6-Deoxyerythronolide synthesis

Entry 2 involves the use of a sterically biased enol boronate with an a-substituted aldehyde. The reaction, which gives 40 1 facial selectivity, was used in the synthesis of 6-deoxyerythronolide B and was one of the early demonstrations of the power of double diastereoselection in synthesis. In Entry 3, the syn selectivity is the result of a chelated TS, in which the (3-p-methoxybenzyl substituent interacts with the tin ion.120... 

Entry 6 is an example of the methodology incorporated into a synthesis of 6-deoxyerythronolide.123 Entries 7 and 8 illustrates the operation of the (3-alkoxy group in cyclic structures. The reaction in Entry 7 was used in the synthesis of phorboxazole B. 

Considering the entire synthesis illustrated in the previous section, clearly the construction of such a complicated molecule with all the desired stereogenic centers is highly tedious and demanding work. Therefore, an entirely different conceptual method based on double asymmetric induction was finally developed as a less complex synthetic strategy. A good example is the synthesis of 6-deoxyerythronolide B (28), which bears the same 10 chiral centers as eryth-ronolide A (compound la of the previous section). 

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... 

Scheme 7-9. Synthesis of a derivative of the seco acid and ring closure to 6-deoxyerythronolide B.

This chapter has introduced the asymmetric synthesis of several types of natural products erythronolide A, 6-deoxyerythronolide, rifamycin S, prostaglandins and baccatin III, the polycyclic part of taxol, as well as the taxol side chain. The... 

Recently, the improved chiral ethyl ketone (5)-141, derived in three steps from (5)-mandelic acid, has been evaluated in the aldol process (115). Representative condensations of the derived (Z)-boron enolates (5)-142 with aldehydes are summarized in Table 34b, It is evident from the data that the nature of the boron ligand L plays a significant role in enolate diastereoface selection in this system. It is also noteworthy that the sense of asymmetric induction noted for the boron enolate (5)-142 is opposite to that observed for the lithium enolate (5)-139a and (5>139b derived from (S)-atrolactic acid (3) and the related lithium enolate 139. A detailed interpretation of these observations in terms of transition state steric effects (cf. Scheme 20) and chelation phenomena appears to be premature at this time. Further applications of (S )- 41 and (/ )-141 as chiral propionate enolate synthons for the aldol process have appeared in a 6-deoxyerythronolide B synthesis recently disclosed by Masamune (115b). 

The potential of "double asymmetric induction" is shown in the synthesis of 6-deoxyerythronolide B (83) accomplished by Masamune and coworkers in 1981 [22d],... 

These highly diastereoselective aldol reactions have been used in a synthesis of 6-deoxyerythronolide B (5), which contains 10 asymmetric centers. Four aldol reactions, indicated by dotted lines, were used to construct the carhon framework with overall stereoselection of 85%.2... 

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. 

Masamune et al. used this aldol strategy to achieve the total synthesis of 6-deoxyerythronolide B (6), a common biosynthetic precursor leading to all the erythromycins presently known4 (Scheme 2.1e). The highlight of the synthesis is... 

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. 

This reaction is accomplished by three megasynthases consisting of 3491, 3567, and 3172 amino acids. The synthesis of deoxyerythronolide B begins with propionyl CoA linked to a phosphopantetheine chain connected to an acyl carrier protein domain. Similarly, the precursor of penicillin [A-(l-aminoadipyl)-l-cysteinyl-d-valine, or ACV] is generated by the following reaction ... 

Kochetkov and coworkers synthesized erythronolides A (20) and B (21) via a different route [26,27,28]. There have been many reports on the syntheses of erythromycin. Among them, four examples are the Yonemitsu synthesis of erythronolide A (20) [29,30], featuring an extremely efficient macrocyclization (the modified Yamaguchi method) Martin s synthesis of erythromycin B (19) [31,32] Evans synthesis of 6-deoxyerythronolide B [33,34], featuring the aldol-based assemblage of each synthetic segment and the Carreira synthesis of erythronolide A (20), featuring the Mg-mediated cycloadditions of nitrile oxides [35]. 

At the time (1981), the Masamune synthesis of 6-deoxyerythronolide B was a landmark achievement in the art of acyclic stereocontrol [83]. Four aldol reactions were used in the synthesis, all proceeding with high selectivity (>93% ds). The first aldol reaction depicted in Scheme 9-65 was used in the synthesis of aldehyde... 

Narbomycin (118b) and its aglycone narbonolide (118a) are both isolated from the fermentation broth of Streptomyces venezuelae MCRL-0376. Masamune has also reported the only synthesis of a member of this class of compounds, employing a route nearly identical to his synthesis of 6-deoxyerythronolide B... 

Chemical degradation of erythromycin A yielded its aglycone, erythronolide A (16, R = R = OH), whereas erythronolide B (16, R = H, R = OH) was obtained from fermentation (63,64). Biosynthesis of erythromycin proceeds via 6-deoxyerythronolide B (16, R = R/ = H) and then erythronolide B (64,65). The first total synthesis of erythromycin-related compounds was erythronolide B (66) syntheses of erythronolide A and 6-deoxyerythronolide B soon followed (67,68). 

Scheme 5.26. Selective coupling of two chiral fragments (double asymmetric induction) in the asymmetric synthesis of 6-deoxyerythronolide B [124,127], For a similar reaction in the synthesis of erythronolide B, see ref. [129],...

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... 

Deoxyerythronolide B (18 Scheme 2), a monocyclic 14-membered lactone containing 10 asymmetric centers, is produced by blocked mutants of Streptomyces erthreus, and is a common biosynthetic precursor leading to all the erythromycins. A convergent total synthesis of 18 requires the appropriate chiral left- and right-hand fragments, which provides an excellent opportunity for these chiral boron enolates to demonstrate their versatility. 

Diverse polyketide-type libraries were synthesized using a-chiral aldehydes attached by a silyl linker to a hydromethylpolysyrene resin (Figure 11.24). " Aldol chain extension with chiral ketone modules, and subsequent ketone reduction and manipulation on the solid support led to elaborated stereopentad sequences found in natural products such as 6-deoxyerythronolide B and discoder-molide. Based on the biosynthesis of erythromycin, the same methodology was used in the combinatorial synthesis of polyketide sequence mimetics with a great variety of chain-extending units. " ... 

Employing this strategy, White and coworkers successfully applied a late stage C—H oxidation for the total synthesis of 6-deoxyerythronolide B with excellent diasteroselectivity (>40 1) (Scheme 2.55). Interestingly, upon addition of tetrabu-tylammonium fluoride as an additive, the opposite diastereomer was favored (1 1.3) due to dismption of the Pd chelate intermediate [110]. The authors reasoned that the... 

Scheme 2.55 Late stage C—H oxidation in the total synthesis of 6-deoxyerythronolide B [110].

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