Polyketide-derived natural product

Leighton and coworkers [217] have also used this approach to develop efficient strategies for the synthesis of polyketide-derived natural products [218]. A main motif of these compounds is a skipped polyol structure, as in 6/2-94 this can easily be prepared by a novel Rh-catalyzed domino reaction of a diallylsilyl ether in the presence of CO, followed by a Tamao oxidation [219]. Thus, reaction of, for example, the silane 6/2-93, which is readily prepared from the corresponding ho-... 

Substituted 5-methylene-l,3-dk>xepines 38 are converted into vinyl acetals 39 by Ni catalysts bearing (R,R)-DuPHOS or (R,R)-ChiraPHOS as chiral ligands (Scheme 11) [16]. Similarly high enantioselectivity can be achieved with 5-methyl-ene-l,3-dioxanes as substrates [17]. Chiral Ru-catalysts are less efficient [18]. Cyclic acetals obtained are an useful starting material for preparation of macrolide antibiotics and other polyketide-derived natural products. 

Su et al. [53] used allylsilanes having C-centered chirality and a distannoxane transesterification catalyst [54] in a sequence of transesterification reactions to rapidly assemble a set of stereochemically diverse macrodiolides reminiscent of polyketide-derivative natural products. Figure 15.20 summarizes the synthesis of stereochemically well defined 14- and 16-member macrodiolides 20.4 and 20.5, resembling known polyketide-derived natural products, from hydroxyl esters 20.2 and 20.3. The feasibility of cyclodimeriztion was studied using different solvents and variable concentrations. Reactions were affected by the choice of the solvent. 

The epothilones 6 (and Fig. la), which are produced by So-rangium cellulosum, are mixed NRPS-polyketide derived natural products that possess potent antitumor activity. Interestingly,... 

Oikawa, Y, Nishi, T, Yonemitsu, O, Chiral synthesis of polyketide-derived natural product. Chemical correlation of chiral synthons, derived from D-glucose for the synthesis of erythromycin A, with chemical cleavage products of the natural antibiotic, J. Chem. Soc., Perkin. Trans. 1, 27-33, 1985. 

Hikota, M., Tone, H., Horita, K., Yonemitsu, O. Chiral synthesis of polyketide-derived natural products. 31. Stereoselective synthesis of erythronolide A by extremely efficient lactonization based on conformational adjustment and high activation of seco-acid. Tetrahedron 1990, 46, 4613 628. 

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 addition of 2-butenyltrifluorosilane 68 to chiral aldehydes has been examined by Roush in the synthesis of the a fi,ant/-dipropionate stereotriad, a common but difficult-to-synthesize subunit in polyketide-derived natural products [54], The synthetic approach involves the 2-butenylation reaction of a-methyl-)9-hydroxy aldehydes 72 with (Z)-68 (Scheme 10-30). Using this approach, the anti,anti-dipro-pionate 73 could be obtained in excellent selectivity. The best selectivity is observed when anti-/]-hydroxy aldehydes are used. When the syn aldehyde is used, a mixture of homoallylic alcohols is produced which may arise from a nonche-lated Zimmenuan-Traxler transition structure. 

Nakajima, N., Hamada, T., Tanaka, T., Oikawa, Y, and Yonemitsu, O., Chiral synthesis of polyketide-derived natural products. Part 10. Stereoselective synthesis of pikronolidc, the aglycon of the 14-memhered ring macrolide pikromycin, from D-glucose. Role of MPM and DMPM protection, 7. Am. Chem. Soc.. 108, 4645, 1986. 

A unique asynunetric isomerization of 2-substituted 5-methylene-l,3-diox-anes 22 to 5-methyl-4H-l,3-dioxins 23 was catalyzed by a ruthenium complex of DIOP under a hydrogen atmosphere (Scheme 3). Although the enantiomeric purity remained in the range of 35 to 50%, cyclic acetals obtained are promising starting materials for the synthesis of macrolide antibiotics and other polyketide-derived natural products [30]. 

Polyketide-Derived Natural Products Containing Three or More Consecutive Stereogenic Centers"... 

New Methods for the Synthesis of Polyketide Derived Natural Products... 

The above enzymatic reductions allowed a highly stereoselective access to poly-propionate-like building blocks or polyketide-derived natural products. 

Porco and co-workers s kibdelone C synthesis makes use of an unusual 671-electrocyclization in the key step that assembles the hexacyclic skeleton of the natural product. The kibdelones are polyketide-derived natural products that were isolated and characterized by Capon and co-workers from Kibdelosporangiton sp., an Australian soil actinomy-cete. - The interest in these compounds is a result of their potent activity against leukemia (SR) and renal cancer cells (SN12C). Selective hydrolysis of the methyl ester function in 69 (Scheme 19.19) was followed by heating of the derived carboxylic acid with cyanuric chloride and pyridine in dichloromethane, leading to 73 in 39% overall yield for... 

Paterson has documented numerous applications in the context of total syntheses of polyketide-derived natural products. The route to the cytotoxic macrolide swinholide A (130, Scheme 4.12) showcases two important uses... 

Hetero-Diels-Alder cycloadditions of oxygen-substituted dienes have also been used for the construction of polyketide-derived natural products. This is exemplified in Danishefsky s synthesis of the zinc-sequestering ionophore zincophorin (213, Scheme 17.29) [111]. The MgBr2-mediated, chelate-con-... 

---