Resolution of atropisomers

One of the most studied polymerization systems employs alkyllithium initiators that are modified by chiral amine ligands for the polymerization of sterically bulky methacrylates [8,38,39,40,41], acrylates [42],crotonates [43], and acrylamides [44]. A primary example is the reaction of triphenylmethyl methacrylate with an initiator derived from 9-fluorenyllithium and (-)-sparteine (3) at -78 °C (Scheme 4). The resultant isotactic polymer is optically active, and is postulated to adopt a right-handed helix as it departs from the polymerization site. This polymer has been particularly successful as a chiral stationary phase for the chromatographic resolution of atropisomers [8]. Many modifications of the or-ganolithium initiator/chiral ligand system have been explored. Recently, Okamo-to has applied enantiopure radical initiators for the enantioselective polymerization of bulky methacrylate monomers [45]. 

In the last 30 years, the so-called chiral chromatographies have been a cornerstone in the tremendous developments of all the aspects of chiros-ciences. Three techniques have been developed for the analysis of enantiomers (a) liquid chromatography on chiral support and elution with an achiral solvent that comprises also supercritical COz (b) gas chromatography on a chiral stationary phase (CSP), and (c) liquid chromatography on an achiral support with a chiral additive in the mobile phase. The resolution of atropisomers that do not presents suitable functional group for classical resolution by formation of diastereomers with optically pure amines or acids became reachable. 

In the following year, Bringmann et al. showed a further application of a biomimetic oxidative coupling of murrayafoline A (7) to the first total synthesis of murrastifoline F (191) (162). This work also includes the resolution of ( + )-murrastifoline F (191), the stereochemical assignment of its atropisomers, and the determination of the enantiomeric ratio present in an authentic root extract of M. homigii. 

We have investigated various factors which contribute to solvent-induced partial resolution or race-mization of 1,1 -binaphthyl (BN). Only photochemical interconversions of BN conducted in cholesteric mesophases influenced the steady state concentration of atropisomers. Thermal equilibriun in cholesteric media or photochemical interconver-sions in chiral isotropic solvents did not alter appreciably the atropisomeric ratio of initially racemic BN. Solvent order accelerates the rate of BN thermal racemization. A discussion of the physical properties of the solvents and BN responsible for the observations is presented. 

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,... 

Third, the diastereotopic facial selectivity between the olefin and the ketyl is determined by the biaryl stereochemistry. This stereocontrol element, set earlier via a kinetic resolution of racemic lactone ( )-28, provided an enantiomerically enriched atropisomer (98% ee) that was carried throughout the synthesis without loss of stereochemical integrity. 

Roussel and Popescu [54] extended this work by developing a lipophilicity parameter, log k w The authors were able to explain the relationship between chiral retention of the enantiomers and their lipophilic interactions with the CSPs. Quantification of the influence of structural parameters Xi, X2 and X3 was also possible. The relationship between lipophilicity and chiral chromatographic behavior was explained for compounds 23-30 and an extension to other alkyl substituted atropisomers was made. A related study concerning the resolution of 23-30 on various p-methylbenzoyl cellulose beads has also been published [55] but will not be described here because it employs the same methodology as above. 

Crystallization of diastereomeric salts obtained from an optically pure acid or an optically pure base is a classical method for the resolution of atropisomeric heterocycles presenting the complementary basic or acid functions. The method requires several trials to find the optimal resolving agent. Atropisomers bearing mono or diphosphine groups are separated using optically pure Pd(ll) complexes. Table 2 reports some selected examples. 

Crawford and Smyth succeeded in the resolution of 4,4 -biquinolyl and 5,5 -biquinolyl enantiomers with (+)-tartaric acid. These atropisomers... 

Chan et al. reported the preparation and resolution of closely related 3,3 -bipyridyl diphosphine atropisomers that differed by the aryl group on the phosphorous. The synthetic route which was used for Ar = Ph (99USP5886182, 00JA11513), R = p-tolyl (01SL1050) and R = 3,5-dimethyl-phenyl (02TL1539) is reported in Figure 13. 

