Manumycins structures

Chatterjee and coworkers45 recently reported the taxonomy, production, isolation, structure elucidation and biological properties of a new antibacterial antibiotic alisamycin (75), a new member of the manumycin group of antibiotics obtained by the fermentation of Streptomyces actuosus. 

The manumycin family is a group of antibiotics produced by the Streptomyces species. They are structurally-related natural products and are exemplified by alisamycin (48), asukamycin (49), U-56407 (50), colabomycin A (51), manumycins A (52), B (53), C (54) and D (55), and nisamycin (56). Similar structural moieties are present in all members of the group a mC7N unit with an epoxyenone structure containing two... 

Manumycin A (52) was the first metabolite isolated from Streptomyces parvulus (strain Tii 64) [110] and its structure and absolute configuration have been described [111]. Other minor components such as manumycin B (53), C (54) and D (55) have similar structural moieties indicating their close structural and biosynthetic relationship [112]. These other compounds differ in the polyketide assembly of the acylamino side chain and in the stereochemistry at C-4. Manumycin D (55) is the first of the manumycin type compounds without an oxirane ring in the mC7N unit. Their structural elucidation has been recently carried out [112] by H NMR spectroscopy using aromatic solvent induced shift (ASIS) effects at the olefinic 3-H and circular dichroism (CD) spectroscopy has been used to determine the absolute stereochemistry of the mC7N unit. 

Unlike most of the other FPP competitive inhibitors, manumycin is devoid of negatively charged groups such as carboxylates and phosphates. This structural deficiency, which is a distinct liability in most of the other FPP competitive inhibitors in terms of their cell penetration, actually helps to facilitate the entry of manumycin into cells. Consequently, several reports describing the activity of manumycin A in various ras-transformed cell cultures have appeared [107-109]. More significantly, manumycin A also reduces growth of Ki-ras-transformed tumors in a dose-dependent manner in BALB/c nude mice [110]. 

Figure 3.68 Structures of the manumycin, asukamycin, and related family of antibiotics.

Class 3, in which the precursor is connected to both structural elements, thus exhibiting the entire carbon skeleton of the parent antibiotic manumycin 220, compound 240 (Figure 3.72) [256, 257],... 

Feeding of 3,4-AHBA chain-extended by one acetate unit 244 and its SNAC 245, two acetate units 246, and three acetate units 247 produced no incorporation into the final product. Likewise, no incorporation was observed for the complete upper chain 248, the 3,4-AHBA chain-extended bearing the complete lower chain including the C5N unit 249, the 3,4-AHBA N-acylated with the complete upper chain 250, and the 3,4-AHBA with both the upper and the lower chain but without the C5N unit 251. However, protoasukamycin 252 was efficiently and specifically incorporated into 221, leaving no doubt that the entire molecular framework of the manumycins is assembled first before the aromatic ring is modified to the final epoxyquinol structure of the type I manumycins. 

Taylor and co-workers employed an asymmetric phase-transfer-catalyzed epoxidation as the key step in the synthesis of (+)-manumycin and revised the structural assignment for the natural antibiotic (—)-manumycin (Scheme 35.31). Using A-benzylcinchonidinium chloride 111 as the phase-transfer catalyst, asymmetric epoxidation of cw-enone 112 provided epoxide 113 in 32% yield (82% based on recovered 112) and 89% ee (>99% ee after recrystallizations). Epoxide 113 was finally transformed into... 

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