The total synthesis of optically pure (9R,13S)- and (9R,13R)-7-deoxy-13-dihydrodaunomycinone
Date
1986
Authors
Russell, R.A.
Irvine, R.W.
Warrener, R.N.
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Journal of Organic Chemistry, 1986; 51(9):1595-1599
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Richard A. Russell, Robert W. Irvine, Ronald N. Warrener
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Abstract
13-Dihydrodaunomycin 1 has long been recognized as the major human metabolite of the antineoplastic anthracycline daunomycin 2.<sup>1</sup> Whilst 1 has been prepared by microbial<sup>2</sup> and chemical reduction<sup>3</sup>of 2, no attempt to assign the stereochemistry at C13<sup>4</sup> has been reported. Recently Cassinelli et al. have reported<sup>5</sup>that 4-demeth-oxydaunomycin 3 (idarubicin) can be reduced microbially to afford an idarubicinol 4 identical with that excreted by patients treated with 3. These authors initially assigned the 13R stereochemistry to this product, although this was subsequently corrected by Broadhurst et al.,<sup>6</sup> who showed that the totally synthetic 13S isomer corresponded to the biologically obtained product. As both dihydroderivatives 1 and 4 are active antineoplastic agents,<sup>2</sup><sup>,7</sup>routes leading to their total synthesis are of considerable interest. In addition another dihydro compound, namely 7-deoxy-13-dihydrodaunomycinone 5, has reportedly been isolated from a strain of Streptomyces (PD.J566) originating from Michaelmas Cay in Australia.<sup>8</sup> Since this product occurred together with known daunomycin derivatives, it was assumed to have the 9R configuration. However, subsequent attempts to synthesize 5 stereospecifically by borohydride reduction of (−)-7-deoxydaunomycinone yielded unseparated mixtures of the9R,13R and 9R,13S isomers.<sup>9</sup> Consequently, the configuration of C13 of the natural product remained undefined. © 1986, American Chemical Society. All rights reserved.
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© 1986 American Chemical Society