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In the couple phase, a variety of intermolecular coupling reactions can be employed to generate a dense array of reactive sites and functional groups on the key building blocks installed during the build phase. Finally, in the pair phase, the intermediates constructed through the build and couple phases take part in intramolecular pairing reactions to yield an array of final products with the desired skeletal and stereochemical diversity Nielsen and Schreiber, ; Kim et al. B Outline of lycopodium alkaloids and their unnatural scaffolds with their respective pairing patterns.

Recently, the ring-distortion strategy has also been developed as a distinctive DOS strategy for the systematic construction of novel small-molecule collections with high structural diversity and complexity. A Schematic representation of the ring-distortion strategy. B The complexity-to-diversity CtD strategy for the construction of diverse and complex compounds starting from readily available natural products.

C The ring-distortion strategy for the construction of macrocyclic lactone and lactam libraries. D The ring-distortion strategy for the construction of biologically relevant benzannulated small molecules. However, in any DOS strategy, the common structural features of existing bioactive molecules have been widely investigated to grant sufficient biological relevancy to the resulting compounds Kim et al.

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As such, natural products are commonly investigated, and their structural features are considered to be potent sources of information in drug discovery. In addition, macrocycles have received a significant amount of attention in the field of drug discovery due to distinguishable structural features compared to other small molecules. Furthermore, privileged structures, which are common structural motifs in a vast number of bioactive natural products and therapeutic agents, contain novel structural features that secure a high biological relevancy Evans et al.

Natural products play a pivotal role in the search of novel therapeutics. Bioactive natural products tend to have complex 3D polycyclic structures rich in sp 3 carbons and stereogenic centers, and their inherent bioactivities may provide clues for the design of novel core skeletons with high biological relevancy Wipf, ; Shimokawa, ; Chen et al. Therefore, the efficient construction of natural product libraries and their unnatural analogs can be considered an important DOS strategy. Selecting lycopodium alkaloids as a model system, they reported the total syntheses of four lycopodium alkaloids and six related unnatural scaffolds.

As shown in Figure 1B , chiral intermediate 1 was formed through the build and couple phases, while intermediate 2 was prepared by means of the early pairing phase, which was crucial to the overall synthetic protocol. Although various macrocycle-based natural products are known to exhibit therapeutic potential, as a sole structural unit, macrocycles have not been traditionally considered as suitable small molecules for drug discovery screening processes Schreiber, However, recent reports have claimed that macrocyclic structures can pre-organize their conformations, which allows improved interactions with extended protein surfaces and subsequent high biological activities Driggers et al.

As such, numerous DOS strategies have been pursued to construct structurally and functionally diverse macrocycles Madsen and Clausen, ; Collins et al. For the efficient construction of libraries containing a diverse array of macrocycles, Spring et al. In this case, the build phase involved the synthesis of fluorous-tagged azido compounds, which were converted in situ into the corresponding pluripotent aza-ylides. These aza-ylides were then coupled with suitable appendages to facilitate the subsequent pairing reactions.

Similarly, in , they reported the synthesis of 45 diverse macrocyclic compounds of various sizes, ranging from to membered rings Nie et al. In this case, the imine moieties branching out from the aza-ylides served as second-line building blocks for diversification of the macrocycle library. The introduction and subsequent modification of the fluorous tag and other reactive sites in these macrocycles could therefore improve the efficiency as well as skeletal diversity of the library synthesis.

Moreover, Marcaurelle et al. Notably, this study presented an excellent example of the DOS strategy to demonstrate its power and efficiency for the highly systematic construction of small-molecule libraries with maximized architectural complexity. A clear definition of privileged structures was made in a seminal article on drug discovery methods reported by Evans et al.

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For example, Nicolaou et al. In this context, the construction of a DOS library derived from privileged structures can be considered crucial to accessing highly biologically relevant molecular diversity Kim et al. We envisioned that incorporating these privileged structures into polyheterocycles enhances the biological relevancy of the resulting compounds with pre-defined conformations, which may be beneficial for specific binding with biopolymers due to the prepaid entropic penalty Oh and Park, ; Kim et al.

In particular, the systematic construction of diverse sp 3 -rich 3D polyheterocycles containing privileged substructures has been emphasized since their rigid and diverse frameworks can selectively bind with biopolymers to induce conformational changes and subsequent functional modulation. In addition, we recently reported a pDOS library in which pyrimidodiazepines were employed as the privileged substructure Kim et al. In this case, the build and couple phases produced key pyrimidodiazepine-based intermediates containing five orthogonal reactive sites.

