Tetraol

Yamamoto et al. have reported a chiral helical titanium catalyst, 10, prepared from a binaphthol-derived chiral tetraol and titanium tetraisopropoxide with azeotropic removal of 2-propanol [16] (Scheme 1.22, 1.23, Table 1.9). This is one of the few catalysts which promote the Diels-Alder reaction of a-unsubstituted aldehydes such as acrolein with high enantioselectivity. Acrolein reacts not only with cyclo-pentadiene but also 1,3-cyclohexadiene and l-methoxy-l,3-cyclohexadiene to afford cycloadducts in 96, 81, and 98% ee, respectively. Another noteworthy feature of the titanium catalyst 10 is that the enantioselectivity is not greatly influenced by reaction temperature (96% ee at... 

We now tum our attention to the C21-C28 fragment 158. Our retrosynthetic analysis of 158 (see Scheme 42) identifies an expedient synthetic pathway that features the union of two chiral pool derived building blocks (161+162) through an Evans asymmetric aldol reaction. Aldehyde 162, the projected electrophile for the aldol reaction, can be crafted in enantiomerically pure form from commercially available 1,3,4,6-di-O-benzylidene-D-mannitol (183) (see Scheme 45). As anticipated, the two free hydroxyls in the latter substance are methylated smoothly upon exposure to several equivalents each of sodium hydride and methyl iodide. Tetraol 184 can then be revealed after hydrogenolysis of both benzylidene acetals. With four free hydroxyl groups, compound 184 could conceivably present differentiation problems nevertheless, it is possible to selectively protect the two primary hydroxyl groups in 184 in... 

The crystalline material was shown to be modified sesquiterpinoid (5) containing two aldehyde functions, one of which is a,/3-unsat-urated (la). It analyzed for C13H22O2 and formed the dioxime. It readily took up oxygen on standing and was converted to the diol on treatment with lithium aluminum hydride. The bisdinitrobenzoate of this diol with osmium tetroxide yielded the tetraol, bisdinitrobenzoate, which was not readily acetylated. 

The reaction was initially monitored using 10% MeOH/CH2Cl2 to follow the disappearance of tetraol 3. The appearance of the diepoxide 4 is monitored using 50% ether/hexane. 

The masked propargylic anfz-l,3-diols obtained in these reactions are useful precursors to more functionalized systems. Lindlar reduction of alkyne 171 generated the (Z)-allylic diol 172, which underwent diastereoselective osmium tetraoxide-catalyzed dihydroxylation to provide the partially protected tetraol 173 (Scheme 28). The propargylic anfz-l,3-dioxane 175,obtained in 88% yield from... 

FIG. 18 (a) 10-pm X 10-pm SPFM image from a nominally 56-A-thick film of Z-Tetraol. A 25-A-thick layer partially covers the surface, (b) SPFM image acquired after contact scanning in the region marked with a box. (From Ref. 70.)... 

Deslongchamps and coworkers [26] used a combination of a transannular Diels-Alder cycloaddition and an intramolecular aldol reaction in the synthesis of the unnatural enantiomer of a derivative of the (+)-aphidicolin (4-74), which is a diterpe-noic tetraol isolated from the fungus Cephalosporium aphidicolia. This compound is an inhibitor of DNA polymerase, and is also known to act against the herpes simplex type I virus. In addition, it slows down eukaryotic cell proliferation, which makes it an interesting target as an anticancer agent... 

Fig. 3. (Top left) Chemical methods used to depolymerize the polyesters. (Top right) Thin-layer and gas-liquid chromatograms (as trimethylsilyl derivatives) of the monomer mixture obtained from the cutin of peach fruits by LiAlD4 treatment. In the thin-layer chromatogram the five major spots are, from the bottom, C18 tetraol, C16 triol, and C18 triol (unresolved), diols, and primary alcohol. Nx = C16 alcohol N2= C18 alcohol Mj = C16 diol M2 = C18 diol D = C16 triol D2 and D3 = unsaturated and saturated C18 triol, respectively, T4 and T2, unsaturated and saturated C18 tetraol, respectively. (Bottom) Mass spectrum of component D3 in the gas chromatogram. BSA = bis-N,O-trimethylsilyl acetamide...

Treatment of the elimination product 107 with triethylamine resulted in smooth isomerization of the olefin, to afford the a,p-unsaturated ketone 108. Ally lie oxidation of 108 then generated the secondary alcohol 109 in 72 % yield. The acetonide and silyl ether functions of 109 were cleaved in one reaction to afford a tetraol intermediate that was regioselectively acylated at the secondary alcohol functions, to provide the triacetate 110 in high yield (89 %). Hydrogenolysis of the benzyl ether... 

