Pentamycin

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]. 

Figure 10.35 Stereoselective generation of chiral precursors for the synthesis of the lichen macrolactone (+)-aspicillin and the macrolide antibiotic pentamycin using FruA catalysis.

Recently, the absolute stereochemistry of pentamycin, an antibiotic from Streptomyces pentaticus with the same gross structure as fungichromin (54), has been reported as being either 62a or 62b. Elucidation of the stereochemical relationship between pentamycin (62)... 

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). 

Scheme 4.19 Correspondence between the configurations at CIS and Cl 4 of pentamycin and those of the C3 and C4 positions of an aldol constructed by FBPA.

Scheme 4.20 Chemical transformation of 7-0-benzyl-6-deoxy-D-xyloheptulose in the precursor of the Cl 1-Cl 6 fragment of pentamycin.

Further chemical transformation of the xyloheptulose derivative afforded a direct precursor of the C11-C16 fragment of pentamycin. 

Stereoselective synthesis of the C11-C16 fragment of the polyene macro-lide antibiotic, pentamycin, has also been accomplished under the aldolase protocol.45 A formyl and benzyl protected aldehyde, available from D-glucose by chemical methods, reacts with DHAP under the influence of FDP aldolase. After phosphatase hydrolysis the essential C11-C16 skeleton of pentamycin is generated. Removal of an additional hydroxyl group at position 1 and isolation of the C11-C16 fragment as a thioacetal, is accomplished in several steps (Scheme 5.23). 

Scheme 5.23. Synthesis of the C11-C16 fragment in the formal total synthesis of Pentamycin. Pase = phosphatase.

Pentamycin (molcidin B), isolated from the mycelium of Streptomyces pentaticus [68, 69] is a sugar-free pentaenic 28-membered lactone having the same constitution as fongichromin [70-72] (lagosin, cogomycin), and these two antibiotics were found to be identical after a detailed comparison of their peracetylated derivatives [66]. A very recent study of the stereostructure by Oishi et al. [66,67] defined the absolute configuration of the twelve asymmetric centers of this substance. 

Acetonide formation and acetylation of pentamycin 59 gave two isomers 60 and 61, of which one was transformed in three steps to ketone 62 (Scheme 8). 

Thioacetal 79, corresponding to the C(ll)-C(16) portion of the polyene antibiotic pentamycin, has been synthesized from D-glucose via fin oside 76. A key step was the use of fhictose 1,6-diphosphate aldolase to couple aldehyde 77 to dihydroxyacetone phosphate to give ketose 78 (Scheme IS). A synthesis of 78 from D-mannitol has also been described. ... 

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],... 

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