Three-Axial Chirality

The introduction of chirality into the NHC framework follows diffoent principles than that of traditional phosphane ligands. Whaeas phosphanes are conically shaped [1] ligands with a tet-rahedrally coordinated central phosphorus atom, NHC are planar disc-like ligands based on the aromatic imidazole system (see Chapter 1). It follows that phosphanes are asymmetric owing to a stericaUy active and stable lone pair, whereas the chirality in the traditionaT NHC defines itself through a peripheral chiral element This element can be an asymmetric atom (central chirality), an axial chiral element (an atropisomeric binaphthyl substiment) or planar chirality (double substitution on an aromatic ring system, planar chiral substituent). Combinations of these three types of chirality are possible and can be realised in a more or less facile protocol. 

The third section describes the hierarchy and supramolecular chirality of molecular assemblies in the crystalline state. The steroidal molecules construct hierarchical assemblies on the basis of sequential information, as in the case of proteins. The notable feature is that each hierarchical assembly exhibits supramolecular chirality, such as three-axial, tilt, helical, and bundle chirality. On the other hand, the primary ammonium salts construct hierarchical hydrogen bonding networks which, in some cases, create supramolecular chirality from achiral components. The creation of chirality can be interpreted from a topological viewpoint, leading us to define the handedness of the supramolecular chirality. At the end of this section we present the general concept that molecular-level information on organic substances can be expressed by their assemblies through non-covalent interactions. 

Since the steroidal molecules are highly asymmetric, the resulting hierarchical assemblies may have the corresponding three-dimensional structures with supramolecular chirality. Starting from molecular chirality, each assembly must be chiral. In this context, we encountered a new problem, how we describe such molecular and supramolecular chirality. The first idea is that the steroidal molecules are analogous to a vertebrate animal which has three-axial chirality based on three directions such as head-leg, right-left, and belly-back. The three-axial chirality enables us to determine the three-axes of the hierarchical assemblies, as in the case of the helices of proteins and DNA. 

Expression of Supramolecular Chirality in Hierarchical Assemblies 26.4.2.1 Three-Axial Chirality... 

In order to distinguish enantiomorphic structures, molecular chirality has conventionally been expressed in terms of center-, axis-, and plane-chirality. In the case of compounds involving several stereogenic centers, however, these terms seem to be insufficient to express their whole molecular chirality or anisotropy, although their local chirality is well confirmed in the conventional manner. Indeed, the steroidal molecules (Figure 26.13a), which have asymmetric, amphiphilic, facial structures with multiple stereogenic carbon atoms, are saddled with such a structural complexity. In order to solve this problem, we introduced a simple but unique concept, three-axial chirality , as shown in Figure 26.13b. Such three-axial chirality is based on the orthorhombic three axes applied in a molecular structure and is expressed by... 

Figure 26.13 Expression for three-axial chirality of cholic acid molecule, (a) A molecular structure of cholic acid, (b) a space-filling model of cholic acid with the three-axial chirality expression, as in the case of (c) a vertebrate amimal.

Figure 26.15 Schematic representation of supramolecular chirality in the 2n helices and their bundles, (a) Three-axial chirality in an asymmetric molecule, (b) assembly modes of the two molecules, (c) terms expressing the chirality of the helix right- or left-handed, up or...

The numerous chiral phosphine ligands which are available to date [21] can be subclassified into three major categories depending on the location of the chiral center ligands presenting axial chirality (e.g., BINAP 1 and MOP 2), those bearing a chiral carbon-backbone (e.g., DIOP 3, DuPHOS 4), and those bearing the chiral center at the phosphorus atom (e. g., DIPAMP 5, BisP 6), as depicted in Fig. 1. 

Bearing this in mind, however, it is not possible to interpret the three cases of 13-15, all characterized by negative diene chirality. If diene chirality and allylic axial contributions act in the same sense, how can we explain a positive Ae for 15, having M chirality This question opens the problem of a more thorough evaluation of all the contributions to the diene optical activity. 

Concurrent with studies on cyclometalation, studies on the effects of the structure of phosphoramidite ligand had been conducted. Several groups studied the effect of the stmcmre of ligand on the rate and selectivity of these iridium-catalyzed allylic substitutions. LI contains three separate chiral components - the two phenethyl moieties on the amine as well as the axially chiral BINOL backbone. These portions of the catalyst structure can control reaction rates by affecting the rate of cyclometalation, by inhibiting catalyst decomposition, or by forming a complex that reacts faster in the mmover-limiting step(s) of the catalytic cycle. 