Apparently, much higher yields can be achieved in the oxidative coupling of 2-naphthol derivatives by means of Fe(III), Cu(I), Cu(ll), Mn(III), or Ti(IV) salts (Scheme 2.66) [27]. These reactions usually proceed very fast. Partially 0-protected binaphthols can be obtained by monoetherification of one hydroxy group via a modified Mitsunobu reaction [28]. Several methods allow the kinetic resolution of racemic atropisomers and, hence, access to optically pure (R)- or (S) binaphthol (BINOL) [27]. 

The kinetic resolution of racemate 134 possessing axial chirality was examined with the chiral arsonium ylide 30, which afforded the non-racemic atropisomer 135 with a satisfactory de of up to 76% [84]. In this reaction, dynamic kinetic resolution was operative to some extent vide infra). The same kind of kinetic resolution... 

As there was an amine handle for the formation of diastereomeric salts, classical resolution of to obtain CP-465,022 was also an option (Scheme 23). With the ability to thermally racemize the wrong antipode, one could envision a dynamic resolution (or, asymmetric transformation). In the presence of the appropriate chiral acid, there would be an equilibrium of the enantiomers of CP-392,110 in solution, with only the desired antipode CP-465,022 crystallizing out as the insoluble diastereomeric salt. Pfizer has developed a number of other atropisomers, and this sort of dynamic resolution has been worked out for one of those candidates. 

B. Morgan, A. Zaks, D.R. Dodds, I. Liu, S. Megati, EG. Njoroge, V.M. Girijavallabhan, Enzymatic kinetic resolution of piperidine atropisomers Synthesis of a key intermediate of the farnesyl protein transferase inhibitor SCH66336,1. Org. Chem. 65 (18) (2000) 5451-5459. 

Atropisomerism of the telenzepine molecule results from highly hindered rotation about the C—N-bond, forming a stereogenic axis. In neutral aqueous solution, the atropisomer interconversion half-life is of the order of 1000 years. The resolution of both enantiomers of... 

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 each mesophase mixture, the dominant atropisomer after photo or thermal resolution experiments was S(+). The sole exception occurred during irradation of a 3% BN solution in mixture C. Since the sample solidified partially during the experiment, the mechanism by which the R(-) atropisomer arose is unclear. The thermal lability of the atropisomers toward interconversion and the possible contribution of cholesteric contaminants in recovered BN samples make an accurate assessment of atropisomeric excess a formidable task. Extreme care was taken to handle all solutions containing BN during work-up at temperatures which preclude significant thermal racemization at 25°C, the half-life for racemization is ca. 10 h in normal isotropic solvents all manipulations were conducted at 4°C or below. 

E. Benicka, R. Novakovsky, J. Hrouzek, J. Krupcik, P. Sandra and J. de Zeeuw, Multidimensional gas chromatographic separation of selected PCB atropisomers in technical formulations and sediments , J. High Resolut. Chromatogr. 19 95-98 (1996). 

These reactions, and other successful resolutions (both classical [20, 21] and on chiral stationary phase [8, 22, 23]) of atropisomeric aromatic amides means that this class of non-biaryl atropisomers are now available enantiomerically enriched. 

Few examples of enzymatic resolution applied to heterocyclic atropisomers have been reported. Atropisomers of l,l -bis(hydroxyalkyl)-3,3 -... 

Another emerging resolution technique is applicable to atropisomers that form conglomerates. Chiral symmetry breaking of C-N axial chirality for N-aryl-2(lH)-pyrimidinone conglomerates was achieved by crystallization induced enantiomer transformation without any outside chiral... 

Independently (96TA285), atropisomers of 167 were resolved by chiral chromatography. Resolution using a chiral palladium complex resulted in the loss of the dimethylaminomethylene group and yielded the unsubstituted biindole derivative 168. The configurational stability of the atropi-someric form was not reported. 

The barrier irt phertartthrerte 215 (160 kj mol ) (X = OEt, R = Me) was 30 kJ mol higher thart irt the rtaphthalene analogue 214. Interestingly, the phenanthrene compound underwent spontaneous resolution. Lactonization resulted in racemization. Optically pure atropisomers were employed to prepare optically pure (S,S)- and (R,R)-pyrocoll derivatives 216 and 217. All these atropisomers were screened with success as catalysts in the ethylation of aldehydes by diethylzinc. 

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