Polyketides 1,3-diols

The challenge lay in the stereochemicaUy correct synthesis of the polyketide part of the molecule. Starting from L-serine (89) (Chart 6) by C2-elongation steps, reduction of the obtained keto functions including adequate protection and deprotection, and introduction of the salicylic acid residue the four stereoisomeric 3,5-diols (90) were obtained. Comparison of the H-NMR data with those of anachelin (10) showed that the isomer with 3R,5S,6S) configuration was the correct starting material. 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

The stereochemistry of sy/i- and a/fr/-13 diols in the polyene macrolide antibiotics and polyketides can be determined from the chemical shifts of the acetal carbons and methyl carbons of the corresponding acetonides. The acetonides of jy/i-l,3-diols [Scheme 3.36] occupy a low energy chair conformation displaying an acetal resonance at b 98.5 and methyl resonances at 6 30.0 (equatorial) and b 19.6 (axial). In both possible chair conformations of the a/i/i-l,3-dioI acetonides. there are severe 13-diaxiaI interactions that are relieved in the corresponding twist-boat. In the twist-boat conformation, the acetal carbon resonates at 6 100.6 whereas both methyl groups resonate at b 24.6 because the methyl groups are in nearly identical environments. The twist-boat conformation is more stable than the corresponding chair conformations by about 2 kcal/mole. 

In summary, 1,3-diols are prominent motives in polyketides, and they can be constmcted by various advanced methods. A practical access to 1,3-diols starts often with an aldol reaction. This aldol reaction can already construct a 1,3-diol if one hydroxyl group is already present in the starting material. Alternatively, syn- or anti-selective reductions of carbonyl groups offer an easy to predict stereoselective way to 1,3-diols. As we have seen in particular in the synthesis of roxaticin, direct reduction of diketones or p-keto esters proves an efficient entry into 1,3-diol segments. 

Gao X, Han H, Krische MJ. Direct generation of acyclic polypropionate stereopolyads via double diastereo- and enantioselective iridium-catalyzed crotylation of 1,3-diols beyond stepwise carbonyl addition in polyketide construction. J. Am. Chem. Soc. 2011 133 12795-12800. 

SCHEME 37.19. Ether transfer methodology in the synthesis i>>n-l,3-diol /tw-methyl ethers in a single step a rapid access to large polyketide structural units. 

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