Sequential complex polyketides

Few examples have been reported of the preparation of oligomers by C-C bond formation. Reggelin described a synthetic protocol that enables the sequential stereo-controlled assembly of polyketides on cross-linked polystyrene (Figure 16.29 see also [273]). Flowever, this strategy involves many steps and only short polyketides have so far been prepared. Shorter and more efficient synthetic protocols will probably have to be developed to give access to larger and structurally more complex polyketides. 

Since the PKS (polyketide synthase) gene cluster for actinorhodin (act), an antibiotic produced by Streptomyces coelicolor[ 109], was cloned, more than 20 different gene clusters encoding polyketide biosynthetic enzymes have been isolated from various organisms, mostly actinomycetes, and characterized [98, 100]. Bacterial PKSs are classified into two broad types based on gene organization and biosynthetic mechanisms [98, 100, 102]. In modular PKSs (or type I), discrete multifunctional enzymes control the sequential addition of thioester units and their subsequent modification to produce macrocyclic compounds (or complex polyketides). Type I PKSs are exemplified by 6-deoxyerythronolide B synthase (DEBS), which catalyzes the formation of the macrolactone portion of erythromycin A, an antibiotic produced by Saccharopolyspora erythraea. There are 7 different active-site domains in DEBS, but a given module contains only 3 to 6 active sites. Three domains, acyl carrier protein (ACP), acyltransferase (AT), and P-ketoacyl-ACP synthase (KS), constitute a minimum module. Some modules contain additional domains for reduction of p-carbons, e.g., P-ketoacyl-ACP reductase (KR), dehydratase (DH), and enoyl reductase (ER). The thioesterase-cyclase (TE) protein is present only at the end of module 6. 

Sequential Catalysis for the Stereoselective Synthesis of Complex Polyketides... 

Figure 14.1 Complex polyketides attractive targets for the development of sequential...

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 biogenesis of n-alkanes in plants presents two points of considerable and novel interest firstly, chain construction. Alkyl chains are built up in plants, animals and microorganisms by sequential condensation of C2 units of acetate to yield fatty acid and related polyketides, but the fatty acid synthetase complexes involved rarely, if at all, catalyse chain elongation beyond compounds thus typically stearic acid CH3(CH2)i6COOH is the end product although palmitic acid (C ) is usually the... 

Many enzymes are involved in the synthesis of secondary metabolites. The modular biosynthetic enzymes polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) are responsible for the generation of a multitude of structurally diverse and biologically important small-molecule natural products. A complex carbon structure is assembled sequentially from simple carbon building blocks (acyl-CoA and amino acids). The elongation of each carbon unit is catalyzed by... 

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