Valiolamines

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... 

DL-Valiolamine (205) was synthesized from the exo-alkene (247) derived from 51 with silver fluoride in pyridine. Compound 247 was treated with a peroxy acid, to give a single spiro epoxide (248, 89%) which was cleaved by way of anchimeric reaction in the presence of acetate ion to give, after acetylation, the tetraacetate 249. The bromo group was directly displaced with azide ion, the product was hydrogenated, and the amine acety-lated, to give the penta-A, 0-acetyl derivative (250,50%). On the other hand. 

Horii and Fukase first succeeded in synthesis of (+)-valiolamine (205) by stereoselective chemical conversion of(+)-203 through the key intermediate... 

In order to develop potent D-glucosidase inhibitors, a synthesis of carba-disaccharides containing valiolamine (205) was attempted by Horii and his coworkers utilizing method c. Coupling 205 with the 4-ketose 403, using NaBHjCN and hydrochloric acid, was effective in DMF, giving, after deprotection, the epimeric carba-disaccharides (404 and 405). The saturated... 

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. 

Lemaire et al. have developed a efficient fructose-1,6-bisphosphate aldolase (FBPA)-mediated synthesis of aminocyclitol analogs of valiolamine [34], This one-pot route involves the formation of two C—C bonds where four stereocenters are created. The first C—C bond formation reaction is catalyzed by the aldolase, coupling DHAP to nitrobutyraldehydes the other one is the result of a highly stereoselective intramolecular Henry reaction occurring on the intermediate nitroketone under acidic conditions during the aldolase-catalyzed reaction and phytase-catalyzed phosphate hydrolysis coupled step (Scheme 4.13). 

Scheme 4.13 Multi-enzyme route for the synthesis of aminocyclitol analogs of valiolamine...

Another unexpected rearrangement was encountered in the synthesis of 1 - e/u -valiolamine, when the alkene 4 was subjected to dihydroxylation conditions. Thus, heating of a mixture of 4 with a catalytic amount of OSO4 in a water/pyridine/t-butanol mixture containing trimethylamine N-oxide under reflux for 2 days gave a mixture of 5 (29%) and the a-diol 6 (14%) together with 46% of unchanged alkene 4. 

The first evidence for aminocarbapyranoses occurring in Nature dates back to early 70s with the discovery of validamine 202 (Chart 3), a carbasugar constituent of Validamycins, an antibiotic complex which shows growth inhibition activity against bacterial diseases of rice plants [50]. Shortly after, validamine 202, along with valiolamine 203 and valienamine 204, (Chart 3), were isolated from the fermentation broth of Streptomyces hygroscopicus var. limoneus [50],... 

The majority of naturally occurring aminocarbasugars bears the amino functionality located at the pseudoanomeric position however, replacement of one or more hydroxyl groups by amino functions on the carbasugar backbone may offer great opportunities for structural and stereochemical variation. This section is subdivided into three subsections, dealing with the synthesis of validamine, valiolamine, and valienamine-type carbaglycosyl amine structures. 

The application of the same protocol to D-galacto- and D-manno-configured lactones 238 and 241 resulted in the construction of two further inosose variants, 239 and 242, the proximate precursors of galacto- and manno-valiolamines 240 and 243. 

Searching for a simple, divergent methodology to access valiolamine 203 and certain structurally varied relatives, Shing and Wang [59] utilized the unsaturated scaffold 244 whose preparation from quinic acid 159 was already established [60]. 

As can be seen in Scheme 39, alkene 244 was first dihydroxylated and then manipulated into partially protected cyclitol 245, a flexible intermediate of this synthetic plan. Incorporation of the nitrogen at the pseudo-anomeric position was then carried out, as usual, by azide Sn2 displacement of the Ci hydroxyl. There was obtained azido-carbapyranose 246, which nicely served to prepare both valiolamine 203 and its C2 epimer 243. 

Fukase, H. et al. Synthesis of a Branched-Chain Inosose Derivative, a Versatile Synthon ofN-Substituted Valiolamine Derivatives from D-Glucose. 3.4.2 1992 [58a]... 

Kameda Y, Asano N, Yoshikawa M, Takeuchi M, Yamaguchi T, Matsui K, Horii S, Fukase H (1984) Valiolamine, a new alpha-glucosidase inhibiting aminocyclitol produced by Streptomyces hygroscopicus. J Antibiot (Tokyo) 37 1301-1307... 

Ogawa S, Tsunoda H (1992) Pseudo-sugars. XXXI. New synthesis of 2-amino-5a-carba-2-deoxy-a-DL-glucopyranose and its transformation into valien-amine and valiolamine analogues. Liebigs Ann Chem 6 637-641... 

Opening a new route to valiolamine analogs, this work broadens the scope of the enzymatic aldol reaction combining in one pot the formation of two carbon-carbon bonds with high stereoselectivity. We demonstrate a short efficient synthesis of new nitro- and aminocychtols that considerably reduces the laborious... 

FIGURE 16.7 The commercially available a-glucosidase inhibitors acarbose 5 and voglibose 8, a derivative of valiolamine 7. 

Valiolamine (89), an aminocyclitol produced by Streptomyces hygroscopicus var. limoneus, is a potent inhibitor of pig intestinal maltase and sucrase, with IC50 values of 2.2 and 0.049 pM, respectively [107]. Numerous iV-substituted valiolamine derivatives were synthesized to enhance its a-glucosidase inhibitory activity in vitro and the very simple derivative voglibose (90), which is obtained by reductive amination of valiolamine with dihydroxyacetone, was selected as the potential oral antidiabetic agent [108]. Its IC50 values toward maltase and sucrase were 0.015 and 0.0046 pM, respectively. Voglibose (the brand name Basen) has been commercially available for the treatment of type 2 diabetes in Japan since 1994. 

---