Pyrenophorin

The diolefin 1064 gives rise to the isoxazoline 1065, which cannot eliminate tri-methylsilanol 4 [122]. Cychzation of the co-nitroolefin 1066 with trimethylchloro-silane (TCS) 14/triethylamine at -35 °C then HCl-induced removal of trimethyl-silanol 4 leads, in 85% yield, to the dimer 1067, which is converted in two more steps into racemic pyrenophorin 1068 [112] (Scheme 7.39). Further cyclizations of co-nitroolefins [109] to monomeric or dimeric isoxazolines have been described. Conjugated dienes such as butadiene afford a mixture of the mono or bis adducts [115-117]. 

A short enantioselective synthesis of (-)-(R,R)-pyrenophorin, a naturally occurring anti-fun-gal 16-membered macrolide dilactone, is prepared from (S)-5-nitropentan-2-ol via the Michael addition and Nef reaction (Scheme 4.23).162 The choice of base is important to get the E-alkene in the Michael addition, for other bases give a mixture of E and Z-alkenes. The requisite chiral (S)-5-nitropentan-2-ol is prepared by enantioselective reduction of 5-nitropentan-2-one with baker s yeast.163... 

We have not yet assigned the stereochemistry of the secondary alcohol centers in Vll or VIII. The simplicity of the NMR spectrum of VIII indicates a symmetrical molecule. This would most plausibly be the molecule with twofold symmetry, but we cannot yet rule out the meso form. Upon oxidation Vll could be converted to pyrenophor-in (VIII). Pyrenophorin was also active in the biological assays, but was not found in D. avenae. It is produced by several other fungi (17). 

Isoxazolines can be transformed into a,p-enones by several methods from the initial aldol product. This strategy was applied by Barco et al. (285) toward the synthesis of ( )-pyrenophorin (98), a macrocychc fow(enone-lactone) with antifungal properties. The hydroxy group was introduced from the nitrile oxide component (95), while the carboxy function was derived from the acrylate dipo-larophile. Thus, cycloaddition of the optically active nitropentyl acetate 94 to methyl acrylate 95 afforded isoxazoline 96 as a mixture of optically active diastereomers. Reductive hydrolysis using Raney nickel/acetic acid gave p-hydro-xyketone (97), which was subsequently utilized for the synthesis of (—)-pyreno-phorin (98) (Scheme 6.63) (285). 

A very short and elegant synthesis of the 16-rtiembered dilactone ( )-pyrenophorin (515) has been accomplished by the dipolar cycloaddition reaction of a trialkylsilyl nitronate (81TL735). Nitromethane was added to 3-buten-2-one and the carbonyl group of the product reduced with sodium borohydride. The nitro alcohol (511) was converted to the acrylate (512) which was then subjected to a dimerization-cyclization reaction by treatment with chlorotrimethylsilane and triethylamine in dry benzene. Hydrogenation of the mixture of isoxazoline products (513) over palladium on charcoal followed by double dehydration of the intermediate bis-/3-hydroxyketone (514) led to ( )- and meso-pyrenophorin (Scheme... 

Hence explain this synthesis of part of the antifungal compound pyrenophorin. 

Lactonization of aliphatic hydroxy acids proceeds with the aid of two reagents, diethyl azodicarboxylate and triphenylphosphine. This fourth procedure has been selected as a method of choice for the final cyclization to yield vermiculine4 and pyrenophorin.4h... 

An alternative ester synthesis, the reaction of a carboxylate anion with an alkyl halide, was used by Madejewski [62] for the preparation of ( , )-l,9-dioxacy-clohexadeca-3,1 l-dien-2,10-dione (76) under dilution conditions. This 16-membe-red dilactone represents a precursor for the synthetic norpyrenophorin 77 a, the physiological activity of which corresponds to the one of the natural products pyrenophorin 77b and vermiculin 77c. The lactone 76 can be obtained in 77% yield by dimerization of ( )-7-bromo-2-heptenic acid (75) in DMF in the presence of potassium carbonate. 

In the first synthesis of the dilactonic antibiotic pyrenophorin 89) by Raphael and coworkers [53], imidazole ester was used to achieve cyclization. As shown in Scheme 29, the linear precursor 87 was converted to the imidazolide by the action of diimidazol-l-yl ketone (ImjCO) and foDowed by l,5-diazabicyclo[4.3.0]non-5-ene (DBN) induced cyclization to give the dilactone 88 in 60% yield. 

Reaction of dithiane with DMF leads to the formation of an aldehyde, a key intermediate for the synthesis of the macrocyciic antibiotic ( )-pyrenophorin. ... 

Staab s A, A -carbonyldiimidazolide method has been applied in a synthesis of pyrenophorine (via 373), in which the indicated bond has been closed. More recently, the usual activated amide (374) has been used to obtain the )V-protected antimycin A3 derivative (374) under acid catalysis (equation 134). ... 

The Mitsunobu procedure has found considerable application, so it has been used for diolide formation in pyrenophorin (equation 138) °° and colletodioF° syntheses. Yamaguchi s method is much infe-rior. As expected, the ring closure in equation (138) proceeds with inversion of configuration. In a... 

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