Rotational isomers, separate synthesis

The nmr of the isolated metabolite 5, a glucuronide, suggested that it existed as a mixture of rotational isomers (rotamers), as did the acylat glucuronide 6, due to the hindered rotation about the triazole-phenyl bond. When the structure was confirmed by synthesis from 2-amino-6-methylbenzothiazole, 7, by a series of steps outlined in Scheme 2, the synthesized glucuronides also appeared to exist as a mixture of rotamers. Further, these rotamers were separate as the acylated ucuronides by liquid chromatography and characterized by their nmr spectra which differed in the proton resonances of the peaks assigned to the 2-methyl, the thiomethyl, and the triazole hydrogen. 

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. 

Thus we found that our purpose of further structural confirmation of 5 by total synthesis was completed, although the absolute value of the optical rotation of synthetic triacetate (6) was smaller than that of natural specimen of 6. The optical purity of the synthetic compound was examined by means of chiral HPLC analysis after conversion of the corresponding alcohol derived from 21 into tetraacetate (7), which had been obtained by ozonolysis of 5 [7], to reveal that the synthetic tetraacetate (7) obtained in this study was 60% ee. The optical purity of synthetic 6 was estimated to be parallel to this result. This result may be attributable to partial racemization during oxidation-reduction process to obtain the erythro-z coho (18). In our previous study [7], chiral HPLC had showed tihat no crucial racemization occurred since the erythro-zXcohoX (18) and its threo-Xsomtr were separated after conversion into monopivaloyl esters (10 and its isomer) by 4-times repeated silica gel chromatographies. 

Pasteur could separate the optical isomers due to the crystalline forms of sodium ammonium tarttate [22], Natural tartaric acid rotates the plane of polarized light. However, tartaric acid from laboratory synthesis does not show any rotation of the plane of polarized light. 

At this point the synthesis intersects with an earlier racemic synthesis of Ziegler. Thus the diester is hydrolysed and decarboxylated, and the monoacid re-esterified with diazomethane, giving a 1 1 mixture of conformational isomers (64) and (65), which can be separated easily and re-equilibrated thermally. There is a rather subtle stereochemical point to be noticed here despite the fact that rotation about the aryl-aryl bond occurs, there is no racemisation. The thermal interconversion does not occur through a planar transition state, due to the extreme conformational restraints on the cyclo-octanone bridge. 

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