Stereogenic Carbon Atom Research Articles

Enantioselective synthesis of molecules with multiple stereogenic elements.

This review explores the fascinating world of molecules featuring multiple stereogenic elements, unraveling the different strategies designed over the years for their enantioselective synthesis. Specifically, (dynamic) kinetic resolutions, desymmetrisations and simultaneous installation of stereogenic elements exploiting either metal- or organo-catalysis are the principal approaches to efficiently create and control the three-dimensional shapes of these attractive molecules. Although most molecules presented in this review possess a stereogenic carbon atom in combination with a stereogenic axis, other combinations with helices or planes of chirality have started to emerge, as well as molecules displaying more than two different stereogenic elements.

Creating a Defined Chirality in Amino Acids and Cyclic Dipeptides by Photochemical Deracemization

Abstract2,5‐Diketopiperazines are cyclic dipeptides displaying a wide range of applications. Their enantioselective preparation has now been found possible from the respective racemates by a photochemical deracemization (53 examples, 74 % to quantitative yield, 71–99 % ee). A chiral benzophenone catalyst in concert with irradiation at λ=366 nm enables to establish the configuration at the stereogenic carbon atom C6 at will. If other stereogenic centers are present in the diketopiperazines they remain unaffected and a stereochemical editing is possible at a single position. Consecutive reactions, including the conversion into N‐aryl or N‐alkyl amino acids or the reduction to piperazines, occur without compromising the newly created stereogenic center. Transient absorption spectroscopy revealed that the benzophenone catalyst processes one enantiomer of the 2,5‐diketopiperazines preferentially and enables a reversible hydrogen atom transfer that is responsible for the deracemization process. The remarkably long lifetime of the protonated ketyl radical implies a yet unprecedented mode of action.

Creating a Defined Chirality in Amino Acids and Cyclic Dipeptides by Photochemical Deracemization.

2,5-Diketopiperazines are cyclic dipeptides displaying a wide range of applications. Their enantioselective preparation has now been found possible from the respective racemates by a photochemical deracemization (53 examples, 74% to quantitative yield, 71-99% ee). A chiral benzophenone catalyst in concert with irradiation at λ= 366 nm enables to establish the configuration at the stereogenic carbon atom C6 at will. If other stereogenic centers are present in the diketopiperazines they remain unaffected and a stereochemical editing is possible at a single position. Consecutive reactions, including the conversion into N-aryl or N-alkyl amino acids or the reduction to piperazines, occur without compromising the newly created stereogenic center. Transient absorption spectroscopy revealed that the benzophenone catalyst processes one enantiomer of the 2,5-diketopiperazines preferentially and enables a reversible hydrogen atom transfer that is responsible for the deracemization process. The remarkably long lifetime of the protonated ketyl radical implies a yet unprecedented mode of action.

Asymmetric Synthesis of Multicyclic Spirooxindole Derivatives Bearing Stereogenic Quaternary Carbon Atoms

An organocatalyzed stereoselective domino reaction as a facile approach to multicyclic spirooxindole derivatives bearing two stereogenic quaternary carbon atoms is reported. The alkyl-substituted chiral thiourea catalyst was efficient for the reaction to tolerate a wide range of substrates, furnishing a new class of spirooxindole derivatives bearing an O,O-acetal-fused tricyclic skeleton or tetrahydroxanthone moiety in moderate to good yields with good to excellent selectivities. The products generated from this method have promising anticancer activities.

Dynamic‐to‐Static Planar Chirality Conversion in Pillar[5]arenes Regulated by Guest Solvents or Amplified by Crystallization

AbstractControlling dynamic chirality and memorizing the controlled chirality are important. Chirality memory has mainly been achieved using noncovalent interactions. However, in many cases, the memorized chirality arising from noncovalent interactions is erased by changing the conditions such as the solvent and temperature. In this study, the dynamic planar chirality of pillar[5]arenes was successfully converted into static planar chirality by introducing bulky groups through covalent bonds. Before introducing the bulky groups, pillar[5]arene with stereogenic carbon atoms at both rims existed as a pair of diastereomers, and thus showed planar chiral inversion that was dependent on the chain length of the guest solvent. The pS and pR forms, regulated by guest solvents, were both diastereomerically memorized by introducing bulky groups. Furthermore, the diastereomeric excess was amplified by crystallization of the pillar[5]arene. The subsequent introduction of bulky groups yielded pillar[5]arene with an excellent diastereomeric excess (95 % de).

