Organocatalysis, conventionally defined as the use of small organic molecules as catalysts to promote asymmetric organic transformations, is now considered a stablished strategy for asymmetric synthesis. This asymmetric approach experienced a rebirth since , when List et al. Its functional amino and carboxylic groups situated at a convenient distance confer the proline a great versatility as organocatalyst since on one side of the molecular structure, the carboxylic acid fragment allows the formation of hydrogen bonds with one heteroatom from a non-enolizable electrophile and on the other side, the secondary amine functionality participates in the formation of a nucleophilic enamine with an enolizable aldehyde or ketone.
With respect to the second point, bifunctional pyrrolidine catalysts have been also obtained from trans -hydroxyproline, whose hydroxy group enables the support of the organocatalyst onto silica gel heterogeneous catalysis or ionic tags ionic liquid catalytic systems , thus facilitating their recovery. Figure 2 depicts grosso modo the development of ligands with an efficient organocatalytic activity, from simple and affordable chiral compounds such as amino acids, up to molecules with greater complexity and versatility.
Given the great diversity of reactions in which it is possible to employ R - or S -proline and its derivatives as organocatalysts, it is worthy to mention that relatively few methods of activation were initially identified. On the other hand, the applications of chiral organocatalysts have not been limited to the development of asymmetric methodologies, but have also fruitfully extended to the asymmetric synthesis of various chiral natural and synthetic bioactive compounds. For instance, Hong et al. Hong et al. The development of this synthetic route also permitted the unambiguous assignment of its absolute configuration by means of X-ray diffraction.
Thus, one of the main aims in our research group is the development of new ligands with potential organocatalytic activity, in which the evaluation of enantioselectivities via chiral HPLC plays a central role. This compound can be easily prepared from trans S -hydroxyproline Scheme 2 , and several derivatives were tested as chiral ligands coordinating metal reagents or as organocatalysts themselves in different asymmetric reactions, inducing enantioselectivities with varying levels of success.
In particular, diethylzinc addition to carbonyls of aldehydes was the most successful. Furthermore, in one of the first examples of organocatalyzed asymmetric Biginelli reaction, the hydrobromide of diazabicycloheptane 1 S ,4 S - R - 30 afforded moderate results Scheme 3. Figure 4 shows a typical example of chromatograms for a product of the tested Biginelli reaction.
Chromatographic conditions: Chirobiotic T 0. More recently, it was found that diastereomeric salts of diazabicycloheptane 1 S ,4 S - 31 combined with R -mandelic acid [ R - 38 ] successfully organocatalyzed the Michael addition reaction under solvent-free conditions. These results were interesting since it has been known that the structural nature of an acidic proton source had no influence on stereoselectivity given that acid additives tend to carry out general acid catalysis type.
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Mechanochemical synthesis involves mechanical grinding of the corresponding reagents under solvent free conditions or in the presence of molar equivalents of a suitable solvent e. The reaction usually proceeds with no heating other than that produced from the conversion of the mechanical energy of milling into heat, being the dispersion and an incremented surface area the determining factors in reactions subjected to the mechanical action. Likewise, asymmetric organocatalysis can also take advantage of mechanochemical tools to carry out solvent free or minimal solvent versions of existing reactions which proceed via enamine formation among other activation mechanisms.
Our research group evaluated the organocatalytic activity of the methyl ester of S -proline- S -phenylalanine dipeptide S,S - 39 in the asymmetric aldol reactions between cyclohexanone or acetone together with various aromatic aldehydes under ball-milling, solvent-free conditions. Furthermore, S -proline-containing thiodipeptides could also be employed for the mechanochemical asymmetric aldol reaction, which in some cases proved to be better organocatalysts relative to their amide analogues [ S,S - 39 vs.
S,S - 43 ]. S - 45 , have been evaluated, 98 as well as amides supported on MBHA 4-methylbenzhydrylamine resin, S - Table 2 also includes the available details of the chromatographic separations of the resulting stereoisomeric products. Figure 5 collects representative chromatograms of enantioenriched diastereomeric mixtures generated with chiral dipeptides as organocatalysts.
It is worthy to note that a slight difference in the substitution pattern may affect the elution order of the aldol products. For example, p -nitro substituted 2 S ,1' R - 42a Table 2 , entries is last eluted under the chromatographic conditions employed with a Chiralpak AD-H chiral column while on the contrary, ortho - and meta -nitro substituted [ 2 S ,1' R - 42b and 2 S ,1' R - 42c , respectively] elute first.