In the pair phase, each reactive site was paired to produce 16 different polyheterocycles containing the pyrimidodiazepine substructure and with a high degree of 3D skeletal complexity in nine distinct scaffolds. Due to the dual i. For the construction of natural product-like compound collections, Hergenrother et al.

In this approach, the molecular frameworks of readily available natural products were converted into structurally complex and diverse core skeletons through various chemoselective ring-distortion reactions Figure 2B. As natural products exhibit an inherent structural complexity with defined stereochemistry Clardy and Walsh, , the resulting core skeletons derived from natural products tend to be structurally and stereochemically more complex and distinct compared to existing compound collections.

In their initial report on the CtD strategy, gibberellic acid, quinine, and adrenosterone were employed as synthetic starting points, and were transformed into 19, 12, and 18 different scaffolds, respectively, through various ring-distortion reactions 3 reaction steps on average; Huigens et al. The subsequent application of traditional diversification strategies to final scaffolds therefore allowed the construction of a membered highly complex compound library.

They also applied the CtD strategy to other readily available natural products such as abietic acid and sinomenine, which afforded 84 and 65 complex compounds, respectively Rafferty et al. Chemoinformatic analysis of the resulting compound collections obtained using the CtD strategy demonstrated a higher skeletal complexity compared to conventional compound collections in terms of higher fractions of sp 3 -hybridized carbon atoms F sp3 , lower clogP values, and greater numbers of stereocenters.

For the systematic construction of diverse macrocycles, several DOS approaches utilizing ring-distortion reactions and in particular, ring-expansion reactions have been pursued Kopp et al. For example, Tan et al. Interestingly, easily accessible polycyclic enol ethers or enamines containing bridging double bonds were found to smoothly undergo oxidative cleavage to generate various macrolactones and macrolactams, regardless of substrate effects, such as ring size, substituents, and stereochemistry.

Subsequent transformations using functional handles in the macrocyclic scaffolds afforded additional structural diversity.

In addition, the chemoinformatic analysis of 32 unprecedented macrocyclic compounds using principal component analysis PCA and principal moments of inertia PMI analysis illustrated the possibilities of the resulting macrocycles to modulate novel biological targets through occupying unique chemical space distinct from the current synthetic drugs. Moreover, the successive ring-expansion SuRE strategy described by Unsworth et al. As shown in Figure 2Cii , the amide functionality present in the cyclic starter unit enabled coupling with the linear fragment via an acylation reaction, and subsequent deprotection and ring-opening along with chain incorporation yielded the ring-expanded product.

The key strength of the SuRE method is that the same coupling and ring-expansion sequence can be repeated as the reactive amide functionality is regenerated in the product.


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Using this simple SuRE strategy, a functionalized macrocycle library was successfully constructed. In this context, Tan et al. This strategy involves the oxidative dearomatization of bicyclic phenol precursors to provide polycyclic cyclohexadienones and a subsequent ring-expansion driven by rearomatization of the phenol ring to afford benzannulated medium-sized rings.

The structural and physicochemical similarities between the resulting 47 scaffolds and benzannulated medium ring-based natural products were confirmed by PCA analysis. Furthermore, Liu et al. In this strategy, the radical 1,4- or 1,5-aryl migration of unactivated alkenes and subsequent intramolecular ring-expansion provided benzannulated medium or large rings. Additional ring-distortion reactions of the resulting core skeletons afforded novel medium-sized and medium-bridged rings with high regio- and stereoselectivities.

PCA analysis and preliminary biological studies confirmed the significant biological relevance of this compound collection. In this mini review, we briefly emphasized the important roles of diversity-oriented synthesis DOS in the field of drug discovery and chemical biology, and introduced the most common DOS strategies for the construction of novel small molecule libraries with maximized molecular diversity.

We also discussed two key diversity-oriented synthetic approaches i. The combination of DOS-based molecular diversity and unbiased phenotypic screening may shed light on the unraveled signaling pathways and other intricate biological processes by allowing the sustainable supply of new drug candidates and chemical probes. SP directed the preparation of this manuscript. All authors critically reviewed the text and figures prior to submission. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Diversity-oriented synthesis of privileged benzopyranyl heterocycles from s- cis -enones. Biomimetic diversity-oriented synthesis of benzannulated medium rings via ring expansion. A strategy for the diversity-oriented synthesis of macrocyclic scaffolds using multidimensional coupling. Solid-phase synthesis of dysidiolide-derived protein phosphatase inhibitors. A planning strategy for diversity-oriented synthesis.