Dynamic-to-Static Planar Chirality Conversion in Pillar[5]arenes Regulated by Guest Solvents or Amplified by Crystallization.

Controlling dynamic chirality and memorizing the controlled chirality are important. Chirality memory has mainly been achieved using noncovalent interactions. However, in many cases, the memorized chirality arising from noncovalent interactions is erased by changing the conditions such as the solvent and temperature. In this study, the dynamic planar chirality of pillar[5]arenes was successfully converted into static planar chirality by introducing bulky groups through covalent bonds. Before introducing the bulky groups, pillar[5]arene with stereogenic carbon atoms at both rims existed as a pair of diastereomers, and thus showed planar chiral inversion that was dependent on the chain length of the guest solvent. The pS and pR forms, regulated by guest solvents, were both diastereomerically memorized by introducing bulky groups. Furthermore, the diastereomeric excess was amplified by crystallization of the pillar[5]arene. The subsequent introduction of bulky groups yielded pillar[5]arene with an excellent diastereomeric excess (95 % de).

Multifaceted View on the Mechanism of a Photochemical Deracemization Reaction.

Upon irradiation in the presence of a chiral benzophenone catalyst (5 mol %), a racemic mixture of a given chiral imidazolidine-2,4-dione (hydantoin) can be converted almost quantitatively into the same compound with high enantiomeric excess (80-99% ee). The mechanism of this photochemical deracemization reaction was elucidated by a suite of mechanistic experiments. It was corroborated by nuclear magnetic resonance titration that the catalyst binds the two enantiomers by two-point hydrogen bonding. In one of the diastereomeric complexes, the hydrogen atom at the stereogenic carbon atom is ideally positioned for hydrogen atom transfer (HAT) to the photoexcited benzophenone. Detection of the protonated ketyl radical by transient absorption revealed hydrogen abstraction to occur from only one but not from the other hydantoin enantiomer. Quantum chemical calculations allowed us to visualize the HAT within this complex and, more importantly, showed that the back HAT does not occur to the carbon atom of the hydantoin radical but to its oxygen atom. The achiral enol formed in this process could be directly monitored by its characteristic transient absorption signal at λ ≅ 330 nm. Subsequent tautomerization leads to both hydantoin enantiomers, but only one of them returns to the catalytic cycle, thus leading to an enrichment of the other enantiomer. The data are fully consistent with deuterium labeling experiments and deliver a detailed picture of a synthetically useful photochemical deracemization reaction.

Individual scale factor approach for the vibrational circular dichroism similarity-guided spectral and conformational analysis of perezone and dihydroperezone.

Evaluation of DFT calculated vibrational parameters for the IR and VCD spectra similarity of perezone (1) and dihydroperezone (2) was undertaken. Conformational sets were obtained using different search engines, and the parameters needed for spectra prediction were obtained using several combinations of commonly employed functionals and basis sets, and then weighted spectra were generated and compared with observed traces to provide infrared similarity (SIR ) and enantiomeric similarity index (ESI) values. These values evidenced a poor performance of the evaluated levels of theory that were overcome when using the individual scaling factors approach, providing 16% to 139% increases of the ESI values. The best performing level of theory was the B3LYP/DGDZVP2 with ESI values of 0.722 and 0.792 for 1 and 2. Moreover, a correlation analysis showed that the irregular DFT performance arises from rotational strength deviations, which suggests to discard conformational abundance accuracy as the main source of differences. Furthermore, a similarity guided conformational analysis showed that conformations with high ESI values prefer particular orientations of the CC bonds directly attached to the stereogenic carbon atom, with more distant dihedral angles having less influence. Additionally, folded and extended conformers appear to be equally capable to yield high individual ESI values, although abundances of folded conformers just account for 16% of the total population. Nevertheless, abundance optimization showed that a high ESI similarity value of 0.834, is possible when the population of these conformers is increased to 26%, suggesting that a larger abundance of these conformers might be present in solution.

Preparation of Chiral Enantioenriched Densely Substituted Cyclopropyl Azoles, Amines, and Ethers via Formal SN2' Substitution of Bromocylopropanes.

