Atropisomeric compounds

N-(2,6-Disubstituted)phenyl-triazolones constitute a very interesting class of atropisomeric compounds (04T4361). They are inhibitors of mitochondrial respiration and it was shown that the biological activity was related to the presence of a substituent in the blocking position of the N-aryl group. 

One of the most interesting properties of photochemistry is that the high energy of excited states allows for the transformation of weak interactions into covalent bonds. A most interesting class of reactions involves atropisomeric compounds, as an example the cycloaddition of diacrylimides 3, which occurs with high diastero (de 99%) and enantioselectivity (ee 99%) in solution in isotropic media and can be carried out both by visible light irradiation and by triplet sensitization, as well in the solid state (Scheme 4). ... 

A particular case in this category is that of atropisomeric compounds (those where chirality originates from a barrier to rotation over a single bond). In a thermal reaction, racemization occurs unless the temperature is sufficiently low. The peculiar temperature independence of photochemical reactions allows to transform axis chirality into point chirality with no loss. 

Optically active 3,3 -bithienyls have served as excellent models for the study of conformational and configurational effects on the c.d. curves of atropisomeric compounds. 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

On page 132, atropisomerism was possible when ortho substituents on biphenyl derivatives and certain other aromatic compounds prevented rotation about the bond. The presence of ortho-substituents can also influence the conformation of certain groups. In 88, R= alkyl, the carbonyl unit is planar with the trans C=0 - F conformer more stable when X=F. When X=CF3, the cis and trans are planar and the trans predominates. When R = alkyl there is one orthogonal conformation but there are two interconverting nonplanar conformations when R=0-alkyl. In 1,2-diacylbenzenes, the carbonyl units tend to adopt a twisted conformation to minimize steric interactions. " ... 

An interesting series of high Ts HTMs based on novel indolo[3,2-b]carbazoles has been discovered by the Xerox group [85]. These compounds not only showed the desired hole transport properties and high Ts of 164°C but also display an unusual atropisomerism with two discrete trans- and U.v-rotational isomers (Scheme 3.14), which greatly improves their tendency to form stable amorphous glasses. 

The concept of atropisomerism developed to a considerable extent following other developments in chemistry, especially those in spectroscopy. Early work by Kohlrausch (4) and Mizushima (3), based on Raman spectra and dipole moment studies, established that rotational isomers—rotamers—must exist in 1,2-dichloroethane. Pitzer established that there are three energy minima when ethane is rotated about its C—C axis (6). Rotamers about single bonds have been found in a wide variety of organic compounds since then, mainly as a result of the application of vibrational spectroscopy to organic molecules (7). 

As has been mentioned, the term atropisomerism has a broad meaning. If we discuss atropisomerism from the standpoint of vibrational spectroscopy, then almost all organic compounds would give rise to atropisomers. If we are discussing atropisomerism from the standpoint of NMR spectroscopy, then it is necessary to specify the temperature at which we measure the spectrum. The strength of the main magnetic Held (or observation frequency) is also a concern. Eliel discussed the term residual isomerism in this connection (12). Since we cannot cover all types of atropisomerism here, the present discussion will be confined to atropisomerism wherein isomers are isolated chemically. 

The most classical examples of atropisomerism, biphenyls, fall into this category. They form enantiomers because the two benzene rings are not coplanar and both rings are substituted unsymmetrically so that the plane passing through the pivot bond and one of the benzene rings cannot be a a plane. If we consider the conformations of biphenyls in more detail, we recognize that there are two diastereomeric conformations possible, as depicted in Scheme 3 for a compound... 

The high barriers in compounds 31 and 32 may be attributed to the fact that in these compounds the two carbonyl groups are coplanar with the enamine moiety, whereas such a coplanar structure is impossible for the open-chain compounds. Based on this point of view, Kdlle and associates extended the work further and were able to isolate a series of compounds (33,34) in one crystalline atropisomeric form (73). 

K. Therefore, the chloro group in compound 124 (M = Si) raises the barrier more than did the methoxycarbonyl group in 125, when the skeleton is 9,10-dihydro-9,10-ethenoanthracene. As expected, when the skeleton was changed from dihydroethenoanthracene to triptycene, the barrier was raised. Thus 9-trimethylsilyl-l,4-dimethoxytriptycene (126) did not show coalescence of the methyl signals, although the solution was heated to 180°C. The barrier to rotation was thus estimated to be in excess of 25 kcal/mol. In order to confirm the indication from NMR spectroscopy that atropisomerism of this type should be... 

The broad and nearly universal applicability of the cinchonan carbamate CSPs for chiral acid separations is further corroborated by successful enantiomer separations of acidic solutes having axial and planar chirality, respectively. For example, Tobler et al. [124] could separate the enantiomers of atropisomeric axially chiral 2 -dodecyloxy-6-nitrobiphenyl-2-carboxylic acid on an C-9-(tert-butylcarbamoyl)quinine-based CSP in the PO mode with a-value of 1.8 and Rs of 9.1. This compound is stereolabile and hence at elevated temperatures the two enantiomers were interconverted during the separation process on-column revealing characteristic plateau regions between the separated enantiomer peaks. A stopped-flow method was utilized to determine the kinetic rate constants and apparent rotational energy barriers for the interconversion process in the presence of the CSP. Apparent activation energies (i.e., energy barriers for interconversion) were found to be 93.0 and 94.6 kJ mol for the (-)- and (-l-)-enantiomers, respectively. 

As has been elaborated elsewhere, activation energies measured for the thermal atropisomerization of these porphyrins and their metal complexes can be correlated with the degree of core rigidity and/or distortion from planarity for the different compounds (31) ... 

Compounds with at least one stereogenic center and one stereogenic axis (this also includes anti-Bredt-olefins that exist in two stable atropisomeric forms). 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

Scheme 77 illustrates some examples of the enantioselective reactions induced by chiral Ni catalysts (187). Atropisomeric binaphthyl or ter-naphthyl compounds can be obtained in high ee with these catalysts. The stereochemistry of the reactions may be determined kinetically by the diastereomeric diorganonickel(II) intermediates. These intermediates have a chiral propeller structure that undergoes little epimerization because of steric hindrance. 

The possibility of optical isomerism arising from restricted rotation (atropisomerism) about the 2,2 -bond in 3-substituted 2-(2-naphthyl)-benzo[6]thiophenes has been recognized by Lamberton and McGrail.54 Schuetz and Ciporin164 have interpreted the UV spectra of six 3-aryl-benzo[6]thiophenes according to a theory of steric hindrance to free rotation about the pivot bond of the two aromatic rings, but the results are now invalid, since some of the 3-arylbenzo[6]thiophenes used in this study have been shown to be the corresponding 2-isomers (see Section IV, C). No attempt appears to have been made to resolve compounds of this type. 

Biaryl bisphosphines, atropisomeric, in hydrogenation, 10, 2 Biaryl-bridged bis(iminooxazolidine) complexes, with Zr(IV) and Hf(IV), 4, 811-812 Biaryl compounds, directed synthesis, 10, 145 Bicyclic arenes, in hexaruthenium carbido clusters,... 

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