Generating skeletal diversity from the C 19 -diterpenoid alkaloid deltaline: Lessons from natural molecules. Diversity-oriented synthesis of macrocycle libraries for drug discovery and chemical biology. The exploration of macrocycles for drug discovery—an underexploited structural class. Methods for drug discovery: Macrocycles by ring-closing-metathesis, XI: Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules. The core technology of thermal expansion control is negative thermal expansion NTE materials: Such development has brought a paradigm shift for the control of thermal expansion.

For further improvement of the NTE functions and for the development of new materials, the achievements of the last two decades in this field are summarized briefly, particularly addressing recently discovered giant NTE materials Figure 1. Classification of negative thermal expansion materials. Materials are divisible into two categories: The origin of thermal expansion of solids can be summarized briefly Cochran, One might consider atoms connected together by springs as a model of solids, but these springs are anharmonic and do not exactly and simply obey Hooke's law. The atoms are prevented from becoming extremely close to one another because of Pauli's exclusion principle.

As a result, excursions to longer interatomic distances occur more readily than those to shorter interatomic distances. Consequently, the average interatomic distance increases concomitantly with increasing temperature T. More intuitively, one can generally infer from Pauli's exclusion principle that as the temperature rises and the thermal vibration of an atom increases, it tries to maintain its distance from other atoms to avoid mutual collision. This increasing distance with vibration explains thermal expansion.

In stark contrast to ordinary materials, some materials contract upon heating. Thermal expansion of these ionic bonds pulls the two-dimensional sheets closer together because these two-dimensional sheets are joined by strong covalent bonds that do not expand when heated Figure 2. This thermal distortion causes unit-cell volume contraction of 0. From another viewpoint, open spaces are filled by the thermal distortion of strong covalent bonds. This concept is exemplified more clearly in the open-framework or flexible-network materials described next. Schematic of anisotropic thermal expansion in the silicates.

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As the shaded layers undergo thermal expansion, they are pulled closer together in the direction perpendicular to the layer, which causes significant thermal contraction in this direction and yields slight net volumetric thermal contraction. Flexible-network materials are a well-known family of NTE materials that includes ZrW 2 O 8 and vanadates and phosphates of certain kinds Mary et al. This network consists of rigid units connected by soft linkages. The rigid units are formed by strong covalent bonds. Therefore WO 4 units are rigid.

They do not expand on heating. Transverse oxygen displacement is induced easily on heating. These displacements consume open spaces in the crystal structure, resulting in volumetric NTE Figure 3. Different from the silicates, anisotropic lattice thermal expansion is unimportant. The volume change related to NTE is much greater. NTE appears at the whole T range below K.

Schematic of negative thermal expansion in a flexible network. A vibrational mode consuming an open space in a crystal lattice is thermally excited, which yields net volumetric thermal contraction. Negative thermal expansion that is explainable from the concept that strong atomic bonds and thermally induced deformation fill open spaces in the crystal lattice explains conventional NTE materials Figure 1 , which include widely diverse materials.

In addition to cyanides Chapman et al.

This type of NTE has a structural origin for its phenomena. Therefore, NTE appears in almost the entire T range, which is extremely important industrially. Because the coexistence of strong and not strong chemical bonds is fundamentally important for conventional NTE, low thermal conductivity and low stiffness are unavoidable in these materials. Low thermal conductivity and low stiffness are weak points even for some phase-transition-type NTE materials described in the next chapter. Diligent efforts are continuing toward overcoming them. For example, high thermal conductivity is indispensable for rapid heat dissipation of devices.

Development of NTE materials with high thermal conductivity is desired. Various attempts have been made to overcome the shortcomings of the conventional NTE materials presented in the preceding chapter. The current trend of NTE material development is to use the phase transition accompanied by volume contraction upon heating. The giant NTE of manganese nitride strongly influenced subsequent NTE research, leading to the discovery of many NTE materials using magnetic, ferroelectric, charge-transfer, and metal—insulator phase transitions. The phase-transition type NTE concept became dominant in the field Figure 1.