Enantiomerically enriched cyclopropyl ethers, amines, and cyclopropylazole derivatives possessing three stereogenic carbon atoms in a small cycle are obtained via the diastereoselective, formal nucleophilic substitution of chiral, non-racemic bromocyclopropanes. The key feature of this methodology is the utilization of the chiral center of the cyclopropene intermediate, which governs the configuration of the two adjacent stereocenters that are successively installed via 1,4-addition/epimerization sequence.

Construction of Benzo‐Fused Heterocycles by Epoxide–Heteronucleophile Cyclization: Applications in the Synthesis of Natural Products and Designed Molecules

AbstractConstruction of benzo‐fused heterocycles, specifically which have one or more sp3 stereogenic carbon atoms on the heterocyclic ring, by intramolecular ring‐opening cyclization of epoxides with O‐ and N‐nucleophiles is a powerful synthetic tool in organic synthesis. In this Review, we analyze the efficiency of such a heterocyclization approach in natural product synthesis and synthetic methodologies published since the year 2000. In addition to briefly discussing the synthetic methods of accessing the requisite epoxide substrates, important aspects of the subsequent cyclization reaction, such as reaction conditions, endo‐ versus exo‐regioselectivity, protecting or functional group compatibility, and enantio‐ and distereoselectivity are surveyed. Although the literature of organic chemistry in the last four decades has witnessed a large number of reviews/book chapters on the epoxide ring‐opening chemistry, the title topic has never been reviewed. Herein, we have systematized it as a dedicated review for the first time.

Stachybotrys Chartarum Secondary Metabolots of Poisonic Microzoquary

Filtered culture fluids of the Stachybotrys chartarum strain were exhaustively extracted with ethyl acetate. The iso lated red residue was subjected to column chro matography (silica gel) with gradient elution, resulting in 2 different fractions. Fraction 1-2 consisted of a crystalline material that showed the same parameters of 1H and 13C as the parameters of staxibotrilaktam and staxibotrilaktam А, a derivative of driman's sesquiterpenoid. The structure proposed for this compound was based on spectroscopic data and no indication of the configuration of stereogenic carbon atoms was obtained. The fungus was produced mainly stachybotrys fully characterized derived sesquiterpenoid of drimana.

Primary Phosphines and Phosphine Oxides with a Stereogenic Carbon Center Adjacent to the Phosphorus Atom: Synthesis and Anti-Markovnikov Radical Addition to Alkenes

Organophosphorus compounds with stereogenic phosphorus and carbon atoms have received increasing attention. In this regards, primary phosphines with a stereogenic carbon atom adjacent to the phosphorus atom were synthesized by the reduction in phosphonates and phosphonoselenoates with a binaphthyl group. Their oxidized products, i.e., phosphine oxides with a stereogenic tetrasubstituted carbon atom, were found to undergo BEt3-mediated radical addition to cyclohexene to give P-stereogenic secondary phosphine oxides with a diastereoselectivity of 91:9. The products were characterized by ordinary analytical methods, such as Fourier transform infrared spectroscopy; 1H, 13C, and 31P NMR spectroscopies; and mass spectroscopy. Computational studies on the phosphorus-centered radical species and the obtained product implied that the thermodynamically stable radical and the adduct may be formed as a major diastereomer. The radical addition to a range of alkenes took place in an anti-Markovnikov fashion to give P-stereogenic secondary phosphine oxides. A variety of functional groups in the alkenes were tolerated under the reaction conditions to afford secondary phosphine oxides in moderate yields. Primary phosphines with an alkenyl group, which were generated in situ, underwent intramolecular cyclization to give five- and six-membered cyclic phosphines in high yields after protection by BH3.

Reversible "On/Off" Chiral Amplification of Pillar[5]arene Assemblies by Dual External Stimuli.

We report dual-stimuli, thermo- and photostimuli, responsive chiral assemblies, of planar-chiral pillar[5]arenes with azobenzene groups on their rims. The azobenzene-substituted planar-chiral pillar[5]arenes were synthesized by copper(I)-catalyzed alkyne-azide cycloaddition "click" reaction of azide-substituted planar-chiral pillar[5]arenes containing S or R stereogenic carbon atoms with an alkyne-substituted azobenzene. These decaazides with stereogenic carbons could act as starting points for a large library of planar-chiral pillar[5]arenes. Homeotropic alignment of azobenzenes, caused by the mesogenic property of the azobenzene groups, was induced by annealing a film of the azobenzene-substituted planar-chiral pillar[5]arenes. The alignment resulted in chiral propagation from the planar-chiral pillar[5]arene cores to the azobenzene area and caused significant chiral amplification consequently. These aligned chiral assemblies were collapsed by trans to cis photoisomerization of the azobenzene groups, resulting in chiral amplification off, and reconstructed by cis to trans thermo-isomerization, again turning on the chiral amplification.

