0-Ribo compounds

Another route to a methyl-branched derivative makes use of reductive cleavage of spiro epoxides ( ). The realization of this process was tested in the monosaccharide series. Hittig olefination of was used to form the exocyclic methylene compound 48. This sugar contains an inherent allyl alcohol fragmenC the chiral C-4 alcohol function of which should be idealy suited to determine the chirality of the epoxide to be formed by the Sharpless method. With tert-butvl hydroperoxide, titanium tetraisopropoxide and (-)-tartrate (for a "like mode" process) no reaction occured. After a number of attempts, the Sharpless method was abandoned and extended back to the well-established m-chloroperoxybenzoic acid epoxida-tion. The (3 )-epoxide was obtained stereospecifically in excellent yield (83%rT and this could be readily reduced to give the D-ribo compound 50. The exclusive formation of 49 is unexpected and may be associated with a strong ster chemical induction by the chiral centers at C-1, C-4, and C-5. 

The stereochemical outcome of epoxidation of 6-suhstitiited 2-al-koxy-5,6-dihydro-2/i-pyrans with peroxy acids is dependent on the configuration and on the type of substituents in the substrate from either isomer, the cis or trails, or (usually) both, stereoisomeric epox-idc(s) are formed. In the case of the Irons isomer, the a-lijxo epoxide (232) preponderates over the a-ribo compound (233). From thee/.v iso-... 

Also, opening of epoxides may afford the keto sugars. The D-ribo compounds 233 were obtained by treatment of the corresponding 3-nitro-D-allo-2,3-epoxide with nucleophiles, epimerization occurring at C-2 444... 

Figure 8 shows the a-D-ribo compounds, where in both acetates and benzoates, the proportion of the 1C4 conformer is similar (l ). This was to be expected, because the 1,3-diaxial interaction in both conformers should be similar. Again, in these derivatives, both conformers exhibit three gauche interactions, which need not be considered. Because of this — in addition to the 1,3-diaxial interactions — only the anomeric effect in the left (1C4) form has to be taken into account. 

When the situation is examined for the g-ribo compound (Figure 9), the 4Ci form on the right shows three, and the 1C4 form on the left, only two gauche interactions. The 1,3-diaxial... 

The conformational analysis of the peracetyl 1,5-anhydro-hex-l-enitol system has been carried out using n.m.r. at 250 MHz all were shown to adopt the (d) conformation except the lyxo isomer, which adopted the (d) conformation. The conformations of all eight 1,6-anhydro-D-aldohexopyranoses and their triacetates have been shown by n.m.r. to be the expected flattened C4 chair with the flattening being more pronounced when the C-3 substituent is cis to the anhydro-bridge. The same group has studied the complete series of 1,6 2,3- and 1,6 3,4-dianhydro-D-hexopyranoses in a similar manner all were shown to exist as or half-chairs. A -(2,3,4-Tri-0-acetyl-/3-D-lyxo-pyranosyl)-p-nitroaniline exists in the conformation, whereas the a-anomer adopts the conformation. A similar situation has been described for the corresponding D-ribo compounds. The non-acetylated iV-(a-D-ribopyranosyl)-p-nitroaniline is in conformational equilibrium between 4 and Ci chairs. 

In a synthesis of 2 -amino-2, 3 -dideoxy-3 -fluoronucleosides, the D-ribo-compounds (66) were prepared as outlined in Scheme 9. Some of the D-lyxo-isomer of (65) was also produced during the oxidation-reductive amination, and was used to make a-D-lyxofuranosyl analogues of (66). 

Also in the hexos-3-ulose series the ketone (7) has been made easily from the D-galacto-alcohol by use of PCC on alumina under reflux in benzene, the D-ribo-compounds (8) were obtained by treatment of the corresponding 3-nitro-D-allo-2,3-epoxide with nucleophiles (epimerization occurring at C-2), and reduction with zinc borohydride of the enolone (9) gave the 3-ulose derivative (10),... 

There has been a Anther report (see VoL 26, p. 227-8) on die formation of intramolecular hemiacetals by uridine-6-carboxaldehyde and related corrqxiunds. The D-ribo- and 2 -deoxy-D-ribo-compounds form hemiacetals involving 0-5, whilst the D-arobino-analogue forms the hemiacetal 14 involving 0-2 2 ... 

The diastereoselectivity is observed in the Henry reaction using optical active niti o compounds or a-heteroatom substituted aldehydes. Lor example, the reaction of O-benzyl-D-lactal-dehyde with methyl 3-niti opropionate in the presence of neubal alumina leads to a mixture of three niti o-aldol products from which D-ribo isomer is isolated by direct crystallization. D-Ribo... 

Several features of the rearrangement have been elucidated. Although in the treatment of the ester 26 with acetic acid the products were isolated in only 64% yield, evidence was obtained (22) that finally no 1,2-unsaturated compounds remained, since the noncrystalline portion on hydrogenation and deacetylation afforded only 3-deoxy-D-ribo and -d-arabino-hexose and no 1,5-anhydrohexitols. That the components of the final mixture were in equilibrium was indicated by the observation that the main component 27 underwent reaction in boiling acetic acid to give a solution with the same optical activity as that of the original reaction mixture. Thus the 2,3-unsaturated compounds are more stable than the hydroxyglycal derivatives and the a isomer 27 is more stable than its anomer 28. 

The 2 -chloro and 2 -bromo congeners of either 748 (FIAC) or 758 (FMAU) are more cytotoxic than FIAC and FMAU, suggesting that these chloro and bromo nucleosides, in contrast to the 2 -fluoro compounds, are comparatively better substrates for deoxycytidine kinase of human lymphocytes than the substrates for viral-specific thymidine kinase. The disposition of the 2 -fluoro group may also be important from the biological viewpoint. It should be noted that the structural difference between RNA and DNA is at the 2 -position. The ribo type of analog (738) of FIAC is 10 times less effective in suppression of HSV replication than is FIAC. Thus Fox, and Watanabe and coworkers concluded that the 2 - up fluorine disposition and the species of the substituent at C-5 are the two important factors influencing antiviral activity. Nevertheless, the mechanism of action of 2 -deoxy-2 -fluorocytidine (737) on certain herpes viruses, including HSV-1... 

B. Solvolysis of Phosphoric Acid Derivatives.—Interest continues in neighbouring-group participation in the solvolysis of phosphate esters. As a potential model compound for investigating the mechanism of ribo-nuclease action, the phenyl hydrogen phosphate ester of c/j-3,4-tetrahydro-furandiol (24) has been the subject of a detailed study. Above (and probably also below) pH 4 hydrolysis gives solely the cyclic phosphate (25)... 

Compound 35 has also been obtained51 from 32, by sequential debenzoylation, and acetalization with 2,2-dimethoxypropane. It has been used in the synthesis, in good overall yield, of versatile, ano-merically functionalized precursors of C-nucleosides having the d-arabino or the D-ribo configuration. 

Simple syntheses of suitable monomers for nylon 5 and nylon 6 analogs, such as 5-amino-5-deoxyaldonic and 6-amino-6-deoxyaldonic acids (51, 54), has been achieved starting from unprotected o-pentono- and hexono-1,4-lactones [68, 69]. Saponification of 5- or 6-azido-D-aldonolactones ribo-, arabino-, xylo-, galacto-, manno-, compound types 49 and 52) provided the corresponding 5- or 6-azido-aldonic acid sodium salts (50, 53). A catalytic hydrogenation after or before treatment with acidic resin afforded compounds 51 and 54 in excellent overall yields (Scheme 16). 

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