In 2004 and 2005, respectively, Bach and Miller independently described the use of chiral thiazolium salts as pre-catalysts for the enantioselective intramolecular Stetter reaction. Bach and co-workers employed an axially chiral A-arylthiazolium salt 109 to obtain chromanone 73 in 75% yield and 50% ee (Scheme 16) [77]. Miller and co-workers found that thiazolium salts embedded in a peptide backbone 65 could impart modest enantioselectivity on the intramolecular Stetter reaction [78]. In 2006, Tomioka reported a C -symmetric imidazolinylidene 112 that is also effective in the aliphatic Stetter reaction, providing three examples in moderate enantioselectivities (Scheme 17) [79]. 

Addition of cinnamyl(mesityl)zinc to the C2 symmetrical cyclopropenone ketal 133 led to excellent diastereoselectivities with respect to the newly formed carbon—carbon bond (de = 97%) and induction from the chiral ketal (de = 91%). Deuteriolysis afforded the cyclopropanone ketal 134 in which three stereocenters have been generated99,10°. A product-like transition state model was proposed, in which the cyclopropene underwent considerable rehybridization and the zinc became preferentially attached to the less hindered equatorial olefinic carbon from the face opposite to the axial ketal methyl group (equation 65). 

Three types of reaction systems have been designed and applied for the enantioposition-selective asymmetric cross-coupling reactions so far. First example is asymmetric induction of planar chirality on chromium-arene complexes [7,8]. T vo chloro-suhstituents in a tricarhonyl("n6-o-dichlorobenzene)chromium are prochiral with respect to the planar chirality of the 7t-arene-metal moiety, thus an enantioposition-selective substitution at one of the two chloro substituents takes place to give a planar chiral monosubstitution product with a minor amount of the disubstitution product. A similar methodology of monosuhstitution can be applicable to the synthesis of axially chiral biaryl molecules from an achiral ditriflate in which the two tri-fluoromethanesulfonyloxy groups are enantiotopic [9-11]. The last example is intramolecular alkylation of alkenyl triflate with one of the enantiotopic alkylboranes, which leads to a chiral cyclic system [12], The structures of the three representative substrates are illustrated in Figure 8F.1. 

Abstract It is well known that spontaneous deracemization or spontaneous chiral resolution occasionally occurs when racemic molecules are crystallized. However, it is not easy to believe such phenomenon will occur when forming liquid crystal phases. Spontaneous chiral domain formation is introduced, when molecules form particular liquid crystal phases. Such molecules possess no chiral carbon but may have axial chirality. However, the potential barrier between two chiral states is low enough to allow mutual transformation even at room temperature. Therefore the systems are essentially not racemic but nonchiral or achiral. First, enhanced chirality by doping chiral nematic liquid crystals with nonchiral molecules is described. Emphasis is made on ester molecules for their anomalous behavior. Second, spontaneous chiral resolution is discussed. Three examples with rod-, bent-, and diskshaped molecules are shown to give such phenomena. Particular attention will be paid to controlling enantiomeric excess (ee). Actually, almost 100% ee was obtained by applying some external chiral stimuli. This is very noteworthy in the sense that we can create chiral molecules (chiral field) without using any chiral species. 

Once the [3+2] mechanism was accepted as the operative one, to investigate the transition states associated with the formation of the osmate ester in a chiral system, one must take into account all of the different ways that an olefin can approach the catalyst. These different paths were classified according to the criteria shown in Fig. 12. The olefin binds to an axial and to an equatorial oxygen, providing three different families of reaction paths labeled as regions A, B and C. When the olefin has one substituent, it can be placed in four different orientations , which are labeled as I, II, III, IV. The... 

The chiral self-discrimination of twelve molecules showing axial chirality (Scheme 3.13), has been studied by means of DFT (B3LYP/6-31+G ) and ab initio (MP2/6-31+G and MP2/6-311++G ) methods [25]. The interaction energy of the complexes was corrected with the inherent basis set superposition error (BSSE) and the zero point energy (ZPE). The results show similar qualitative tendencies for the three methods considered. 

ABSTRACT Numerous molecules containing a biaryl unit have been found in Nature. Many of them exhibit a variety of biological actions. In this review, we will focus only on natural bridged biaryls that possess axial chirality and exhibit antimitotic activities. Thus, we will first present the occurrence and structure of three families of natural compounds that display these particular structural and biological features the allocolchicinoids, steganes and rhazinilam-type compounds. We will then describe the semi-synthetic and synthetic approaches to biaryls belonging to these three series. Their interaction with tubulin, a heterodimeric protein that is critical for the formation of microtubules and consequently of the mitotic spindle, will be discussed. 

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