Enantiopure nanohoops through racemic resolution of diketo[n]CPPs by chiral derivatization as precursors to DBP[n]CPPs.

Strained conjugated nanohoops are attractive synthetic targets due to the bending of their π-system, which leads to intriguing optoelectronic properties, among others. By incorporating non-mirror-symmetric aromatic panels, chiral nanohoops can be obtained. We herein present a strategy to enantiopure nanohoops by racemic resolution through chiral derivatization of diketone-embedded hoops. The resulting diketo[n]CPPs (n = 6, 7) contain two stereogenic carbon atoms each and possess high fluorescence quantum yields paired with circularly polarized luminescence. These are versatile precursors to chiral dibenzo[a,e]pentalene-based nanohoops DBP[n]CPPs with antiaromatic character and ambipolar electrochemical behavior. Due to their strained structures the DBP[n]CPPs do not racemize at room temperature, which is supported by high calculated isomerization barriers. X-ray crystallographic investigations on the DBP[n]CPPs and their precursors as well as DFT calculations provide insight into the build-up of strain energy during the synthetic transformations.

Transformation from triple helicene to double helicene embedding adjacent stereogenic carbon atoms and axial stereogenicity.

Transformation of triple helicene (TH) to double helicene (DH) with adjacent stereogenic carbon atoms and axial stereogenicity was achieved by the unexpected conjugate addition to the central aromatic ring of TH-1. We also studied the boundary at which different reactivities to addition reactions occur in some helicenes with different π-extension.

The Chiral 1:2 Adduct (S)S(S)C(-)589-Ethyl 2-Phenylbutyl Sulphide-Mercury (II) Chloride:(-)589[(S)S(S)C-Et(2-PhBu)S.(HgCl2)2]. Stereoselective Synthesis, Asymmetric Oxidation, Crystal and Molecular Structure and Circular Dichroism Spectra.

Optically active (−)589ethyl (S)-2-phenylbutyl thioether, (−)(S)C-Et(PhBu)S (I), and its new diastereoisomeric mercury (II) chloride adduct, 1:2, (−)[(S)S(S)C-Et(PhBu)S.(HgCl2)2]2, (II) were stereoselectively synthesized; the absorbance (UV) and circular dichroism (CD) spectra were measured and the crystal and molecular structure of complex (II) was determined by single-crystal X-ray diffraction. Two different Hg centres are present whose coordination environments are built by two short bonds to chloride ligands in one case, and to one chloride and one sulphur in the other one. These originate digonal units. Electroneutrality is achieved by a further chlorine, which can be considered prevalently ionic and bonded to the two Hg centres, forming square bridging systems nearly perpendicular to the digonal molecules. The coordination polyhedra can be interpreted as 2 + 4 tetragonally-compressed octahedra with the four longer contacts lying in the equatorial plane. IR spectroscopic data are consistent with the presence of one bent and one linear Cl–Hg–Cl moiety. The absolute configurations at both stereogenic centres of the formed diastereoisomeric complex (II) are (S). The (S)S absolute configuration at the stereogenic sulphur atom bonded to the mercury(II) atom in complex (II) has been related with the negative Cotton effect assigned in its circular dichroism (CD) spectrum to a charge-transfer transition at ca. 230 nm. The stereoselective oxidation of (I) and (II) with hydrogen peroxide, induced by the stereogenic carbon atom (S)C of the enantiopure sulphide, gave (−)598ethyl (S)C-2-phenylbutyl(S)S-sulphoxide, (−)598[(S)S(S)C-Et(PhBu)SO], (III), having 18.1% de. Oxidations carried out in the presence of a 200 molar excess of mercury(II) chloride gave (−)598ethyl (S)C-2-phenylbutyl(R)S-sulphoxide, (−) 598[(R)S(S)C-Et(PhBu)SO], (IV) with 31% de, showing the cooperative influence of mercury(II) chloride on the selectivity of the oxidation reaction.

