Total synthesis 6-deoxyerythronolide

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... 

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). 

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. 

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].

The 5-ketone (16), which is readily obtainable from 5-mandelic acid, is converted into the /8-hydroxy-a-methylcarboxylic acid (17) in high enantiomeric and diastereoisomeric excess by the aldol condensation of the corresponding dicyclopentylborinyl enolate (Scheme 13). This simple yet highly effective idea, and its extensions, provides the cornerstone of one of the major achievements reported this year, the total synthesis of 6-deoxyerythronolide B (see Section 4). 

Masamune used the S-tert-butyl ester as an intermediate in the total synthesis of 6-deoxyerythronolide B (17), and activation of the thioester by a heavy metal efficiently promoted cyclization to form the desired polyoxygenated macrolactone (Scheme 5.3) [25]. 

The synthesis of polypropionate by the (3-ketoimide-aldol reaction features the subsequent stereoselective reduction of the (3-ketone. As shown in the total synthesis of 6-deoxyerythronolide B 59 (Scheme 8.8), aldol adduct... 

Masamune et al. applied the concept to the total synthesis of 6-deoxyerythronolide B 59 (Scheme 8.33)." Chiral boron enolate 219 reacted with propionaldehyde 218 to give the syn adduct 220 with 14 1 ratio of stereoselectivity. The chiral auxiliary of 220 was removed by oxidative cleavage to provide carboxylic acid 221, which was further converted into aldehyde 222. In contrast, chiral aldehyde... 

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