Streptovaricins acetates

Li, L.H., Moran, D., Wiley, P.R. Relative biological activities of individual streptovaricins and streptovaricin acetates. Biochem. 13, 861 (1974)... 

The most extensively studied streptovaricin derivatives are the streptovaricin acetates 103). As noted in Section II.A., acetylation was a key reaction in interrelating the structures of the streptovaricins. Since streptovaricins A, G and K all give the same compound, streptovaricin G triacetate (streptovaricins A and K diacetate), on acetylation, and streptovaricins A and K have one more acetate group than streptovaricin G, streptovaricins A and K are monoacetates of streptovaricin G. Similarly, streptovaricins C, B and J give the same compounds, streptovaricin C tri- and tetraacetates (streptovaricins B and J di- and triacetates), and streptovaricins B and J have one more acetate group than streptovaricin C. The positions of the acetates in streptovaricins A, B, J and K were located by shifts of appropriate protons in magnetic resonance spectra. 

The ansa-chain of the ansamycins streptovaricins (4), rifamycins (263), geldanamycin (4), and herbimycin (32) has been shown to be polyketide in origin, being made up of propionate and acetate units with the 0-methyl groups coming from methionine. The remaining aromatic C N portion of the ansamacroHdes is derived from 3-amino-5-hydroxybenzoic acid (264—266) which is formed via shikimate precursors. Based on the precursors of the rifamycins and streptovaricins isolated from mutant bacteria strains, a detailed scheme for the biosynthesis of most of the ansamacroHdes has been proposed (95,263). 

An analogous addition is observed in the conversion of lumihecogenin acetate (281) into photohecogenin acetate (282),304 and an addition of this type has also been proposed to account for the photolytic loss of acetic anhydride in streptovaricin (283).305... 

Using carbon-13 magnetic resonance spectroscopy, Rinehart and his collaborators have shown49 that the biosynthesis of the streptovaricins is very similar to that of the rifamycins. Streptovaricin D is synthesized from a C7N unit of unknown origin to which 8 propionic acid residues and two acetic acid residues are attached, whereby the direction of growth is the same as that of the rifamycins. In contrast to the... 

Studies using 14C-labelled precursors and C-l3 carbon magnetic resonance have suggested that the biosynthesis of the benzenic ansamycin geldanamycin follows essentially the same pathway as that of the rifamycins and streptovaricins50. Geldanamycin is composed of 3 acetate and four propionate units which are attached to a C7N unit in the same direction of growth as is found in rifamycins and streptovaricins. The incorporation of three acetate units into the ansa chain, as opposed to two in the naphthalenic ansamycins, excludes the existance of a common precursor. 

Schreiber, S.L., Wang, Z., and Schulte, G., Group selective reduction of acetals related to the ansa chain of the streptovaricins. Conformational and stereochemical analysis. Tetrahedron Lett., 29, 4085, 1988. 

The related antibiotics streptovaricin D (231) and rifamycin S (232) are derived along similar mixed acetate-propionate pathways, deduced as above by use of... 

A similar C7N unit [heavy bonding in (231) and (232)] of unknown origin is again apparent in both antibiotics. Neither the usual precursors of aromatic rings, such as shikimate or acetate, served as precursors for this unit in rifamycin S (232) nor was label from propionate incorporated into the C7N unit of streptovaricin D (231 ). "... 

It was proposed that the polyketide chain of rifamycin S (2) was formed by a linear condensation, in the appropriate sequence, of eight methylmalonates and two malonates [199] and it was also pointed out that the incorporation pattern of propionates and acetate for streptovaricin D (45) was in an amide-head direction. Namely, the amide carbonyl was derived from the carboxyl group of propionate by the incorporation study... 

The origin of the ansa chain and the direction of the synthesis of geldanamycin (85) were reported [139]. According to the report, the ansa chain consists of acetic and propionic acid moieties, and the direction of the biosynthesis was through the amide-head pathway, like that of streptovaricin D (45) (Fig. 10) [91]. It was also reported that two C2 units of the ansa moiety of geldanamycin (85) at C-5-C-6 and C-1 l-C-12 arose from two glycolate (G) units [177]. Consequently, the biosynthetic building units and their sequence on 85 are indicated as P-A-G-P-P-G-P (the P unit corresponds to a C-1 carbonyl, C-2 and a methyl at C-2). 

With respect to those ansamycins consisting of 17 carbon ansa chains, the moiety except for the part derived from the m-CyN unit of each alkaloid has been considered [3]. Thus, the biogenetic units of these moieties were P-A-P-P-P-P-P-P-A-P (P is propionic acid, and A is acetic acid), with no exception. For example, although it appears that the chemical structures of rifamycin B and streptovaricin C are quite different, the biogenetic units of these two alkaloids, and their sequence, are the same as P-A-P-P-P-P-P-P-A-R... 

Although the use of C-labelled acetates and propionates had demonstrated that they were precursors in the formation of rifamycin S it was only by the use of various C-precursors and assignments of the NMR spectra that the labelling pattern from acetate and propionate was established [216]. C-NMR has also been used to establish the biosynthetic pathway of streptovaricin D the use of sodium [l- C]propionate established that the amide carbonyl was derived from the carboxyl group of propionate [217]. The use of methionine ( C-methyl) and sodium [l- C]propionate showed that geldanamycin followed the same biosynthetic pathway as rifamycin and streptovaricin D [218]. 

Infrared spectra of the ansamycins are rather unexceptional, with the expected absorptions being observed for quinone, hydroxyl, ester, and amide groups. Among the more distinctive bands are those for the enol acetate of the streptovaricins (sometimes observed as a shoulder) near 1760 cm 84) and the lactide band of rifamycin O at 1822 cm (727). 

Further study (42) using [methylene- C m2i ondiiQ has shown that, while the ansa chain of geldanamycin contains four propionate units, only one acetate (malonate) unit is incorporated, at C-3 and C-4. Since four ansa-chain carbon atoms (C-5, C-6, C-10, C-11) remain biosynthetic-ally undefined, geldanamycin is biogenetically distinct from rifamycin S and streptovaricin D. The C7N unit of geldanamycin has, like that in rifamycin S (755), been shown to be derived from glucose D-[6- C -... 

Thus, the three ansamycins whose biosyntheses have been investigated are derived from closely related biosynthetic pathways. The streptovaricin and rifamycin ansa chains are derived from seven propionate and two acetate (malonate) units, the geldanamycin ansa chain from four propionate, one malonate and two still unidentified 2-carbon units. In two of the three antibiotics (and presumably in streptovaricin as well) a C7N unit is derived from glucose via a shikimate-type pathway. Although a number of late intermediates in the biosynthesis of rifamycin and streptovaricins have been identified, much remains to be done. 

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