Macrodiolides

Metz P (2005) Synthetic Studies on the Pamamycin Macrodiolides. 244 215-249 Metzner P (1999) Thiocarhonyl Compounds as Specific Tools for Organic Synthesis. 204 127-181... 

An unusual class of heterocydes are polyketide-derived macrodiolide natural produds. The groups of Porco and Panek have recently shown that stereochemically well-defined macrodiolides of this type can be obtained by cyclodimerization (transesterification) of non-racemic chiral hydroxy esters (Scheme 6.154) [301]. Preliminary experiments involving microwave irradiation demonstrated that exposing dilute solutions of the hydroxy ester (0.02 m) in chlorobenzene to sealed-vessel microwave irradiation conditions (200 °C, 7 min) in the presence of 10 mol% of a distannoxane transesterification catalyst led to a 60% isolated yield of the 16-mem-bered macrodiolide heterocycle. Conventional reflux conditions in the same solvent (0.01 m in the hydroxy ester) provided a 75% yield after 48 h at ca. 135 °C. 

Abstract The pamamycins are structurally intriguing 16-membered macrodiolides displaying a wide range of interesting biological activities. A comprehensive survey of the total syntheses reported in this area so far and the various synthetic approaches to the hydroxy acid constituents of the pamamycins described to date is presented. 

Keywords Pamamycins Macrodiolides Antibiotics Synthesis Hydroxy acids... 

So far, four total syntheses of the homolog pamamycin-607 (lb) have been reported [4-7]. This section will detail the different routes and strategies that were utilized to access this macrodiolide. 

AT-Boc group, was followed by reductive debenzylation of 30 and Yamaguchi lactonization of the resultant hydroxy acid to provide macrodiolide 31 in 25% yield accompanied by a dimer. Finally, removal of the N-Boc group and reductive N-methylation yielded pamamycin-607 (lb). In total, ca. 40 steps were required to access the target from ester 4, aldehyde 22, and allyl stannanes 10 and ent-lO. 

With both building blocks 103 and 109 in hand, the total synthesis of lb was completed as shown in Scheme 17. Coupling of acid 103 and alcohol 109 under Yamaguchi conditions to give ester 110 and subsequent desilylation followed by chemoselective oxidation provided hydroxy acid 111. Lactonization of the 2-thiopyridyl ester derived from 111 in the presence of cupric bromide produced the macrodiolide 112 in 62% yield, which was finally converted to pamamycin-607 (lb) via one-pot azide reduction/double reductive AT-methylation. In summary, 36 steps were necessary to accomplish the synthesis of lb from alcohols 88 and 104, sulfone 91, ketone 93, and iodide rac-97. 

The high versatility of 38 as a key intermediate towards macrodiolides is amply demonstrated by its ready hydrolysis to the respective hexenal 40 or, when preceded by hydrogenation, to the 5/Miydroxyhexanal 39, whilst... 

Mulzer and Berger used the Midland reduction en route to the total synthesis of the boron-containing macrodiolide antibiotic tartrolon B (90), which acts... 

Su et al. [53] used allylsilanes having C-centered chirality and a distannoxane transesterification catalyst [54] in a sequence of transesterification reactions to rapidly assemble a set of stereochemically diverse macrodiolides reminiscent of polyketide-derivative natural products. Figure 15.20 summarizes the synthesis of stereochemically well defined 14- and 16-member macrodiolides 20.4 and 20.5, resembling known polyketide-derived natural products, from hydroxyl esters 20.2 and 20.3. The feasibility of cyclodimeriztion was studied using different solvents and variable concentrations. Reactions were affected by the choice of the solvent. 

High dilutions reduced the amount of oligomers formed. Preliminary experiments on enantio-enriched hydroxyl esters 20.6 and 20.7, using distannoxane transesterification catalyst, produced stereochemically diverse homo- and heterodimers 20.8-20.10. Functionalization of the macrodiolides was investigated in an effort to create additional structural diversity. Electrophilic epoxidation of macrodiolide 20.9 afforded bis-epoxide 20.11. Further diversification was achieved by treating the macrodiolide bis-epoxide with DBU, which resulted in epoxide ring opening to afford a,P-unsaturated macrolide 20.12. 

The Cj symmetrical macrodiolide elaiophylin (41) consists of two identical polyketide chains which are linked to a deoxyfucose at C-13 [83]. Here, it was assumed that macrodilactone formation is the last biosynthetic step, and only one glycosyl transfer step is necessary prior to lactonization. However, incorporation experiments with the complete (glycosylated) octaketide half 42 failed. Later, after changing the fermentation parameters, the asymmetrical mono-glycosyl derivative 43 was isolated, indicating that the two glycosyl transfer steps take place after generation of the macrodiolide 44 [83-85] (Scheme 16). 

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