Atropisomer selectivity

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... 

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. 

Once again, this bridged biaryl may be ring opened atropisomer-selectively with achiral nucleophiles. Due to the greater steric hindrance compared with the dioncophylline A-lac-tone , lactone 6 may also be ring opened with O-nucleophiles11 and good atropisomer ratios are obtained even for alcohols as small as 2-propanol (d.r. 20.9 1) or methanol (d.r. 15.3 1). Even better selectivities are obtained for the chiral O-nucleophile (-)-menthol (d.r. 23.2 1). 

Restricted rotation about the biaryl axis as a result of bulky substituents leads to the existence of atropisomers. Depending upon the degree of steric hindrance due to the ortho substituents, three or four substituents are needed to produce a sufficient barrier to rotation at room temperature. This particular form of axial chirality is not generally resistant to heat. To produce acceptable yields of hindered biaryls under Suzuki conditions, high temperatures (60-110 °C) [78, 85] and reaction times of several hours are required. In atropisomer-selective reactions, these conditions would be deleterious to the discrimination between dia-stereomeric transition states and could racemize the biaryls formed. As a consequence, it is necessary to carry out such Suzuki reactions at ambient temperature. Recently, conditions employing Pd(OAc)2 and 95 % ethanol were used to generate mono-ortho-substituted biaryls at 20 °C (Eq. (54)) [86],... 

The low atropisomerselectivity in the above synthesis of ancistrocladine (1) prompted a study into a more efficient process (ref. 58).The helical lactones 88 and 89 interconvert quickly (Ti/2 < 1 min) and represent thermodynamic ratio favouring atropisomer 88. This dictates the ratio of attopisomers obtained in the reduction step to stable isomers 90 and 91. Since this ratio cannot be improved upon to give either atropisomer selectively and unstable lactones 88 and 89 are difficult to separate, a less planar ether bridge was utilised in the hope that epimerisation would occur more slowly. 

SCHEME 12 Atropisomer selective synthesis of 1 and 92 by thermodynamic isomerisation. 

The first asymmetric intermolecular synthesis of 0-methylancistrocladine (2) involved the use of a Meyers biaryl coupling, successfully utilised in the earlier synthesis of dehydroancistrocladine (66), to construct the biaryl linkage atropisomer-selectively (ref. 60,61). It was envisaged that 2 could arise from the acetamide 102 which in turn could be derived from biaryl 103 (Scheme 14). A coupling between the Grignard reagent 104 and chiral oxazoline 105 could then provide 103 stereospecifically. This approach required the synthesis of chiral oxazoline 105 which is outlined in Scheme 15 and begins with the nitrile 71 available in three steps from 1,5-diacetoxynaphthalene (see Scheme 8). 

Although the synthesis was not atropisomer selective at this stage, the undesired atropisomer 192 can be converted back to axially prostereogenic lactone 191 and ring opened again to provide the thermodynamically controlled mixture of isomers. A more efficient process was to simply expose isomer 192 to the NaOMe/MeOH conditions and this caused epimerisation to provide the... 

In looking at vancomycin and teicoplanin, the hydroxyls are but one choice for functionalization reactions. Each natural product also possesses electron-rich arenes, which may be platforms for electrophilic aromatic substitution reactions. In parallel studies of enantioselective and atropisomer-selective bromination reactions [161-164], we were gaining experience with catalyst-controlled bromina-tions, and we wondered whether these might be extended to site-selective reactions. We speculated that an appropriately positioned Lewis base, such as a dimethyl amide unit, could assist in the delivery of electrophilic bromine... 

Despite the prevalence and importance of atropisomerism in organic structures, the field of asymmetric catalysis has not yet recorded extensive success in the development of catalysts, which control this stereochemical feature. Indeed, catalytic reactions of this nature are presently rare and only modest atropi-somer selectivity has been observed. In this context. Miller s group recently developed the DKR of biaryl atropisomers via peptide-catalysed asymmetric bromination. The reaction proceeded via an atropisomer-selective electrophilic aromatic substitution reaction using a simple bromination reagent such as A7-bromophthtalimide. As shown in Scheme 5.27, a series of chiral bromi-nated biaryl compounds could be prepared with excellent enantioselectivities of... 

Using the same concept, the biaryl portion of isokotanin A was prepared in 2002. In this case, the atropisomer-selective ring cleavage reaction was achieved by using an 0-nucleophile such as potassium (li )-mentholate (Scheme 5.41). 

---