Of -aristeromycin

Kitagawa and coworkers have used this strategy for the preparation of pseudo-nucleosides exhibiting various biological activities. The synthesis of (-)-aristeromycin from D-glucose is demonstrated in Scheme 7.17.90... 

Very recently, there have been reports of the utility of TASF for the synthesis of 2 -deoxy-2 -fluoroinosine ( ) and of the p-6 -fluoro analog of ( )-aristeromycin (A8). 

The rather low reactivity of the 3-p-tolylsulfinyl acrylates (they do not react with furan even under forcing conditions) prompted the search for more reactive dienophiles. In this context, pyridylsulfinyl derivatives proved to be more efficient than the arylsulfinyl ones. Thus, menthyl-3-(2-pyridylsulfinyl)propenoates 14a and 14b were prepared from (+)-menthyl propiolate in low yields [34]. Their reactions with cyclopentadiene proceed smoothly in the presence of Et2AlCl at -70°C to afford just one endo diastereoisomer 15a or 15b [35] (in the absence of the catalyst the 7r-facial selectivity for the endo approach was lower than that observed for the p-tolylsulfmyl derivatives [10c]). These compounds were transformed into 16a or 16b [36] respectively (Scheme 8), both allowing the synthesis of the bicyclic lactone 17 (known as Ohno s lactone), a key intermediate in Ohno s synthesis of (-)-aristeromycin and (-)-neplanocin A [37]. 

Boyer, S.J. et al. Carbocyclic Nucleoside Analogs. I. Concise Enantioselec-tive Synthesis of Functionalized Cyclopentanes and Formal Total Synthesis of Aristeromycin. 2.4 1997 [109]... 

Parry, R.J. et al. Investigations of Aristeromycin Biosynthesis Evidence for the Intermediacy of a 2a,3a-Dihydroxy-4j3-(hydroxy-methyl)cyclopentane-1 /3-amine. 2.4 1991 [167]... 

Winson MK, Todd M, Rudd BAM, Jones A, Alsberg BK, Woodward AM, Goodacre R, Rowland JJ, Kell DB (1998) A DRASTIC (Diffuse Reflectance Absorbance Spectroscopy Taking in Chemometrics) approach for the rapid analysis of microbial fermentation products quantification of aristeromycin and neplanocin A in Streptomyces citricolor broths. In Kieslich, K (ed) New Frontiers in Screening for Microbial Biocatalysts. Elsevier Science B.V., The Netherlands, p 185... 

Trost and his group have used both of these palladium-catalysed alkylations in a synthesis of aristeromycin from epoxycycl ope nta diene. The cis stereochemistry of this carbocyclic nucleotide analogue is of paramount importance and was completely controlled by retention of configuration in both substitutions. 

One of the best examples of an enzymatic dephosphorylation for a synthetic purpose is shown in the entry 5 ofTable 13-6. A 5 -ribonucleotide phosphohydrolase was used in the synthesis of (-)-aristeromycin, a carbocyclic analog of adenosine. The (-)-enantiomer of aristeromycin shows some cytostatic and antiviral activity, while the (+)-enantiomer is inactive. The racemate ( )-5 -phosphorylated aristeromycin was resolved by selective hydrolysis of the (-)-enantiomer with the hydrolase. The (-)-alcohol and the (+)-5 -phosphate derivative were separated easily on a silica gel column. Hydrolysis of the (-t-)-enantiomer with calf intestinal phosphatase yielded pure (+)-alcohol. 

A synthesis of aristeromycin" makes use of the displacement of a pyrimidine 4-chloride to allow introduction of the amine and the generation of the 4,5-diaminopyrimidine for subsequent closure of the five-membered ring. 

A DRASTIC (Diffuse Reflectance Absorbance Spectroscopy Taking In Chemometrics) Approach for the Rapid Analysis of Microbial Fermentation Products Quantification of Aristeromycin and Neplanocin A in Streptomyces citricolor Broths. 

The similarity between the diffuse reflectance FTIR spectra of aristeromycin and neplanocin A (Figure 2) and the complexity of the supernatant background FTIR spectra (see Figure 3) necessitates the use of multivariate methods for quantitative analysis of the components. Training data for the construction of multivariate calibration models and test data for model validation were provided by HPLC and FTIR analysis of the S. citricolor mutant fermentation supernatants with a total of 48 samples taken from duplicate fermentations after 3 and 6 days incubation. 

Figure 2. Representative FTIR absorbance spectra of Aristeromycin and Neplanocin A.

Figure 3. FTIR absorbance spectra of supernatants from four different S. citricolor mutants in the wavenumber ranges (a) 4000-600/cm-i (b) 1700-I000/cm-i. The background variation of the S. citricolor mutant culture supernatants and the general similarity between the FTIR spectra of aristeromycin and neplanocin A (see Figure 2) necessitates the use of multivariate data analysis for quantification and classification.

PLS (Partial Least Squares) regression was used for quantification and classification of aristeromycin and neplanocin A (Figure 4). Matlab was used for PCA (Principal Components Analysis) (according to the NIPALS algorithm) to identify correlations amongst the variables from the 882 wavenumbers and reduce the number of inputs for Discriminant Function Analysis (DFA) (first 15 PCA scores used) (Figure 5). 

Quantification of neplanocin A in the presence of aristeromycin was found to be such an example. Accurate quantification of neplanocin A under these circumstances was not possible using PLS regression performed on the whole data set (see Figure. 4) however, PCA followed by DFA was successfully used to discriminate between the mutant classes (Figure... 

The results of this study, using quantification of aristeromycin and neplanocin A in a model S. citricolor fermentation system, illustrate for the first time that the DRASTIC approach provides a novel, rapid and successful method for screening microbial strains for metabolite overproduction in titre improvement programmes. 

In the area of carbocyclic nucleoside antibiotics, a full account of syntheses of (—)-aristeromycin and (—)-neplanocin A (see Vol. 31, p. 261) was mentioned above. " The known intermediate 174, prepared from D-ribose, has been used for the first synthesis of neplanocin C (175), a minor component of the neplanocin family. The diastereomeric epoxide was also obtained. In efforts to prepare prodrugs, the oxetanocin analogue 176, an antiviral agent (lobucavir), has been selectively aminoacylated with l-valine on either of the hydroxymethyl groups using enzymic methods. A synthesis of the cyclohexenyl nucleoside antibiotic pyralomycin Ic is mentioned in Chapter 18. 

Koizumi and coworkers have developed a new enantiomerically pure a,p-unsaturated sulfoxide dienophile bearing the isoborneol group as a chiral auxiliary, dimethyl (f )-2-(10-isoborneolsulfinyl)maleate (214), which has been successfully employed as a chiral synthetic equivalent of dimethyl acetylenedicarboxylate [174], The dienophile (214) underwent cycloaddition with cyclopentadiene, in the presence of zinc chloride, with high stereo- and diastereoselectivity (92% single endo diastereoisomer, 6% single exo diastereoisomer) to yield the major cycloadduct (215), which was subsequently transformed into the half-ester (216), an intermediate in the syntheses of (-)-aristeromycin (199) and (-)-neplanocin A (200). Cycloadduct (215) has also recently been used for the synthesis of bicyclo[2.2.1]heptane lactone (217) [175,177], which itself is an intermediate in the synthesis of the iridoid (-)-boschnialactone [176] (218) (Scheme 5.69), and also in the formal synthesis of (-)-aristeromycin (199) and (-)-neplanocin (200) [177]. 

There has been a further report on the synthesis of aristeromycin... 

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