Fragmentation macrolide antibiotics

Discovery and development of a novel immunosuppressant. Tacrolimus hydrate (FK-506), macrolide antibiotic with piperidine and tetrahydrofuran fragments 97YZ542. 

Using FmA catalysis and protected 4-hydroxybutanal, compound (97) has been stereoselectively prepared as a synthetic equivalent to the C-3-C-9 fragment of (-F)-aspicillin, a lichen macrolactone (Figure 10.35) [160]. Similarly, FruA mediated stereoselective addition of (25) to a suitably crafted aldehyde precursor (98) served as the key step in the synthesis of the noncarbohydrate , skipped polyol C-9-C-16 chain fragment (99) of the macrolide antibiotic pentamycin [161,162]. 

Shimagaki et al. reported the synthesis of the C11-C16 fragment of the penta-mycin based in the stereoselechve C—C bond formation reaction catalyzed by FBPA [45]. Pentamycin is a polyene macrolide antibiotic, whose configurations at C15 and C14 would correspond to those of the C3 and C4 posihons of an aldol constructed from addihon of DHAP-derived from FBP by use of FBPA and TIM-to the corresponding aldehyde catalyzed by FBPA (Scheme 4.19). 

A. F. Sviridov, A. Yu. Romanovich, and O. S. Chizhov, Synthetic studies in polyene macrolide antibiotics. 1. Synthesis of C1-C6 and C7-C12 fragments of amphothericin-B from carbohydrate precursors, Bioorg. Khim., (1987) 1665-1671. 

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). ... 

It is also common to find synthetic routes where both methods are employed in sequence as in the construction of the C18-C34 fragment of the macrolide antibiotic antascomicin A (Eq. 143).250... 

A route to 3,5-dideoxy heptitols is depicted in Scheme 3 with the preparation of 3,5-dideoxy-wieso-xyloheptitol which represents the C-16 to C-22 and C-18 to C-24 fragments found in the macrolide antibiotics roxaticin and mycoticin A (and B), respectively. Other related studies were also performed. ... 

Eu E, Loh T-P (2009) An asymmetric synthesis of the polyol fragment of the polyene macrolide antibiotic RK-397. Tetrahedron Lett 50 3530-3533... 

The very largest of the polyketides are the macrolide antibiotics, e.g. nystatin 3.106). Further examples are the ansamycins which derive by a mixed acetate-propionate pathway (Section 7.6.1). Intermediate in size are the cytochalasins which derive by an acetate (malo-nate) pathway (Section 7.6.2). Where propionate units account for C3 fragments in the ansamycins, methionine and acetate serve in the cytochalasins. The macrolide antibiotics discussed below all follow the former way of generating C3 units. It is clear that, if methyl groups are introduced by two different pathways, this is not adventitious. The methyl groups must have a function possibly like the double bonds in dictating the conformation of the macrocycle. 

The complex sixteen-membered-ring macrolide antibiotic tylosin (191) is extensively used today as a therapeutic agent and a nutrient. The molecule has been at the focus of a number of synthetic investigations. This year, Nicolaou and co-workers have described the elaboration of the three fragments (186), (187), and (188) for the synthesis of 0-mycinosyltylonolide (190) in their appropriate optically active forms, and all three were formed from carbohydrate precursors. Combination between (186) and (187) gave rise to an intermediate which, with (188), was then elaborated to the keto-phosphonate (189). The... 

The fragmentation of a-chlorothioethers has been studied by use of the model reaction shown in Scheme 8, before application to the synthesis of vinyl thioether 42, a segment of trienomycin and mycotrienin macrolide antibiotics. ... 

C9 fragment of the lichen marcolactone (+)-aspicillin [143]. A FraA-mediated stereoselective addition also served as the key step in the synthesis of the noncarbohydrate, skipped polyol C9-C16 fragment 82 of the macrolide antibiotic pentamycin [144,145],... 

Total synthesis of macrolide and ionophore antibiotics containing fragments of tetronic acid 92YZ358. 

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