Polyoxins synthesis

Phenylthio)nitromethane is useful in polyoxin synthesis. A ribose nitroalkene (2), derived from (phenylthio)nitromethane and the corresponding aldehyde (93%), was found to react with opposite stereochemical biases with potassium trimethylsilanoate (eq 5) and phthalimide (eq 6) followed by ozonolysis. The hydroxy acid (eq 5) was further transformed into polyoxin C. 

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 synthesis of carbocyclic polyoxin C from cis-(N-tert-butylcarbamoyl)cyclopent-2-en-l-ol, as shown in Scheme 5.11.89 This synthesis features 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). 

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... 

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). 

This method was used in the synthesis of thymine polyoxin C [38]. A similar method was also used in the synthesis of 5-aminohexofuranoses (see Sec. I1I.B). 

P. Gamer and J. M. Park, Glycosyl ot-amino acids via stereocontrolled buildup of a penaldic acid equivalent. An asymmetric synthesis of thymine polyoxin C, Tetrahedron Lett. 30 5065 (1989). 

An application of the deracemization strategy has provided efficient entry to a novel amino acid substituent of the antifungal agents, polyoxins and nikkomycins, as shown in Scheme 8E.20. The versatile five-carbon building block was obtained from phthalimidation of the hydroxymethyl-substituted epoxide in 87% yield and 82% ee. Straightforward synthesis of polyoxamic acid was then accomplished by subsequent dihydroxylation and selective oxidation of the alkylation product. 

Since the first synthesis of polyoxin J by Kuzuhara in 1973 several other total syntheses have been reported.7 This problem is based on the stereoselective and convergent total synthesis described by Gosh and co-workers in 1999.8... 

The synthesis of (-t-)-polyoxin J 14 is completed by selective ester hydrolysis with aqueous lithium hydroxide. The resulting carbamoylpolyoxamic acid was then coupled with the protected thymine polyoxin C 8 with the BOP reagent (Castro s reagent)14 (benzotriazol-1 -yloxytris(dimethyl-amino)phosphonium hexafluoro-phosphate) 37 to furnish the peptide derivative in 63 % yield. 

The stereoselective synthesis of (+)-polyoxin J is accomplished by Gosh in 24 steps and 3 % overall yield. The key intermediates are protected thymine polyoxin C 8 and the 5-Ocarbamoyl polyoxamic acid 2, which were synthesized from D-ribose and dimethyl L-tartrate. Key steps are two different epoxidation reactions, one carried out with MCPBA and the other under Sharpless conditions with the D-(-)-tartrate. Both epoxides are opened with diisopropoxytitanium diazide. The coupling of the two fragments was realized with the BOP reagent 37. This synthesis provides an easy access to the synthesis of various (+)-polyoxin J analogs for biological evaluation. 

Sulphoxides, sulphates and sulphonyl compounds have also been used as substrates in stannane-mediated reductions. Gethin and Simpkins reported the Bu3SnH-mediated removal of the tosyl group in substrate (79) in their preparation of protected thymine polyoxin C (equation 53)293. Similarly, Xu and Lu described the removal of the tosyl group in 80 under similar conditions during their synthesis of pentabromopseudilin (equation 54)294. Padwa and his associates utilised B SnH to remove the sulphone moiety in cyclopentenone (81) (equation 55)295, while Wnuk and coworkers discuss... 

Recently, Nishimura et at. (47) have reported the discovery of polyoxin resistant strains of A. kikuehiana in some orchards of Tottori Prefecture, Japan. Hori et at. (48) suggested that the resistance is caused by a lowered permeability of the antibiotic through the cell membrane into the site of chitin synthesis. 

In this context the comparison of the insecticide diflubenzuron with the fungicide polyoxin D is interesting in more than one respect. It not only closes the circle in our paper, so to speak, but it can also furnish strong circumstantial evidence to support our hypothesis of the mode of action of diflubenzuron. Marks and Sowa were the first to compare diflubenzuron and polyoxin D in their effects on the A ecdyson-dependent in-vitro synthesis of chitin by the cockroach (Leucophaea maderae) leg regenerates (4, ) These authors found that both compounds almost completely inhibited the incorporation of C-labeled D-glucosamine into the chitin fraction. In a later study with 1 C-labeled N-acetyl-D-glucosamine similar results were obtained, and the I50 value of inhibition of chitin synthesis was found to be 6.1 1 x 10 -10m for diflubenzuron and 7.53 x 10"7 M for polyoxin D (4 8) The difference in intrinsic activity can partly be explained by the roughly hundredfold accumulation of dif lubenzuron in the insect tissue. 

The bicyclic isoxazolidine 76 was prepared by nucleophilic addition of 2-trimethylsilyloxyfuran to A-gulosyl-nitrones and employed in a formal synthesis of Polyoxin... 

Gijswijt, M.J., Deul, D.H., and de Jone, B.J., Inhibition of chitin synthesis by benzoyl-phenylurea insecticides. III. Similarity in action in Pieris brassicae (L.) with Polyoxin D, Pestic. Biochem. Physiol., 12, 87,1979. 

In the synthesis of ( + )-polyoxamic acid36, representing a common structural feature of the polyoxin-type antifungal antibiotics, rearrangement of a trichloroacetimidate 1, derived from L-tartrate, gives a 1 1 mixture of diastereomers 2 and 3, showing no induction by the stereogenic centers outside the electrocyclic arena. 

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