Validamycins

Valence shell electron pair repulsion theory, 1, 564 Valence tautomerism photochromic processes and, 1, 387 y-Valerolactone, o -allyl-a -2-(pyrido[2,3-6]-imidazolyl)-synthesis, 5, 637 Validamycin A as fungicide, 1, 194 Valinomycin... 

Validamydns Validamycin A and Validoxylamine Various bacteria and yeasts... 

Among the carba-sugar derivatives, the most important and attractive members are amino carba-sugars, particularly 5a-carba- -D-glucopyran-osylamlne (validamine) and its unsaturated derivative (valienamine). These amino carba-sugars have been synthesized successfully, as well as validamycin antibiotics and some of the aforedescribed enzyme inhibitors. 

Carba-glycosylamines [2,3,4-trihydroxy-5-(hydroxymethyl)-1 -cyclohex-ylamine] and related compounds are well known to exist as components of the antibiotic validamycin complex and carba-oligosaccharidic alpha amylase inhibitors. ... 

Microbial degradation of validamycin A (8) with a cell suspension of Pseudomonas dentrificans afforded validamine (202) and valienamine (203). Hydrogenolysis of validamycin B, followed by acid hydrolysis, yielded hydroxy validamine (204). Valiolamine (205) was isolated and shown to be a component of validamycin G. ° Biosynthesis of these carba-glycosylamines was extensively studied, and the intramolecular aldol addition of the... 

Synthetic studies of validamycins were initially devoted to establishing the structure of validamycin A. The structure in which a ) -D-glucopyranosyl group is attached to 0-3 of the validamine residue was initially proposed on the basis of degradative studies. However, the original structure was re-... 

Two validamycin A isomers were synthesized by coupling of the protected derivative of 355 and the epoxides 243 and 244. 

Total synthesis of (+)-validamycins A and B starting from a common synthetic intermediate was elaborated by the following sequence. Tetra-(9-benzyl-(-l-)-valienamine (370), derived from 211, and the di-O-benzyl derivative (371) of the epoxide were coupled in 2-propanol to produce the protected dicarba compound (374), the structure of which was confirmed by conversion into (-1-)-validoxylamine B nonaacetate. Concurrently, compound 372 was glycosylated and the product oxidized with a peroxy acid, to afford a mixture of products from which the desired epoxide (373) was obtained in 70% yield. Coupling of 370 with 373 in 2-propanol at 120° afforded two carba-trisaccharides, and the major product (47%) was depro-tected and characterized as the dodecaacetate of validamycin B. The pro-... 

Reaction of368 with hepta-O-acetyl-a-maltosyl, -cellobiosyl, and -lacto-syl bromide in 1,2-dichloroethane in the presence of silver triflate gave the respective carba-tetrasaccharides, including validamycin D. 

Glycosylation of the 7-hydroxy compound, prepared from 367 by trityla-tion, benzylation, and detritylation with acid, afforded the protected validamycin D in good yield. 

Several mono-carba-oligosaccharidic alpha amylase inhibitors, such as acarbose and its homologs, amylostatins, trestatins, oligostatins, adipo-sins, and so on, have been isolated from cultures of micro-organisms, and considerable interest in the biochemistry and chemistry of this class of inhibitors has been stimulated. The characteristic core-structure for inhibitory action is composed of a trihydroxy(hydroxymethyl)cyclohexene moiety and a 4-amino-4,6-dideoxy-D-glucopyranose moiety, bonded by way of an imino linkage at the allylic position. A similar structural unit has been found in the antibiotic validamycins. 

Activity of Validamycins and Validoxylamines against Pellicularia sasakii... 

Inhibitory Activity (M) of Validamycin and Validoxylamine against Trehalase... 

Among other carba-sugar derivatives, the most important compounds are amino carba-sugars having an amino group at C-1. They are known as validamine, valiolamine, hydroxyvalidamine, and valienamine, and are found in validamycin antibiotics as unique components they have been synthesized in dl forms and also in optically active forms. 

Such carba-disaccharides as validoxylamines A and B were synthesized as intermediary compounds in the total synthesis of validamycin antibiotics. Carba-disaccharides related to maltose, isomaltose, cellobiose, the trehaloses, and trehalosamine modifications have also been synthesized. 

Validamycin A is the only commercial fungicide active against this target (Figure 4.9). The compound is an aminoglycosidic pseudosaccharide and is a secondary metabolite produced in the fermentation of Streptomyces hygroscopicus var. limoneus. Validamycin A was introduced by Takeda Chemical Industries Ltd. for the control of Basidiomy-cetes and Corticiaceae, especially sheath blight, Rhizoctonia solani, in rice. 

Other antibiotics of some importance are griseofulvin, cycloheximide, streptomycin and validamycin A. All aspects of antifungal antibiotics have been usefully reviewed (B-77MI10709, B-77MI10710). 

The dithiane derivative 60 (Scheme 14) is such a compound, it being made from 2,3 5,6-di-0-isopropylidene-D-mannose by treatment with 2-lithio-l,3-dithiane to give a heptose dithioacetal that was refunctionalized at C-2-C-3 by way of the C-l anion and then converted to the 6,7-epoxide following selective acid-catalyzed cleavage of the 6,7-acetal ring. Treated with n-butyllithium it gives, in 70% yield, the cyclized 61, which is efficiently convertible into validatol 62, a component of validamycin A, by desulfurization with Raney nickel and de-O-protection by use of boron tribromide in dichloromethane [31]. 

Wakae, 0. Matsuura, K. (1975) Characteristics of Validamycin as a Fungicide for Rhizoctonia Disease Control. Review of Plant Protection Research 8, 81-92. 

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