Macrolide 6-deoxyerythronolide

Synthesis of the macrolide 6-deoxyerythronolide B 28 is one of the successful demonstrations of double asymmetric induction applied to the construction of complicated natural products.5 Retro synthetic analysis (Scheme 7-7) shows that 28 can be obtained from thio-seco acid 29, which consists of seven propionate building blocks. This is a typical aldol product in which a boron reagent... 

Thus the two mandelic acid-based boron enolates described in this section may be regarded as sources of propionic acid which add to aldehydes to give erythro aldol products of high stereochemical purity. An elegant synthesis of the macrolide, 6-deoxyerythronolide B, uses three mandelic acid-based boron enolate/aldehyde reactions. The retrosynthetic analysis of the synthesis is shown in Figure B5.ll. 

Modular PKS enzymes are responsible for the synthesis of a wide diversity of structures and seem to have more relaxed specificities in several of the enzymatic steps. Their enormous appeal for combinatorial purposes, though, derives from the presence of multiple modules that can be manipulated independently, allowing the production of rings of different sizes and with potential stereochemical variation at each PK carbon. The higher complexity of these pathways has somewhat hindered their exploitation, but recently, several have been fully characterized. Among them, by far the most studied modular multienzyme complex is 6-deoxyerythronolide B synthase (DEBS 240,266,267), which produces the 14-member macrolide 6-deoxyerythronolide B (10.70, Fig. 10.45). DEBS contains three large subunits each of which contains two PKS enzyme modules. Each module contains the minimal PKS enzyme vide supra) and either none (M3), one (ketoreductase KR Ml, M2, MS, and M6), or three (dehydratase DH-enoyl reductase ER-ketoreductase KR, M4) catalytic activities that produce a keto (M3), an hydroxy (Ml, M2, MS and M6), or an unsubstituted methylene (M4) on the last monomeric unit of the growing chain (Fig. 10.45). A final thioesterase (TE) activity catalyzes lactone formation with concomitant release of 10.70 from the multienzyme complex. Introduction of TE activity after an upstream module allows various reduced-size macrolides (10.71-10.73, Eig. 10.45) to be obtained. 

Thanks to the reliability of these conversions, compounds like 70-73 can all be regarded as products of a condensation between carbonyl components described in terms of an interaction between an electrophile and a nucleophile. Hence, an important recommendation in retrosynthetic analysis is to identify the presence of fragments identical to 70-73 (or easily derivable from them). Retrosynthetic cleavage of the respective C-C bond will then reveal the structures of possible carbonyl precursors. The retrosynthetic analysis of 74, a basic fragment of the complex macrolide antibiotic 6-deoxyerythronolide B, provides a good example of how workable this principle might be (Scheme 2.27). ... 

Oleandolide, 6-Deoxyerythronolide B and Erythronolide A. The 14-membered macrolides, oleandolide (224), 6-deoxyerythronolide B (225) and erythronolide A (226) have proved to be popular synthetic targets for the development of new reactions for acyclic stereocontrol. The first two compounds differ only in the pres-ence/absence of the epoxide functionality at Cg and substitution at C14 while erythronolide A has two tertiary alcohols one at Cg and the other at Cp (Scheme 9-61). 

The biosynthesis of erythromycin can be divided into two phases (Scheme 1). In the first constructive phase of the pathway a set of key enzymes, collectively known as the polyketide synthase (PKS), assembles the typical polyketide chain by sequential condensation of one unit of propionyl-CoA and six units of methylmalonyl-CoA 6. The initially formed chain is cyclised to give the first macrocychc lactone (macrolide) intermediate 6-deoxyerythronolide B 7 [6,7]. In the second phase 6-deoxyerythronohde B is elaborated by a series of tailoring enzymes which carry out regiospecific hydroxylations, glycosylations and a methylation (of an added sugar residue) to give finally erythromycin A. The core polyketide structure is generated by the PKS in phase one, but the later steps of phase two are essential to produce active antibiotics. 

