SCIENCE
Method aids stereo control in macrocycles Use of conformational preferences of large-ring compounds to control stereochemistry of reactions has been demonstrated by chemists at Columbia University [/. Am. Chem. Soc, 106,1148 (1984)]. Their achievement may allow chemists to use a very few optically active centers to create new asymmetric atoms in distant parts of molecules. With the new approach, it also may be possible someday to calculate the conformations of reaction i n t e r m e d i a t e s most likely to give the desired handedness. Organic chemistry professor W. Clark Still and graduate student Vance J. Novack demonstrated the method by synthesis of racemic 3deoxyrosaranolide, a derivative of the 16-membered lactone antibiotic rosaramicin. The work, supported by the National Science Foundation ai}d National Institutes of Health, introduced seven new potentially asymmetric centers into a simpler lactone. Though the product was a racemate, beginning with optically active starting material would have produced a single optical isomer. Still points out that chemists long have used familiar conformational preferences of six-membered rings to guide stereochemical introduction of new groups. Six-membered rings are often open to attack from both sides, however, so this approach is not always successful. Also, some chemists have thought that eight- to 16-membered rings are too flexible to use preferred conformations to guide stereochemistry. Still
has demonstrated that substituted macrocycles have decided conformational preferences because of the need to avoid too-close approach of groups across rings and too many eclipsed hydrogen atoms at adjacent carbons. Moreover, each introduction of new groups can change the preferred conformation drastically. In the past, Still has used effective force field calculations to predict favored conformations of substituted eight- to 10-membered lactones and cyclic ketones [Tetrahedron, 37, 3981 (1981)]. These calculations use empirical thermochemical, conformational, and spectroscopic data for large numbers of known compounds to predict such properties as strain energies for unknown ones. He has used this information to rationalize stereochemical courses of methylations and hydrogenations of such compounds. In the present work, the Columbia chemists were not able to calculate likely conformations of such complex intermediates. Nevertheless, the conformational preferences were there. Of 11 reactions used, eight gave stereoselectivity of at least 15:1, and three gave 5:1 to 10:1. Intended methylation of an enolate at C-4 gave greater than 40:1 of the wrong isomer. This result led to a circuitous creation of the methyl group in the right geometry via hydroxymethylation of the enolate, elimination to a methylene group, conversion to a phenylthiomethyl derivative, and desulfurization with Raney nickel. •
Conformational preferences dictate stereochemistry of added functional groups
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CIRCLE 9 ON READER SERVICE CARD February 27, 1984 C&EN
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