1 - atropisomers

If compounds have the same topology (constitution) but different topography (geometry), they are called stereoisomers. The configuration expresses the different positions of atoms around stereocenters, stereoaxes, and stereoplanes in 3D space, e.g., chiral structures (enantiomers, diastereomers, atropisomers, helicenes, etc.), or cisftrans (Z/E) configuration. If it is possible to interconvert stereoisomers by a rotation around a C-C single bond, they are called conformers. 

Chiral separations are concerned with separating molecules that can exist as nonsupetimposable mirror images. Examples of these types of molecules, called enantiomers or optical isomers are illustrated in Figure 1. Although chirahty is often associated with compounds containing a tetrahedral carbon with four different substituents, other atoms, such as phosphoms or sulfur, may also be chiral. In addition, molecules containing a center of asymmetry, such as hexahehcene, tetrasubstituted adamantanes, and substituted aHenes or molecules with hindered rotation, such as some 2,2 disubstituted binaphthyls, may also be chiral. Compounds exhibiting a center of asymmetry are called atropisomers. An extensive review of stereochemistry may be found under Pharmaceuticals, Chiral. 

In addition to constitution and configuration, there is a third important level of structure, that of conformation. Conformations are discrete molecular arrangements that differ in spatial arrangement as a result of facile rotations about single bonds. Usually, conformers are in thermal equilibrium and cannot be separated. The subject of conformational interconversion will be discussed in detail in Chapter 3. A special case of stereoisomerism arises when rotation about single bonds is sufficiently restricted by steric or other factors that- the different conformations can be separated. The term atropisomer is applied to stereoisomers that result fk m restricted bond rotation. ... 

The property of chirality is determined by overall molecular topology, and there are many molecules that are chiral even though they do not possess an asymmetrically substituted atom. The examples in Scheme 2.2 include allenes (entries 1 and 2) and spiranes (entries 7 and 8). Entries 3 and 4 are examples of separable chiral atropisomers in which the barrier to rotation results from steric restriction of rotation of the bond between the aiyl rings. The chirality of -cyclooctene and Z, -cyclooctadiene is also dependent on restricted rotation. Manipulation of a molecular model will illustrate that each of these molecules can be converted into its enantiomer by a rotational process by which the ring is turned inside-out. ... 

Meyers has also reported the use of chiral oxazolines in asymmetric copper-catalyzed Ullmann coupling reactions. For example, treatment of bromooxazoline 50 with activated copper powder in refluxing DMF afforded binaphthyl oxazoline 51 as a 93 7 mixture of atropisomers diastereomerically pure material was obtained in 57% yield after a single recrystallization. Reductive cleavage of the oxazoline groups as described above afforded diol 52 in 88% yield. This methodology has also been applied to the synthesis of biaryl derivatives. 

The axially chiral natural product mastigophorene A (70) was synthesized via a copper-catalyzed asymmetric homocoupling of bromooxazoline 68. Treatment of 68 with activated copper in DMF afforded 69 in 85% yield as a 3 1 mixture of atropisomers. The major atropisomer was converted into mastigophorene A (70) the minor regioisomer was transformed into the atropisomeric natural product mastigophorene... 

It is in the study of this phenomenon where two-dimensional GC offers by far the most superior method of analysis. The use of chiral selector stationary phases, in particular modified cyclodextrin types, allows apolar primary and atropisomer selective secondary separation. Reported two-dimensional methods have been successful... 

Atomic spectroscopy, 1, 231-234 Atropisomers, 1,200 Aurintricarboxylic acid beryllium(II) complexes, 2, 482 Aurocyanides dissolution, 6,784 Autotrophic bacteria... 

There is no plane of symmetry and the molecule is chiral many such compounds have been resolved. Note that groups in the para position cannot cause lack of symmetry. Isomers that can be separated only because rotation about single bonds is prevented or greatly slowed are called atropisomers. 9,9 -Bianthryls also show hindered rotation and exhibit atropisomers. °... 

Atropisomerism occurs in other systems as well. A sulfoxide (16), for example, forms atropisomers with an interconversion barrier with its atropisomer of 18-19kcal mol . The atropisomers of hindered naphthyl... 

Here, ry is the separation between the molecules resolved along the helix axis and is the angle between an appropriate molecular axis in the two chiral molecules. For this system the C axis closest to the symmetry axes of the constituent Gay-Berne molecules is used. In the chiral nematic phase G2(r ) is periodic with a periodicity equal to half the pitch of the helix. For this system, like that with a point chiral centre, the pitch of the helix is approximately twice the dimensions of the simulation box. This clearly shows the influence of the periodic boundary conditions on the structure of the phase formed [74]. As we would expect simulations using the atropisomer with the opposite helicity simply reverses the sense of the helix. 

A methylenation of cyclic carbonates such as 6/4-132 using dimethyltitanocene to give a ketene acetal, followed by a subsequent Claisen rearrangement, allowed the synthesis of medium-ring lactones such as 6/4-133 in good yields these are otherwise difficult to obtain. In this transformation, 6/4-133 is formed as a l l-mix-ture of the two atropisomers 6/4-133a and 6/4-133b (Scheme 6/4.33). The substrate... 

The barrier to atropisomerization is also lower for the hypocrellins due to introduction of the seven-membered ring bridging the Cl,Cl -positions. In fact, hypocrellin A (7) and hypocrellin (ent-1) both exist as rapidly atropisomerizing mixtures of diastereomers at room temperature, as revealed by NMR studies by Mondelli. Here, two sets of sharp peaks of the resultant diastereomers are observed in the NMR spectra of each natural product [35]. Figure 7.2 presents the structures of hypocrellin A (7) and its atropisomer, atrop-1, which exist as an equilibrium... 

VT NMR showed that N3-[3]polynorbomane 164 existed as an equilibrium mixture of the syn-atropisomer 164a and anti-atropisomer 164b (ratio 1 1.7). NMR spectroscopy allowed distinction between the isomers on the basis of symmetry. The syn-isomer 164a exhibited two well-separated ester methyl resonances (8 3.67, 4.05) as predicted for the isomer with Cs-symmetry, whereas the anft -isomer 164b displayed a single ester methyl resonance (8 3.85) in accord with that expected for a compound with C2-symmetry. It was not possible to isolate the separate atropisomers in this system since the energy barriers governing rotation were too low. 

More success was obtained in the WL, NZ-diazasesquinorbomane series where it was possible to lock the N-Z isomers in conformations that were stable in solution to well above 100 °C. Thus, reaction of the N-Z 7-azanorbomadiene-2,3-anhydride 165 with N-Z pyrrole 166 yielded a single stereoisomer 167 in which the N-Z bridges were syn-facially related (Scheme 30). H NMR spectroscopy indicated that the N-Z groups were undergoing rotation in solution at room temperature and provided evidence for syn- and anri-atropisomers being present at lower temperature. 

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