Total Synthesis and Stereochemical Confirmation of (-)-Olivil, (+)-Cycloolivil, (-)-Alashinols F and G, (+)-Cephafortin A, and Their Congeners: Filling in Biosynthetic Gaps.

For the first time, we describe the stereocontrolled total syntheses of olivil, cephafortin A, 4-des-O-methyl-4-O-rhamnosyl cephafortin A, and alashinol F from a common precursor using a combination of chemoenzymatic and biomimetic methods for the systematic introduction of functional groups on three vicinal stereogenic carbon atoms. We revised the previously assigned stereochemistry of (+)-cephafortin A, which was reported as the enantiomer. Natural and unnatural congeners provide insights into the biogenetic interrelations of members of this family.

Generation of Heteroatom Stereocenters by Enantioselective C–H Functionalization

C–H functionalization has been established as an efficient way to generate molecular complexity. The formation of stereogenic carbon atoms by asymmetric C–H functionalization has seen tremendous pr...

Maxwell-Boltzmann statistics applied in the study of photoluminescent emission bands in the (S)-(-)-1-(4-bromophenyl)-N-1,2,3,4-(tetrahydro-1-naphthyl)methanimine organic crystals

The morphological, structural and optical properties of a new crystalline enantiopure imine derived from p-bromobenzaldehyde were examined, namely the (S)-(−)-1-(4-bromophenyl)-N-1,2,3,4-(tetrahydro-1-naphthyl)methanimine compound. The analysis of the molecular packing associated with the surface morphology was carried out by means of Scanning Electron Microscopy (SEM). The absorbance vs. λ(nm) spectrum showed a relative maximum located in the ~350–650 nm (~3.54–1.90 eV) range assigned to π→π* and n→π electronic transitions characteristic of organic materials. Also, an inflection point located at ~559 nm (~2.21 eV) was tentatively associated with the behavior of π-resonance as well as the inductive effect generated by the halogen (-Br) atom and the stereogenic carbon atom. The band gap energy (Eg) was examined by applying the Tauc model, and presented four electronic transitions located at ~2.45 eV, ~2.66 eV, ~2.81 eV, and ~2.88 eV. A monoclinic crystal system and a P21 space group were established by single-crystal X-ray Diffraction (XRD) for the enantiopure imine. The Photoluminescence (PL) spectrum at room temperature showed two emission bands located in the Vis-region identified as a violet emission (VE) band located at ~412 nm and a yellow emission (YE) band at ~601 nm. These bands were associated with native crystalline defects. From the deconvolution of PL bands arose three different emission bands located at ~426, ~561, and ~631 nm, respectively. In order to investigate their origin, the statistical Maxwell-Boltzmann model was applied for the first time as an original approach, under the assumption that crystal defects correspond to vacancies and molecular interstices. The vibrational modes were investigated by Raman spectroscopy and compared with those obtained by theoretical and experimental analysis.

Green emission band induced by crystal defects in halogenated (-Br, -Cl, -F) chiral imines with a benzo[b]thiophene-based moiety

Four different chiral imines were analyzed in solid state, by changing systematically the halogen atom –X (-F, -Cl and -Br) in the para-position of the benzene ring in the chiral moiety of benzo[b]thiophene-based imine compounds. The molecular packings showed a significant distortion induced by the effect of the stereogenic carbon atoms and the corresponding halogen atom, resulting in nonplanar angular-shaped small molecules. Morphological studies by Scanning Electron Microscopy (SEM) were performed and changes in aspect and shape of the crystals can be clearly seen. The absorbance was registered in the UV-region (~200–400 nm), and showed typical transitions that are commonly displayed in organic molecules with π→π* and n→π* electronic transitions. The band gap was quantified by the Tauc model, and four electronic transitions were found, associated with those observed in experimental results by absorbance, located in the ~3.34–5.86 eV range. By X-ray diffraction (XRD) studies, a monoclinic→orthorhombic variation in the crystals was observed. Photoluminescence (PL) signals were examined in the Vis-region at room temperature and a green emission (GE) band located in the ~450–750 nm range was observed, which was associated with crystalline defects and the existing chromophores. Likewise, a PL signal located in the ~526–583 nm (~2.35–2.12 eV) range showing the shift of the green-yellow emission was noted. By using Raman spectroscopy, the vibrational modes displayed in these crystals were analyzed. A theoretical support of HOMO-LUMO analysis for these organic crystals is also reported.