Corcoran and co-workers first fed labelled precursors to S, erythraea and detected their incorporation into 6-deoxyerythronolide B 1 (Scheme 3) [20]. These results gave the first evidence that the macrolide core is derived from one pro-pionyl-CoA and six methylmalonyl CoA units. Subsequently Cane and coworkers [21] fed [ O]propionate and demonstrated that all the oxygens attached to carboxyl-derived carbons in the macrolide core were retained from the propionate precursor and were not derived from molecular oxygen or water. These results are consistent with reduction of each keto group of the putative... 

Antibiotic Macrolides A. A26771B Methymycin Neomethynolide 6-Deoxyerythronolide B Narbonolide Erythromycins... 

Shafiee, A. Hutchinson, C. R. Macrolide antibiotic biosynthesis isolation and properties of two forms of 6-deoxyerythronolide B hydroxylase from Saccharopolyspora erythraea (Streptomyces erythreus). Biochemistry 26, 6204-6210 (1987). 

Manipulation of the DEBS system has led to the most impressive demonstration of combinatorial biosynthesis to date. McDaniel and coworkers have utilized specific module-swapping strategies to access a variety of 6-deoxyerythronolide B analogs with modifications at each carbon of the macrolide backbone [26]. Modules 1-6 of DEBS were systematically replaced with individual rapamycin synthase components to alter oxidation state and methylation in the final polyketide product. The study produced 60 unique structures at yields ranging from 1 to 70% of that of 6-deoxyerythronolide B (Fig. 9.2-5). However, each new compound required independent synthase engineering, which made library construction quite tedious. 

The final example illustrates yet another use of the biomimetic approach. Figure 10.9shows a retro-synthetic analysis for Masamune s synthesis of deoxyerythronolide B (213). The biosynthetic building blocks of this and other macrolide antibiotics are known to be acetate and/or propionate units combined head-to-tail, as seen in 213. 7 xhe stereocenters in 213 are clearly shown in the acyclic (seco acid) form of the macrolide 215. The specific biopathway is not utilized but rather modified to include the basic building blocks, seven propionate units (bold lines in 213).Seco acid 215 was constructed by sequential aldol condensation reactions (sec. 9.4.A) of propionaldehyde units, as shown by the disconnections in Figure 10.9. Asymmetric... 

The most ambitious application of this chemistry is in the ring closure to form 6-deoxyerythronolide B 3.104 (Scheme 3.45). Macrolides are most commonly prepared by lactonization of a hydroxy acid, so there is a need to carry the hydroxy functional group through the synthesis. The allylic CH activation method avoids this need, requiring just an alkene. Controlled by the conformation of the substrate, allylic oxidation of the precursor 3.101 provided a single diastereoisomer of the macrolide 3.103. A bis-sulfoxide 3.102 was found to be the optimum ligand for palladium. The macrolide 3.103 could be converted to 6-deoxyerythronolide B 3.104 by simultaneous reduction of the alkene and the PMP acetal, selective oxidation of one hydroxyl group, and acetonide removal. 

Evans DA, Kim AS, Metternich R, Novack VJ. General strategies toward the syntheses of macrolide antibiotics. The total syntheses of 6-deoxyerythronolide B and oleandolide. J. Am. Chem. Soc. 1998 120(24) 5921-5942. 

Masamune [91]. It is recognized as particularly relevant in the context of stereoselective aldol reactions. Masamune developed the chiral ketones (J )-and (S)-179, derived from each enantiomer of mandelic acid, to conduct dia-stereoselective aldol reactions with both achiral and chiral aldehydes (Scheme 4.19) [91-93]. Subsequent to aldol addition, desilylation and oxidative cleavage of the chiral controlling group provides a carboxylic acid. The synthesis of the macrolide aglycon 6-deoxyerythronolide B (187) showcases the use of these ketones and represents the first successful application of double asymmetric induction in the context of a complex target [91, 93, 94). 

---