The tetraols were found to be highly sensitive toward acidic and basic conditions. Under Bronsted acidic conditions, the hemiaminals readily eliminated to generate a tetraene, while under basic conditions, the tetraol either decomposed or epimerized to generate a mixture of diastereomers. It is speculated that the base-mediated epimerization proceeds through ring-chain tautomerization involving a putative alpha-keto amide derivative. It is also of note that simple dissolution of tetraol (+)-95 in methanol also leads to its degradation to a complex mixture of products. 

Consistent with these observations, the use of highly basic reagents for the deprotection of the thiols proved futile. As with tetraol (+)-95, base sensitivity of the tetrathiol product necessitated the use of neutral reagents. After significant... 

Epoxidation of the 3,4-dihydrodiol with m-chloroperbenzoic acid afforded stereospecifically the corresponding anti diol epoxide (74). Peracid oxidation of the bay region 1,2-dihydrodiol gave a mixture of the anti and syn diol epoxide diastereomers. Assignment of the major isomer as syn was made through analysis of the NMR spectra of the acetates of the tetraols formed on hydrolysis of the individual diol epoxides (42). Peracid oxidation of the 10,11-dihydrodiol is reported to yield the corresponding anti diol epoxide (12). However, it is likely for steric reasons that the syn isomer is also formed. 

The experimentally observed pseudo-first order rate constant k is increased in the presence of DNA (18,19). This enhanced reactivity is a result of the formation of physical BaPDE-DNA complexes the dependence of k on DNA concentration coincides with the binding isotherm for the formation of site I physical intercalative complexes (20). Typically, over 90% of the BaPDE molecules are converted to tetraols, while only a minor fraction bind covalently to the DNA bases (18,21-23). The dependence of k on temperature (21,24), pH (21,23-25), salt concentration (16,20,21,25), and concentration of different buffers (23) has been investigated. In 5 mM sodium cacodylate buffer solutions the formation of tetraols and covalent adducts appear to be parallel pseudo-first order reactions characterized by the same rate constant k, but different ratios of products (21,24). Similar results are obtained with other buffers (23). The formation of carbonium ions by specific and general acid catalysis has been assumed to be the rate-determining step for both tetraol and covalent adduct formation (21,24). 

Meehan and Bond (23) on the other hand, have taken an opposite view, namely that k3I1(C) k3I(C), while k3II(T) k3I(T). Thus, in this view, the hydrolysis occurs at external binding sites, while covalent binding occurs at intercalation sites. Furthermore, they reject the common intermediate model (Equation 2) on the basis of their belief that the rates of reaction for tetraol formation and adduct formation and the ratio of the products should be the same in such a model. While these rates of reaction are the same and the product ratios are observed to be different, this is fully consistent for a set of parallel pseudo-first order reactions involving a common intermediate (29) as pointed out above. Thus, the data of Meehan and Bond does not demonstrate the validity of the two-domain model (23). 

We find that the fluorescence yield of freshly prepared covalent (+)-anti-BaPDE-DNA adducts in oxygen-free solutions is 66+2 lower than the yield of the tetraol 7,8,9,10-tetrahydroxytetrahydro-benzo(a)pyrene (BaPT) in the absence of DNA. Since the fluorescence lifetime of BaPT under these conditions is 200ns, the mean fluorescence lifetime of the adducts (see reference T7) can be estimated to have a lower limit of 3ns, which is close to the mean value of 0.52x1.6 + 0.42x4.0 = 2.7 ns estimated from the two short fluorescence components of Undeman et al (10). 

The simplicity of this assay makes it highly attractive for further development. Some of the limitations include the need for the preparation of relatively large amounts of appropriately modified DNA for the initial immunization. This may be reduced with the development of in vitro immunization techniques in which as little as 5ng of antigen can be effective. The antibodies must also be characterized once prepared. For example, a variety of monoclonal antibodies against B[a]PDE-modified DNA have been prepared (42) which show varying specificity. At one extreme, some require the full structure of the adduct bound to DNA, at the other, BtalP tetraol will effectively compete. What is not clear at the moment is how specific such antisera are for a particular PAH. Will these antisera recognize only B[a]P tetraol structures or those of any diol epoxide modified DNA ... 

An alternative approach used to investigate the covalent binding of B[a]P to mouse skin has been to release the hydrocarbon-DNA adducts from the isolated DNA by acid hydrolysis (60.61). Since, in the case of BPDE-DNA adducts, they are acid labile and the tetraols produced are not only more fluorescent than the adducts themselves but also more easily extracted from the large excess of unmodified bases, this provides a convenient approach. The method does, however, require the certainty that hydrolysis of the adducts will occur and that the products will be stable or, if degradation occurs, that they can still be recognized. 

Reactions can be performed with cellular or subcellular preparations and ( )- or (+)-BP-7,8-dihydrodiol and the tetraol hydrolysis... 

Studies also show that by using catalyst 76a or 78 derived from one single chiral tetraol with the same absolute configuration, both enantiomers of the Diels-Alder reaction product can be obtained. For example, reaction of 2-methyl-... 

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