Polyoxins

FOUR-MEMBERED HETEROCYCLIC RINGS AND THEIR FUSED DERIVATIVES 

In this section, we will deal with biosynthetic studies conducted on the natural polyoxins A, F, H, I, and K 14-18, all bearing the four-membered ring of POIA. The other members of this family have parallel biosynthetic pathways and will not be treated in this book. 

It was also proposed that the incorporation of from [U- C]methionine, [U- C]threonine, and [l- C]glutamate into POIA could occur only after 

In the polyoxin gene cluster, a series of proteins which very likely could catalyze the biosynthesis of the nucleoside skeleton were identified PoLB 

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A stereospecific total synthesis of polyoxin C and related nucleosides is reported, in which thereacdon of l-Cphenylthioi-l-nitroalkenes v/ith nucleophiles and siibseqiientozono lysis are key reacdons Addidonof potassium trimethylsilanoate to l-Cphenylthioi-nitroalkenes derived from D-ribose followed by ozonolysis gives the cr-hydroxy thioester, which is formed v/ith excellent diastereoselecdvity fScheme 4 5 This conformadon meets the stereo-electronic requirements for andperiplanar addition of the nucleophile with the result of high 5-fS stereochemical bias in the reacdons... 

Miller and coworker report a total syndiesis of carbocyclic polyoxin C from cis-(N- en-butylcarbamoyl cyclopent-2-en-Tol, as shovm in Scheme 5.11. This syndiesis feanires a... 

Transformation of chiral nitrones into enantiomer enriched a-chiral N -hydroxylamines and their derivatives, has been successfully employed in the enantioselective synthesis of (+ )-(R)- and (—)-(S)-zileuton (216). An expeditious synthesis of thymine polyoxin C (347), based on the stereocontrolled addition of 2-lithiofuran (a masked carboxylate group) to the A-benzyl nitrone derived from methyl 2,3-O-isopropylidene-dialdo-D-ribofuranoside, is described (Scheme 2.151) (194). 

Antifungal antibiotic (+ )-polyoxin J can be obtained in 46,4% yield by combining the derivative of 5-O-carbamoylpolyoxamic acid (348) with thymine polyoxin C (347) (Scheme 2.152) (196, 583)... 

Nucleophilic addition of furan to nitrone occurs upon treatment with trimethyl-silyl triflate (TMSOTf) (586, 587). Catalyzed TMSOTf stereoselective addition of 2-[(trimethylsilyl)oxy]furan to chiral nitrones was carried out in a short synthesis of [IS (la, 2[), 7f>, 8a, 8aa)]-l,2-di(t-butyldiphenylsilyloxy)-indolizidine-7,8-diol (588). Addition to N -gulosyl-C-alkoxymethyl nitrones led to the synthesis of the core intermediate of polyoxin C (218). 

The reaction of silyl ketene acetal addition to nitrones has been used for the synthesis of optically active (2S,3S)-benzoyl- and /V- oc-phenyl isoserine (636a) of isoxazolidine nucleoside-analog of thymine polyoxine C(636b) and of... 

Michael additions to sugar nitro olefins have received considerable less attention than the Henry reaction involving nitro sugars. Early examples of Michael addition include the synthesis54 of licoricidin by Paulsen in 1982, the addition of phosphorous nucleophiles to a D-glucose based nitro olefin55 by Yamashita in 1987 and the synthesis of the natural antibiotic polyoxin published by Barret in 1990.56... 

Actidione5Actinomycin D, Blasticidin, Chloramphenicol, Citrinin, Daunomycin, Dextro-mycin, Ferrimycidin, Formycin, Imanin, Kanamycin, Laurisin, Miharamycin, Mitomycin C, Naramycin, Ohyamycin, Pentaene G8, Polyoxin A, Puromycin, Streptomycin. 

The discovery of the polyoxin group (1) of antifungal nucleoside antibiotics (2) spurred the attention of synthetic chemists as well as biologists for a number of reasons. Their unusual structural features combined with unique biological activity fostered studies on many fronts (3). During their studies on the biosynthesis of the polyoxins, Isono, Crain and McCloskey (4) discovered three novel acidic nucleosides which they called octosyl acid A, B and C,... 

Further, convenient syntheses of the two fragments of Polyoxin J, deoxypolyoxin C and 5-0-carbamoylpolyoxamic acid, have been achieved in a highly stereoselective manner starting from the same chiral building block, 4-0-benzyl-2,3-0-isopropylidene-L-threose, leading to a formal total synthesis of Polyoxin J (36). 

The reaction protocol was further extended to the concise synthesis of poly-oxamic acid, the unique polyhydroxyamino acid side-chain moiety of the antifungal polyoxin antibiotics (63). Treatment of the template 205 under standard thermal cycloaddition conditions with (5)-glyceraldehyde acetonide led to the formation of a single diastereoisomer 208 in 53% yield. Subsequent template removal released polyoxamic acid 209 in essentially quantitative yield. This represents a matched system, with the mismatched system leading to more complex reaction mixtures (Scheme 3.70). 

Fermentation procedures for preparing uridine 5 -(2-acetamido-2-deoxy-a-D-glucopyranosyl pyrophosphate) have also been reported. One of them255 involves the cultivation of Helminthosporium sativum in the presence of 2-amino-2-deoxy-D-glucose and the antibiotic polyoxin the latter is an inhibitor of chitin biosynthesis. The other256 utilized the incubation of yeast cells with uridine 5 -phosphate in the presence of an excess of 2-amino-2-deoxy-D-glucose and inorganic phosphate.257... 

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