Taking u - 42c as example of analyte, Table 3 collects diverse chromatographic conditions employed for analysis of aldol reactions catalyzed by selected organocatalysts as recently described in the literature. When evaluating new ligands as organocatalysts, unambiguous assignment of the absolute configuration of products obtained from organocatalytic reactions is crucial to make an appropriate analysis of chromatograms corresponding to racemic and enantioenriched samples.
For example, Gandhi and Singh developed an enantioselective synthetic route to prepare the bicyclic azetidine R,S,S - 55e from aldol product S,R - 42e , that had been obtained in a reaction catalyzed by diamino-sulfonamide S,R,R - 52 Scheme 5. Gandhi and Singh assigned the configuration of the new chiral centers by means of nuclear Overhauser effect nOe experiments; in particular, they observed an enhancement in the peak intensity of H 2 by irradiating H 1 , and vice versa.
In the case of organocatalyst S,S - 44 , chromatographic examination of the experimental stereochemical results see Table 2 , conditions described in entry 12 led to propose a reasonable transition state to explain the observed stereocontrol Figure 6. It is worth mentioning that high-speed ball milling has been recognized as an environment-friendly mechanochemical technique given that it enhances atom economy by diminishing or eliminating solvent usage when carrying out organocatalytic reactions. Kokotos et al. Similarly, in our research group, a different series of thiohydantoins derived from proline was prepared by means of the synthetic route presented in Scheme 6.
The importance of solvent-free reaction conditions to maximize the suitable intermolecular interactions affording the desired stereocontrol constitute salient features of these catalytic systems Scheme 7. The resulting aminoazide was reduced and deprotected to obtain diamine S - 68a , that was used as precursor of a diazaborolidine, in turn tested as catalyst in the asymmetric reduction of prochiral ketones. The N -Boc protecting group on the pyrrolidine nitrogen allowed the functionalization of the primary amino group into various amide, alkylated amine, sulfonamide and triazole derivatives [ S - 68a-f ] Scheme 8.
In each case, carefully controlled conditions were required to generate the desired derivatives from the sterically hindered benzhydrylamine moiety. Nolte E. First published: 25 September Book Series: Topics in Stereochemistry. About this book Topics in Stereochemistry, Materials-Chirality provides comprehensive information on the stereochemistry of materials. Coverage includes the chirality of materials and the important role stereochemistry plays in the physical properties of polymers, liquid crystals, and other materials.
Reviews "…this volume represents a well-balanced assembly of research topics from which readers can gain valuable information…can be recommended to anyone wishing to explore an area of sterochemistry in any subject. Author Bios Mark M. Free Access. These ideas, in turn, gave rise to the stereochemistry of chiral stereoisomers.
It was realized that the spatial orientation of different functional groups governs the patterns of specificity in chemical reactivity . The interaction between the chiral and achiral components was widely studied in the biological organic reactions. The dynamics of organic reactions in particular those that take place within the spatially ordered environment of an enzyme protein interaction exhibit stereoselectivity and stereospecificity. The excellent review of the stereo-dynamic of chiral objects, including natural molecular structures and artificial molecular devices, can be found in .
It is notable, that both the stereoselectivity and stereospecificity are based on the recognition of the symmetry-related characters such as polarity, chirality, and helicity. Progress in the studies of molecular chirality transformation is helpful in resolving three questions. First, what kind of determinants can provide a favor in the production of one enantiomer over the other? Second, what is the mechanism of intermolecular propagation and preservation of chirality? And third, what is the mechanism of chirality propagation from the molecular level to a higher degree of biological organization?
Chiral Phase Transitions in Relation to Chirality Transfer Physical System Among the variety of the topological phase transitions  several sub-categories, including the order—disorder , chirality-related  and geometry-induced [,] transitions, were discovered. In condensed matter physics, phase transitions exhibit sensitivity to external physical parameters pressure, fields, electro-magnetic radiation, sonication, XVIII and doping. Spontaneous QFTs take place at the mesoscopic level at zero temperature and are driven by the quantum fluctuations XIX according to Heisenberg's uncertainty principle.
For the two above facts, the sensitivity to external physical parameters and the concept of the spontaneous phase transitions are of great importance. Biological Systems In relation to the biological systems, the chirality of the sub-cellular structures such as hair bundles was observed in auditory and vestibular sensory neurons of vertebrates [87,].
The phase transitions are the common effects, observed in the chiral molecules with pyramidal atomic centers such carbon and nitrogen. The frequency of a pyramidal inversion tunnel quantum-mechanical effect depends on the value of the energy barrier and set of external physicochemical factors. Chirality transfer from molecular to morphological level is observable in a diversity of physical objects as well as biochemical and synthetic materials [,].
