Liver (HLAP) was able to hydrolyze a series of linear and cyclic β,β-dialkyl-γ-nitroesters, in spite of the well-known reluctance of hydrolytic enzymes to recognize and transform hindered substrates, such as those possessing a stereogenic quaternary carbon atom next to the reaction site. The resulting optically active γ-nitroesters gave access to optically active β,β-disubstituted γ-aminoacids as well as α,α-disubstituted succinic acids, both being biologically relevant compounds.

Chiral Ammonium Betaines as Ionic Nucleophilic Catalysts

Chiral betaine NAB is a highly enantioselective catalyst for the Steglich rearrangement of oxazolyl trichloroethyl carbonates (I) providing oxazolones bearing a quaternary stereogenic carbon atom.

Using a Combination of Magnetic Anisotropic Effects for the Configurational Assignment of Amino Alcohols

The combined magnetic anisotropic effects generated by two auxiliary moieties of 2-methoxy-2-phenylacetic acid (MPA), introduced on two families of terminal 1,2-amino alcohols (prim/sec and sec/prim), determine the signs of the Deltadelta(RS) parameters-the differences in chemical shifts between the bis-(R)-MPA and the bis-(S)-MPA esters-of the hydrogen atoms placed at both sides of the stereogenic carbon atoms, thereby allowing the determination of the absolute configuration of those heterobifunctional compounds. Theoretical (AM1, B3LYP) and experimental (CD, (3)J, low-temperature NMR spectroscopy, isotopic labeling) studies, together with testing with a number of representative compounds, permit one to establish the foundations of this methodology.

Agrocybone, a novel bis-sesquiterpene with a spirodienone structure from basidiomycete Agrocybe salicacola

The isolation, structure elucidation, and relative stereochemistry assignment of a novel illudane–illudane bis-sesquiterpene, agrocybone (1), from the basidiomycete Agrocybe salicacola, were reported. Agrocybone represents a structure with eight rings (including two spiro rings) and seven stereogenic carbon atoms. Agrocybone was found to exhibit weak antiviral activity against respiratory syncytial virus (RSV) with IC50 value of 100 μM.

Determination of kinetic parameters of enantiomerization of benzothiadiazines by DCXplorer

Benzothiadiazines differently substituted at the sulfonamidic nitrogen atom, at the stereogenic carbon atom and at the anilinic nitrogen atom have been synthesized and fully characterized. Enantioseparation of these compounds has revealed rapid on-column enantiomerization. The recently developed software DCXplorer has been successfully applied to calculate enantiomerization kinetic parameters. Enantiomerization barriers of 3-phenyl substituted benzothiadiazines, calculated in this work, have indicated a higher enantiomerization rate suggesting that the aromatic substituent exerts a strong effect on the enantiomerization process. Methyl substitution on N(2) position led to higher free energy barriers of enantiomerization, suggesting negative influence of methyl in the N(2) position on enantiomerization kinetics. However, methylation on N(4) position increases the enantiomerization rates significantly. The results obtained have been employed to postulate an enantiomerization mechanism for chiral benzothiadiazine type compounds.

Bioconjugates of 1′‐Aminoferrocene‐1‐carboxylic Acid with (S)‐3‐Amino‐2‐methylpropanoic Acid and L‐Alanine

AbstractFormal CH2 insertion in bioconjugates composed of 1′‐aminoferrocene‐1‐carboxylic acid (Fca) and alanine Boc‐Ala‐Fca‐Ala‐OCH3 gives Fca bioconjugates with the β‐amino acid (S)‐3‐amino‐2‐methylpropanoic acid (Aib). The novel homologous conjugates of ferrocene were fully characterized by spectroscopic and analytical methods. NMR, CD and IR spectroscopy in concert with DFT calculations suggest that the formal “L‐Ala–to–(S)‐β‐Aib mutations” can exert ferrocene helix inversion due to the different stereogenic carbon atoms of L‐Ala and (S)‐β‐Aib. Furthermore, the mutation (de‐)stabilizes the conserved secondary structure with two intramolecular hydrogen bonds, depending on the “mutation site”. The systematic work presented provides a firm basis for understanding the factors that determine folding in bioconjugates of ferrocene and β‐amino acids and will guide the rational design of metallocene peptidomimetics incorporating β‐amino acids.

A vibrational circular dichroism approach to the determination of the absolute configuration of flexible and transparent molecules: fluorenone ketals of 1,n-diols

The infrared absorption (IR) and vibrational circular dichroism (VCD) spectra for five ketal molecules, three of which obtained from 1,2-diols and two from 1,3-diols, were recorded in the mid-IR region. The spectra have been satisfactorily reproduced by DFT calculations, even with not too large wavefunction basis sets, especially due to the low number of conformers to be considered. The mobility of some moieties provides a recognizable signature. A characteristic couplet of VCD bands attributed to normal modes involving the methine and a phenyl ring bonded to the stereogenic carbon atom is evidenced for two ketals of the series as a signature of the absolute configuration; due comparison with existing literature is made. A relation is discussed of the present VCD data with the literature VCD data of simple alcohols and diols.

いかにしてフォトクロミック電子環状反応を立体選択的に行うか

The development of highly diastereoselective photochromic compounds that our group has carried out in the past 15 years is described here. Observations by 1H NMR of the enantiomeric isomerization of helically chiral hexatriene moiety of a fulgide which undergoes photochemical 6π-electrocyclization are first described, followed by discussions on the optical resolution of a fulgide and diastereoselective photochromism of an (R)-binaphthol-modified fulgide. A new concept of diastereoselective photochromism has also been realized by using diarylethenes as the template. The concept consists of: (i) Allylic 1,3-strain and (ii) electronic and steric repulsions between the oxygen atoms on a substituent on the stereogenic carbon atom attached to the ring-closing carbon atom located at one terminal of the hexatriene moiety and the heteroatom on the second heteroaromatic ring. Finally, a general strategy to achieve extraordinarily high diastereoselectivity of up to 100:0 has been demonstrated by the introduction of dual chiral stereocontrolling substituents to diarylethenes.

Enantioselective Fujiwara–Moritani Indole and Pyrrole Annulations Catalyzed by Chiral Palladium(II)–NicOx Complexes

AbstractThe catalytic asymmetric Fujiwara–Moritani ring closures of several indole‐ and pyrrole‐based cyclization precursors are reported. These unprecedented oxidative palladium(II)‐catalyzed annulations allow for the formation of a stereogenic quaternary carbon atom, and decent levels of enantiocontrol are seen in 5‐exo‐trig cyclizations (54 % ee for an indole and 76 % ee for a pyrrole) while 6‐exo‐trig ring closures afford essentially racemic material. Novel oxazoline ligands with a nicotine platform (NicOx) are pivotal for good catalytic turnover as conventional PyOx ligands failed to produce acceptable chemical yields. The preparation of these NicOx ligands as well as the syntheses of the cyclization precursors are described in detail.