The taumycin A macrocycle: Asymmetric total synthesis and revision of relative stereochemistry

Abstract

The first asymmetric total synthesis and revision of the relative configuration of the 12-membered taumycin A macrocycle is described. Key to the success of this work was a novel α-keto ketene macrocyclization that provided an efficient means by which to access two diastereomers of the desired macrolide without the need to employ additional coupling agents or unnecessary oxidation state adjustments.T he symbiotic association of marine microorganisms with their host sponges continues to be an extraordinary source of hybrid polyketide/nonribosomal secondary metabolites that often possess unique structures in conjunction with interesting biological activity.1 Recently, taumycins A and B (1−2, Figure 1) were isolated by Kashman and co-workers, in extremely small amounts, from a Madagascar sponge of genus Fascaplysinopsis.2a Of particular note, taumycin A (1) was shown to inhibit UT-7 cell growth in the micromolar range, whereas taumycin B (2), which lacks the terminal oxazole moiety at C(12), is completely devoid of this activity.2a To date, extensive biological evaluation has not been performed on either metabolite, and the mechanism of action of 1 remains unknown. 2aThe relative configuration of the macrolide common to 1 and 2 was assigned using both detailed multidimensional NMR analyses and degradation studies (cf. 3); however, due to its remote location, the configuration about the side chain C(9) methyl remains undefined. As determined by Kashman, 2a,b the taumycin macrolide contains one L-and one D-isoleucine residue (Figure 1) which, in the absence of an X-ray quality crystal, made it difficult to establish absolute stereochemistry due to what was perceived to be potential ambiguity surrounding the correct sequence of amino acid subunits within the macrocycle.We were attracted to taumycin A as a synthetic target not only because of its biological profile but also due to the reported presence of enantiomeric isoleucine residues. A careful examination of the isolation report, however, revealed that there was no clear discussion on how the data collected guided the authors to distinguish between D-isoleucine and D-alloisoleucine (Figure 1). 3With this in mind, the relative stereochemistry as drawn by Kashman in the isolation report is somewhat unclear, as it does not adequately address the two stereocenters in each isoleucine residue (cf. Kashman vs. Expanded Stereochemistry, Figure 1). The presence of a D-amino acid is usually regarded as the empirical evidence that allows one to claim the source of a natural product to be bacterial derived, as it has been well established that certain bacteria are able to epimerize L-amino acids to their D-form. 4 In the case of isoleucine, however, α-epimerization would only affect the amino center, leaving the β-methyl center unchanged. Using this reasoning, L-isoleucine (4) can only be converted to its diastereomer, D-allo-isoleucine (5), and not its enantiomer, D-isoleucine (6). This is further supported by the fact that D-allo-isoleucine has been found previ...