Deoxyerythronolide

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. 

Kato, Y., Bai, L., Xue, Q. et al. (2002) Functional expression of genes involved in the biosynthesis of the novel polyketide chain extension unit, methoxymalonyl-acyl carrier protein, and engineered biosynthesis of 2-desmethyl-2-methoxy-6-deoxyerythronolide B. Journal of the American Chemical Society, 124, 5268. 

Kennedy, J., Murli, S. and Kealey, J.T. (2003) 6-Deoxyerythronolide B analogue production in Escherichia coli through metabolic pathway engineering. Biochemistry, 42, 14342. 

Wang, Y. and Pfeifer, B.A. (2007) 6-Deoxyerythronolide B production through chromosomal localization ofthe deoxyerythronolide B synthase genes in E. coli. Metabolic Engineering, 10, 33-38. 

Pfeifer, B., Hu, Z., Licari, P. and Khosla, C. (2002) Process and metabolic strategies for improved production of Escherichia coli-derived 6-deoxyerythronolide B. Applied and Environmental Microbiology, 68, 3287-3292. 

Lau, J.,Tran, C., Licari, P. andGalazzo, J. (2004) Development of a high cell-density fed-batch bioprocess for the heterologous production of 6-deoxyerythronolide B in Escherichia coli. Journal of Biotechnology, 110,... 

Murli, S., Kennedy, J., Dayem, L.C. et al. (2003) Metabolic engineering of Escherichia coli for improved 6-deoxyerythronolide B production. Journal of Industrial Microbiology and Biotechnology, 30 500—509. 

Ward, S.L., Desai, R.P., Hu, Z. et al. (2007) Precursor-directed biosynthesis of 6-deoxyerythronolide B analogues is improved by removal of the initial catalytic sites of the polyketide synthase. Journal of Industrial Microbiology and Biotechnology, 34, 9-15. 

Figure 12.5 A. Comparison of the CHS monomer (left) and P-ketoacyl synthase monomer (right). The structurally conserved secondary structure of each monomer s upper domain is colored in blue (a-helix) and gold (P-strand). Portions of each protein monomer forming the dimer interface are colored purple. The side-chains of the catalytic residues of CHS (Cysl64, His303, Asn336) and P-ketoacyl synthase (Cysl63, His303, His340) are shown. B. Sequence conservation of the catalytic residues of CHS, 2-PS, p-ketoacyl synthase (FAS II), and the ketosynthase modules of 6-deoxyerythronolide B synthase (DEBS), actinorhodin synthase (ActI) and tetracenomycin synthase (TcmK). The catalytic residues are in red.

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). 

Deoxyerythronolide B (28), produced by blocked mutants of Streptomyces erythreus, is a common biosynthetic precursor leading to erythromycins. A different route to this compound was developed with aldol methodology.5 In this approach, all the crucial C C bond formations involved in the construction of the carbon framework are exclusively aldol reactions. 

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.

Target Molecule 6-Deoxyerythronolide B Erythronolide A Derivative Ansa Chain of Rifamycin B 66 66... 

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],... 

Scheme 24 Example of acyl carrier proteins (ACPs) in type I PKS. The 6-deoxyerythronolide B is shown as a representative polyketide. Seven ACPs are found in the seven modules, each depicted in a different color, responsible for the incorporation of the seven building block constituents of 6-deoxyerythronolide B.

ERYTHROMYCIN D Staunton 1997 Wu 2000) high-performance production of 6-deoxyerythronolide has been achieved by fermentation of a metabolically engineered strain of Escherichia coli Pfeifer 2001 methvmvcins. calicheamicins. and pikromvcins METHYMYCIN-CALICHEAMICIN-class and pikromycin-calicheamicin-class Micromonospora echnospora CalH - Streptomyces venezuelae mutant Zhao 1999). 

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... 

Figure 21-11 Catalytic domains within three polypeptide chains of the modular polyketide synthase that forms 6-deoxyerythronolide B, the aglycone of the widely used antibiotic erythromycin. The domains are labeled as for fatty acid synthases AT, acyltransferase ACP, acyl carrier protein KS, 3-ketoacyl-ACP synthase KR, ketoreductase DH, dehydrase ER, enoylreductase TE, thioesterase. After Pieper et al.338 Courtesy of Chaitan Khosla.

Deoxyerythronolide B synthase (DEBS) is a modular Type I PKS involved in erythromycin biosynthesis (see page 96) and its structure and function are illustrated in Figure 3.85. The enzyme contains three subunits (DEBS-1, 2, and 3), each encoded by a gene (eryA-l, II, and III). It has a linear organization of six modules, each of which... 

DJ Bevitt, J Cortes, SF Haydock, PF Leadlay. 6-Deoxyerythronolide-B synthase 2 from Saccharopolyspora erythraea. Cloning of the structural gene, sequence analysis and inferred domain structure of the multifunctional enzyme. Eur J Biochem 204 39-49, 1992. 

Figure 4 Modular PKS gene organization. The 6-deoxyerythronolide B (DEBS) and rapamycin (RAPS) PKSs are composed of 6 and 14 modules, respectively. DEBS catalyzes the formation of 6-deoxyerythronolide B (6-dEB) from a propionyl-CoA primer unit and six methylmalonyl-CoA extender units. Rapamycin is formed from a cyclohexenoyl starter unit, seven malonyl-CoA (modules 2, 5, 8, 9, 11, 12, and 14), and seven methylmalonyl-CoA (modules 1, 3, 4, 6, 7, 10, and 13) extender units, and pipecolic acid. For RAPS, only the domains which are believed to be functional in the PKS are shown.

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