Polyketide methodology

Nature gives us some illustrative examples of iterative methodologies in its biochemical mechanisms. The fatty acid-polyketide biosynthesis is one of them. The assembly of acyl units by sequential Claisen-type condensations to form a polyketide or fatty acid takes place at a multi-enzyme complex, at which the initial molecule is lengthened by one C2-unit per pass of a reaction cycle (Fig. 2). 

The power of this methodology is demonstrated with the synthesis of polyketide-like structures by repetitive application of the same procedure (Scheme 22) [76]. 

As shown below, the attack of epoxide 6 with lithium dimethylcuprate is a key step of Hanessian et al. s erythronolide synthesis [23]. This methodology was also applied to the preparation of other polyketide-derived macrolides. Specific to erythronolide, introduction of the methyl group at C2 was achieved according to Scheme 11.3. 

Amongst the earliest applications of labelling was the use of doubly labelled [1, 2- C2] acetate to trace the mode of incorporation of intact acetate units into a wide range of metabolites. This has been one of the major recent developments in biosynthetic methodology and permits information to be obtained which would have been impossible or at best extremely difficult to obtain by classical radio-isotope labelling techniques. The basic concept can be illustrated by a model polyketide system (Fig. 1). 

Over the past decade the enantio- and diastereo-selective aldol methodology has been developed mainly with the purpose of synthesizing polyketide-type natural products such as macrolides and iono-phore antibiotics. These natural products have the basic structural units that result from propionate and acetate addition a-methyl-P-hydroxycarbonyl (27a-d) and (3-hydroxycarbonyl (28a and 28b). Discussions on the construction of these units will be followed by comments on the stereoselective assembly... 

In addition to the array of molecules prepared in this study, the authors suggest numerous possibilities for production of related structures through alternative bimodular combinations. In all, a library of over 100 known and predicted aromatic polyketides could be described with this methodology. 

P-Siloxy-e-acetoxy--y,8-unsaturated carbonyl compounds undergo reductive transposition on exposure to HCOONH4, (dba)3Pd2, and BuiP in DMF to afford the 8,e-unsaturated products with (all) syn-isomers predominating.- In conjunction with the enantioselective aldol access to the substrates, this process expands the methodology of existing polyketide synthesis. 

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