Isomers atropisomers

The crystal and molecular structure of (S)-7-phenyldinaph[2,l-h T,2 -d]arsole (82), which was obtained by spontaneous resolution of the racemate from hot methanol, reveals appreciable bending of the distorted naphthyl residues away from each other (Scheme 4) . The molecule is fluctional in solution on the NMR time scale, however, with similar barriers between the conformational isomers (atropisomers) for the 7-phenyl [AG 59 1 kJ mol" (259 K)] and the 7-methyl [AG 65 1 kJmol" (287 K)] compounds. The analogous phospholes are also unsuitable for resolution because of similarly low barriers to inversion of the atropisomers - Both arsenic ligands, when coordinated to iron(II) in complexes of the type [( -C5H5) l,2-C6H4(PMePh)2 FeL]PFg,... 

The existence of stable conformational isomers (atropisomers) may be a complication, since mixtures can be formed during a derivatization but it offers (in principle) additional synthetic possibilities which have already been widely used in the calix[4]arene series, where the four basic conformers are easily distinguished by NMR (Table 3). 

TABLE 3. H NMR signals in conformational isomers (atropisomers) of caUx[4]arene tetraethers la with Y = CH2R (R is a residue which shows no coupling with the adjacent CH2 group) and R = C(CH3>... 

The reaction of 2,2 -dilithio-l,l -biiu hlhyl with RASCI2 (R=Me or Ph) provided the corresponding (+)-7-R-ditiaphtho[2,1 -fe 1, 2 -d]arsoles [ (6)]. The molecules are fluxional in solution with barriers between the conformational isomers (atropisomers) of 6S 1 (R=Me) and 60 1 kcal mof (R=Ph). An X-ray diffiaction study of [(5 - (6, R=Ph)], vdiich crystallized out by spontaneous resolution, revealed appreciable bending of the distorted luqshthyl residues away from each other. ... 

The total synthesis of CP-465,022 is described. This former drug candidate exists as two separable rotational isomers (atropisomers). The discovery and separation of these rotational isomers is described, as well as the methodology used to prepare the pyridyl sidechain and the quinazolinone nucleus. Testing showed that the desired biological activity existed in just one of the atropisomers. 

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. 

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. °... 

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. 

Those organic compounds that exhibit separate signals in vibrational or other kinds of spectroscopy due to rotamers do not necessarily give rise to atropisomers in the classical sense of Kuhn. It is now well known that, in order to recognize two isomers by a spectroscopic method, the mean lifetime (t) of the isomer must exceed... 

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. 

Even though we define the atropisomerism as above for present purposes, there remain some ambiguities. sym-Tetrabromoethane was obtained in different modifications according to the method of crystallization at low temperature (13). These were found by spectroscopy to correspond to retainers. Similar situations occur in other alkyl halides and acetates (14,15). Such cases will not be included in the discussion, mainly because crystalline atropisomers are isolated at far lower temperatures than die ambient, and their barriers to rotation have not been determined by equilibration. Also excluded is the isolation of chlorocyclohexane (16). The isolation of the equatorial and axial conformational isomers was possible only by crystallization of the former at - 150°C, although it was possible to observe equilibration between the equatorial and the axial forms at higher temperatures. 

Since atropisomers are conformational isomers, their stereochemistry should be designated by IUPAC nomenclature rule E (23). For the convenience of the reader, the rule will be outlined here. A sequence number is given to substituents connected to the rotational axis according to the Sequence Rule (24), as follows. 

The barrier to rotation was 21.5 kcal/mol at 160°C. They extended this work in 1969 and were able to isolate the atropisomers of 4-(/V-benzyl-/V-methylaminomethy lene)-1,2-diphenyl- l,2-diazolidine-3,5-dione (32). The E isomer was isolated pure, and the Z isomer 93% pure (72). An equilibrium mixture in chloroform-d solution at 28.5°C contained 40% Z and 60% E. To distinguish the barriers to rotation about the C=C and the C—N bonds, the barriers were... 

Such barriers are high enough for the isolation of atropisomers if the benzene ring is properly substituted. Miller and Curtin (112) brominated 71 and were able to isolate 86% pure ap isomer of the dibromo compound (73). The barrier... 

Treatment of either the sc or the ap atropisomer of the diester (97) with potassium hydroxide effected the hydrolysis of only one of the ester groups for steric reasons, to afford monocarboxylic acid sc-98 and ap-98, respectively. The sc isomer was converted into a nienthyl ester (99) for resolution into optical isomers. Thus the three rotameric forms of the monocarboxylic acid ( + sc, -sc, ap) were isolated (142). 

In the syntheses of these compounds, very high stereoselectivity was noted. In every case, the entering dienophile approaches the least hindered side of the substituted anthracene. Thus tire ap isomer is the almost exclusive product of the reaction. As an extension of this finding, atropisomers of 9-(l,I-dimethyl-2-phenylethyl)-2,3-dichlorotriptycene (101) were prepared separately the ap form by treating 9-( 1,1 -dimethyl-2-phenylethyl)anthracene with 4,5-dichlorobenzyne, and the sc form by treating 2,3-dichloro-9-(l,l-dimethyl-2-phenylethyl)-... 

Stable, isolable atropisomers 170 and 171 of the C-20 unsubstituted carbo-methoxycleavamines 172 and 173 (Scheme 46). On heating to 40°C (for 171) or 100°C (for 170), these compounds could be converted to their respective lower energy conformational isomers 172 and 173 121). 

However for the tetraphenylporphyrin diacid the increase in conjugation resulting from interaction of the almost coplanar phenyl TT-systems with the porphyrin 7r-system results in a red shift of the visible bands ( ). For the individual atropisomers of H PF,THA the 4,0 isomer exhibits a net blue shift upon protonation while the diacid of the trans-2,2 isomer is significantly red shifted. Small spectral shifts are seen for the cis-2,2 and 3t1 isomers. This has in turn been interpreted to mean that in the excited singlet state "stabilities are shifted such that trans-2,2 > 3,1 > cis-2,2 > 4,0 for this diacid. A comparison of the spectral shifts observed upon protonation is given in Table IV. 

In contrast, the enantiomerically pure, nitrogen-free compound (4.S )-l,2,3,4-tetrahydro-4,7,8-trimethyl-6-naphthalenol is oxidatively coupled using potassium hexacyanoferrate(III) to give the (/ -biaryl derivative (P)-4 with a very high atropisomer selectivity the corresponding (Af)-isomer is not detected in the reaction mixture5,6. 

Alternatively, the lactone mixture 7 and 8 may be ring opened by hydrolysis, followed by the separation of the corresponding carboxylic acids. The desired atropisomer may be converted into the product alkaloid, whereas the undesired isomer may be recycled by conversion back to the lactone mixture using oxalyl chloride for the acyl activation36. 

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