Specifications of the recently discovered giant NTE materials are presented in Table 1. Despite that operating temperature window limitation, it is of great importance that it suppresses the thermal expansion of plastics, which has heretofore been difficult. Parameters related to crystallographic negative thermal expansion for prototypical materials. For phase-transition-type NTE materials, a certain mechanism causes excessive shrinkage that can overcome positive lattice thermal expansion.

The mechanisms of prototypical phase-transition-type NTE are described in this chapter.

It is noteworthy that the mode of classification, including the conventional type, is not absolute. For example, ferroelectric transition and charge-transfer transition have a common point of charge disproportionation. Other phase transitions such as structural phase transition are often coupled with the magnetic transition. It is difficult to increase it artificially. The magnetovolume effect is a phenomenon by which the volume changes according to the amplitude of the magnetic moment in itinerant systems.

Generally speaking, less-itinerant electrons are necessary for magnetism. Electronic spins are aligned via the exchange interaction. That exchange interaction does not work well when electrons are itinerant. Volume expansion decreases the overlap of electronic orbitals and makes electrons less itinerant.

This effect is explainable by the electronic theory of solids as follows: Therefore, if possible, the system expands the volume to assist magnetism when the magnetic order sets in. This expansion is the magnetovolume effect, which is intimately related with the origin of magnetism in metals.

Therefore, it has persisted as a central topic in the field of condensed-matter physics. Relation between volume and density of states at the Fermi level D E F schematic. Volume expansion shrinks the electronic band width and therefore enhances D E F , which is favorable for the magnetic state. It also strengthens the electronic repulsion effects. The materials classified into this category include 36Ni-Fe alloy Invar alloy, which has low thermal expansion rather than negative thermal expansion Wasserman, , Fe 3 Pt Sumiyama et al. The low thermal expansion of 36Ni-Fe Invar alloy was reportedly explained by the difference in atomic radius in the early stages of research.

A controversy has long persisted van Schilfgaarde et al. Although details are not included herein, metallic electronic images are regarded as superior in the sense that they can universally explain the magnetovolume effect of various materials, not merely Invar alloys.

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Nevertheless, differences in atomic radius between high-spin and low-spin states can play an important role in volume change in real materials such as cobalt oxides Burley et al. Negative thermal expansion is reported also for localized-moment magnets of certain kinds.

Actually, NTE is known to appear in the T range of several tens of degrees on the high T side of the magnetic transition with a compound having a certain spinel or breathing pyrochlore structure Hemberger et al. In these materials, NTE disappears below the critical temperature at which the magnetic long-range order is formed. The generalized framework extended to the strain derivative of J is also discussed Filippetti and Hill, The argument based on the Bethe—Slater curve of single J discussed previously is too naive to explain the diverse phenomena of real materials.

However, if there exist multiple e. From general consideration of the relation between valence and bond length, the averaged bond length in the charge disproportionate case is greater than the bond length in the charge uniform case Evans, , Figure 6. Atomic bonds are readily expanded, but they are difficult to shrink. We can regard that fact as representing a kind of anharmonicity of atomic bonds. It is noteworthy that anisotropy is fundamentally important for NTE materials of this type.

Phenomenologically, dielectric polarization corresponds to volume change Chen et al. Schematic of negative thermal expansion in a ferroelectric material with charge disproportionation. When charge disproportionation occurs, because the higher-valence interatomic bond length does not shrink as much as the lower-valence one expands Bottom , the bond length becomes longer than that of the averaged case Upper. When charge transfer occurs between the constituent elements, atoms with an increasing number of valence electrons become larger. On the other hand, those with a decreasing number of valence electrons become smaller.

However, the change in the atomic radius varies according to the atomic species, electronic configuration, etc. In addition, the effect of the atomic radius on the crystal size depends on the atom's position in the crystal structure. If the contribution from atoms with a decreasing number of valence electrons upon heating is greater, then one can expect net NTE. A famous example of charge-transfer-type NTE materials, bismuth-nickel oxides Azuma et al.

When these oxides are warmed, charges are transferred from Ni to Bi. Therefore, the atomic radius of Ni contracts and that of bismuth expands on warming, but the atomic radius of nickel dominates the lattice volume because the Ni—O octahedron dominates the lattice volume. For that reason, the net volumetric NTE occurs in the bismuth-nickel oxide. Negative thermal expansion is also induced by intra-atomic charge transfer that increases the 4 f electron number with decreasing temperature.