The hierarchical propagation of chirality was found between the objects of different size, shape, and dimensionality . The chirality breaking in the nonequilibrium systems Bloch walls was studied in magnetic materials . Variety of Spatially Related Events Among the variety of spatially related events, the phase transitions and the symmetry transformations are known as the most closely associated.
We will focus mostly on the phenomena of the chirality transfer. The chirality transfer from the molecular to morphological scales was documented in nano-materials  and polymers . In our review, we explore what is currently known about how the molecular chirality is transformed into to the laterality of cognitive functions. Sensitivity of Chirality Transfer to Internal, External, Local and Global Conditions Symmetry transformation arising from chemical and physical origin is one of the hottest issues in the field of molecular chirality .
Before the further consideration it is essential to emphasize that hypothesis about the distinction between internal and external determinates in the living organism being very productive could become irrational in the form of an absolute opposition. The most convincing example of the link between external and internal factors is the function of a digestive system, which permanently transforms the external factors into the very internal.
He was also the first who realize the fact of the chirality transfer from the molecular level to the level of macroscopic solid crystal . The ideas were great, but the success was limited. Much later the empirical evidence of the role of the forces of nature on the chiral compounds was obtained. The early idea of Pasteur was supported by modern experimental capabilities [,]. Both results, accompanied by the discovery of the spontaneous  and induced chirality provided the tools to disclose the previously mysterious homochirality of life .
In particular an essential result was derived by Barron . He demonstrated that supramolecular helices formed from achiral monomers have been controlled by applying the combination of the gravitational and rotational forces . The transfer of stereochemical information in the form of chirality and helicity was observed between chiral and achiral constituents of the molecular complexes in general and of biological systems in particular . The transfer of chirality from protein to the cellular and embryonic level was suggested in several studies [,].
The critical role of a molecular and cellular chirality as the determinants of LR asymmetric in the animal body, and functions has gradually emerged . The explosive advance in the study of asymmetric catalysis over the last four decades has dramatically altered the view on the biomolecular chirality dynamics [,].
Before the era of chiral catalysis, the most common characteristic of the enantiomers was the absence or little difference in the chemical and physical properties. Resent progress in the synthesis of the chiral compound associated with the study of the catalytic asymmetric reactions of carbonyl compounds, allow an understanding of the principles governing the dynamics of structural conformations in the amino acids and proteins of the living organisms . Molecular chirality and correspondently a chirality transfer are recognized as sensitive to the broad range of modulators including the internal, external, localized, and diffused determinants.
It is notable that molecular chirality exhibits sensitivity to all types of the chemical binding including ionic, covalent, and not-covalent . The generation of chiral imbalance in the chiral molecular systems can occur spontaneously, due to intrinsic instability or induced by external factors . In accordance with this instability, the chiral self-organization of molecular complexes is sensitive to the impact of many external factors including electrical metal ions , magnetic, electromagnetic photon , mechanical, and gravity force fields.
The discovery of magnetically induced optical activity by Faraday was the first demonstration of the sensitivity of a molecular chirality to the physical parameters of an environment XX . Since then, the sensitivity of the chiral objects to the environmental parameters has been explored at cosmological , molecular , atomic , and elementary particles levels . Thus, it is reasonable to be aware that different molecular structure can have the same or different physical properties depending on the nature of the physical effect and chemical environment. XXI In the specific case of the stereoisomers interaction with an electromagnetic field, we have at last three different situations depending on the energy diapason such as IR, UV and NMR spectra , and method used such as the circular dichroism .
The photons chiral object itself of different energy interact with the chiral components of the molecular complex such as electron or proton compromising its equilibrium spatial configuration. The recent discovery of the quantum chiral light—matter interaction offers fundamentally new functionalities for the charity transfer of the bio-molecular structure related to brain quantum information-processing capability .
The chiral molecules reveal the capability of the self-organization of the helical superstructures. The intermolecular interactions related to the modulation of chirality are the part of the supramolecular chemistry  and interfacial sciences [,].
Chirality in rotaxanes and catenanes
The chiral sensing based on the concept of chirality transfer is of great importance. Chain of Cirality Transfer Several relatively new fields of science provide the bridge between dynamic chirality in solid matter physics and bio-chirality. The chirality transfer or the transfer of handedness is observed between organic and inorganic molecular structure . The central point of these studies is the chirality transfer in the variety of forms.
XXI I Among them, we can mention the stereo-physics of liquid crystals  and chiral catalysis . The modeling macroscopic chirality emerged from the chiral molecular elements is a challenge for theory, computations, and experiments . Numerous experimental results demonstrate the transfer of chirality among different length scales ranging from dimensions of the elementary particles to the macro-scale the length of the axon .