In the case of Sm, two electronic configurations of 4 f 5 5 d 1 and 4 f 6 compete energetically, but the atomic radius is determined mainly by the 4 f electron number. Therefore, NTE appears if the electrons are transferred from the 5 d to the 4 f orbitals with decreasing temperature. An example in which the effect of electronic repulsion manifests as an apparent physical property is a Mott insulator Mott, In transition metal compounds of a certain kind, the metallic state is often lost because of electronic correlations at low temperatures and the system becomes an insulating state.

This transition is called a Mott transition. Generally, a Mott insulating state appears at the lower- T side. The volume of the low- T insulating phase is known to expand upon Mott transition for V 2 O 3 1. The mechanism of volume expansion in the insulating state might resemble a magnetovolume effect in the itinerant-electron magnets Figure 5. It can be understood that volume expansion suppresses the bandwidth and that it therefore enhances electronic-correlation effects, which stabilizes the low- T Mott insulating state.

Furthermore, Ca 2 RuO 4 Takenaka et al. Some materials are also known to have volume of the low- T phase which becomes greater than that of the high- T phase with the phase transition because of mechanisms other than the four explained above. They are not understood so systematically as the four above, but they are suggestive for the development of new materials. They are therefore explained here. Silver iodide, AgI Lawn, ; Kumar et al. Related to a structural phase transition, certain martensitic transformations accompany volume expansion on cooling.

For example, MnCoGe is known to expand by 3. Correlation between magnetism and structure in these materials is an interesting subject that has yet to be explored Kanomata et al. Although the relation between NTE and superconductivity is not well understood, Ca 0. These results suggest that an orbital-ordering transition might be a universal mechanism of NTE. From the viewpoint of the mechanism of how the sharp volume change accompanying the first-order phase transition becomes a gradual change with temperature, the phase-transition-type NTE materials are broadly divisible into two categories: In the former category, which includes bismuth-nickel oxides Azuma et al.

NTE is induced because the volume fraction of the L phase increases concomitantly with decreasing T. In the latter category, which includes magnetic NTE materials such as antiperovskite manganese nitrides Takenaka and Takagi, ; Hamada and Takenaka, ; Wang et al. Negative thermal expansion of these materials is characterized by a gradual increase in the unit-cell volume of a single phase with decreasing T without phase separation.

For manganese nitrides, a detailed neutron diffraction study Iikubo et al. For the phase-transition-type materials, the mechanism of broadening the volume change is a key issue dominating the operating-temperatures of NTE. To elucidate the broadening mechanism, a certain kind of diffraction study and microscopic observations are required in addition to dilatometry. Negative thermal expansion discussed in the former chapters is associated with NTE of the crystallographic unit cell. For these materials, NTE of the unit cell found using a crystallographic technique such as x-ray diffraction and NTE of the bulk measured using a dilatometric technique are fundamentally equal.

Data related to the warming process were collected using a laser interference dilatometer. Referred from earlier reports Takenaka et al. For comparison, data of MnCo 0. Therefore, Ca 2 RuO 4 is classified as the metal—insulator transition category of NTE described in the preceding chapter. Even in our sample showing a huge bulk NTE, during warming from to K, the c axis expands by 4. The colossal NTE of Ca 2 RuO 4 ceramics is proposed as explainable by anisotropic thermal deformation of the crystal grain which fills in the volume of pores that are contained in the sintered body Figure 8.

Such deformation is trivial in the field of ceramics. The ceramic body consists of crystal grains with anisotropic thermal expansion and pores. When the temperature increases, the crystal grain expands in one direction and contracts in a perpendicular direction. If there exists open space in the direction in which the crystal grain expands, then this ceramic body contracts.

The ruthenium oxides are characterized by rather low onset temperatures of anisotropic thermal expansion of the unit cell, which is about K. Therefore, the inner stress accumulates greatly during cooling to room temperature. Compared with those, the accumulated inner stresses are expected to be much smaller for the ruthenates. Recently reported theoretical calculations indicate that the microstructural effects without cracks can reproduce the gigantic NTE observed in the ruthenate sintered body Takezawa et al.

Examples for which the material structure is deeply involved in the bulk function of NTE do not exist among recently discovered NTE materials.