In particular, it was shown that the chirality at the molecular scale amino, acids, proteins, and polysaccharides could be transferred to the macroscopic and macro- level neurofilaments and inorganic crystals as shown in . The issue of dimensionality in the chirality transfer effects is critical for brain information processing in the brain and artificial intelligence devices. XXIII The examples of macroscopic chirality are found in the plant kingdom, animal kingdom and all other groups of organisms.
Physical Systems In the quantum spin systems, the symmetry-related phase transitions [78,,] and the transfer of the stereospecific symmetry characters XXIV [97,] are well-known phenomena. The recent advance in the experimental and theoretical areas of many disciplines related to stereochemistry revealed the chirality-induction effects in the various inorganic materials with mono-chiral and hybrid-chirality structures including plasmonic, semiconducting, metal oxide and silica-based compounds .
The most prominent among the field-induced chirality effects are the following: Coulomb near-field, dipolar , electromagnetic, and plasmonic mechanisms . The chirality transfer from the spin-quantum system of elementary particles to the atomic structure level is an essential element of basic knowledge and serves as the necessary introduction to the understanding of the chemistry and biochemistry.
The nuclei of atoms and associated electron system have an innate chirality. The chemical phenomena are viewed as associated with the chirality of electron system and nuclear XXV constituents . The molecular chirality is the consequence of the chirality transfer from the dynamic complex of elementary particles. The transfer of molecular chirality from monomers to polymeric structures has been widely explored and utilized .
In particular, the non-reciprocal single-photon devices allow utilizing the quantum information processing based on the superposition of two operational states in chiral spin—photon system . Thus, the stereo-specific effects, including the chirality transfer, are not the unique properties of the organic world.
XXVI Quit contrary stereospecific effects are the universal and fundamental character of both organic and inorganic materials. Biological Systems: Basic Set of the Chirality Transfer Levels From the physical world chiral events diversity and complexity point of view our primary concern is the chain of the chirality transfer in biological systems. The very essential prediction of the sequential chain of chital events in the organism was done long before the modern progress in biostereochemistry .
Taking the review of newly discovered facts as a basis, we will clarify the natures of elements in this chain and the hierarchy of these elements within the chain. Referring to the hierarchy of a chirality transfer, we will assume based on the review of current publications that it consists of several distinct levels.
Dynamically Chiral Helical Polymers: A New Frontier in Asymmetric Catalysis?
The basic set of these levels includes the transfer of following types:. After reviewing the elements of the chiral hierarchy, we will examine what is currently known about the sensitivity of each of the hierarchical levels of chirality to the internal and external determinants. Several reviews provide information about the range of chirality related events [44,45].
From Elementary Particles to Atomic Level The chirality transfer from the elementary particles to the arrangement of atomic orbital was considered in the previous paragraphs. The energy difference parity violation between the ground and excited states of molecular enantiomers in the presence of weak nuclear force is predicted by theory and proved experimentally [,].
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From Atomic Orbitals to Molecular Level The wavefunctions of electron orbitals are traditionally considered to be the determinants of the molecular chirality . Consequently, in the stereochemistry, the spatial arrangement of the atomic orbital is the primary determinant of the chiral center's function in bio-molecules, including the amino acids, sugars, and phospholipids. At present, it is a common recognition that the electronic orbitals of the carbon atom constitute the root contributing to the molecular chirality XXVIII [,]. In this sense the molecular chirality, is the principal initiator of the origin of the life.
We will review the chirality transfer events in the order of their natural sequence. The transfer of the symmetry patterns chirality-induced helicity or chirality-helicity transfer from the amino acids to peptides  and proteins  is broadly studied.
Four main categories of biological-macromolecules, which exhibit chirality, are proteins, lipids, carbohydrates, and nucleic acids [,]. In the human body about , different proteins introduce the charity phenomenon for all the key physiological, perceptual, cognitive and psychological function of an organism. The chirality transfer from amino acids to proteins secondary and higher order structure is one of the most studied fields in biochemistry.
The chirality of protein folding gained attention in condensed matter physics [14,] and molecular biology [36,]. The stereo-transformations of proteins are a highly dynamic field of science involving the most advanced analytical capabilities [,]. A similar mechanism is responsible for the transfer of molecular-level stereo-specificity chirality to the supra-molecular level helicity in cell membrane rafts during endocytosis .
The establishment of helical handedness can be formed at the macro-molecular level due to the stereo-ordering regularity of constituted chiral entities at the intra-molecular and intermolecular interactions .