Tetrol

Macrocyclic polyethers containing the 2.2-paracyclophane unit are interesting structures and several such compounds have been prepared . Despite the diverse structural possibilities, the syntheses of these molecules have generally been accomplished by straightforward Williamson ether syntheses. The only unusual aspect of the syntheses appears to be a novel approach to certain paracyclophanes developed by Helgeson (see footnote 7a in Ref. 91). The first step of Eq. (3.28) illustrates the formation of the required tetrol, which is then treated with base (KOH or KO-t-Bu) and the appropriate diol dito-sylate to afford the macrocycle. 

II, 20-dione to the corresponding tetrol has been given as 43 hours at room temperature in aqueous methanol. ... 

When 3a,17a-dihydroxy-5jS-pregnane-ll,20-dione is allowed to react at room temperature overnight with sodium borohydride in aqueous methanol, no crystals form and only 5j5-pregnane-3a,l ljS,17a,20j5-tetrol is isolated in good yield. If the reaction is halted at the end of 3 h y the addition of water and extraction with chloroform, it is possible xo obtain a 55% yield of 3a,17a,20jS-trihydroxy-5j5-pregnan-ll-one, mp 218-220°,after recrystallization of the chloroform residue from aqueous methanol. The analytical sample, crystallized once more, has mp 219.0-220.6° [a][, 36° (acetone), reported mp 220° [aJu 38°. 

A total of 50 ml (0.15 moles) of a 3 ethereal solution of methylmagnesium bromide is added slowly to a vigorously stirred solution of 5.8 g (12.5 mmoles) or 3,3 20,20-bisethylenedioxy-5a,6a-epoxy-5a-pregnane-ll/l,17a,21-triol in 400 ml of tetrahydrofuran. The solution is heated under reflux for 24 hr, cooled and treated with 32 ml of saturated ammonium chloride solution. The supernatant is decanted and the residue is washed with several portions of tetrahydrofuran. The combined supernatants are evaporated and extracted with ethyl acetate, washed with saturated salt solution, dried and concentrated to give 4,55 g (75%) of 3,3 20,20-bisethylenedioxy-6 -methyl-5a-pregnane-5a,ll, 17a,21-tetrol mp 170-172° after crystallisation from acetone-petroleum ether. The analytical sample is crystallized from acetone-petroleum ether mp 175-177° [aJo —11° (CHCI3). 

Paper strip chromatography showed approximately equal amounts of substrate and a more polar product (A -pregnadiene-9a-fluoro-11/3,l6a,17a,21-tetrol-3,20-dione 16,21-diacetate) together with very small amounts of two less polar products. Partition chromatography of 0.25 gram of the residue (diatomaceous earth column system 2 parts ethyl acetate,... 

Crystallization from acetone-petroleum ether gave 13 mg of colorless needles of A. -pregna-diene-9a-fluoro-11/3,16a,17a,21-tetrol-3,20-dione 16,21-diacetate melting point (Kbfier block) about 150° to 240°C with apparent loss of solvent at 150°C. Recrystallization from acetone-petroleum ether did not alter the melting point. 

Preparation of A -Pregnadiene-9a-Fluoro-11, 16a,17a,2l-Tetrol-3,20-Dione A solution of 100 mg of A -pregnadiene-9a-fluoro-11, 16a,17a,21-tetrol-3,20-dione 16,21-diacetate was dissolved in 10 ml of methanol and cooled to 0°C. After flushing with nitrogen, a solution of 35 mg of potassium hydroxide in 2 ml of methanol was added to the steroid solution. After standing at room temperature for 1 hour, the solution was neutralized... 

Water was added, and after cooling, the product was filtered and washed with water to afford 52 mg of A -pregnadiene-9a-fluoro-11/3,16a,17a,21-tetrol-3,20-dione, melting point 246° to 249°C. Three crystallizations from acetone-petroleum ether gave 29 mg of the tetrol, melting point 260° to 262.5°C, according to U.S. Patent 2,789,118. 

The cyclohexanediols, -triols, and -tetrols each have three structures (e.g,. 1,2 1,3 and 1,4 for the diols), but the cyclohexanepentols and -hexols and cyclohexanol itself each have only one structure. For these twelve structures a total of fifty diastereomeric forms (28 meso, 22 racemic) is possible. Cyclohexanol and the -diols have long been known,... 

In the past, periodate titrations have been of limited value for establishing the structure of quercitols or cyclohexanetetrols. The former show overoxidation, because of the fact that malonaldehyde is formed, and this compound undergoes further oxidation. Some isomers of the tetrols... 

It is now reported by P. Szabo that the quercitols can be titrated with completely normal results, by using suitable experimental conditions, and especially low temperature and low pH, for the titrations (40,41). This method might also be applicable to the estimation of the tetrols. 

Carba-y5-DL-idopyranose (77) was prepared from (readily accessible) (l,2,4/3)-5-(hydroxymethyl)-5-cyclohexene-l,2,3,4-tetrol (75) by hydrogenation over a platinum catalyst, acetylation of the product, and 0-deacetylation. 

The absence of taste for cyclohexane-1,2/4,5-tetrol is puzzling, as it contains AH,B systems. This behavior was attributed to the presence of... 

Figure 6. Analysis (29) according to Eq. 7 of gel-point data (25, 26, 28) from reactions of HDI and diphenylmethane diisocyanate (MDl) with POP trilos (LHT-240, LHTII2) and tetrols (OPPE-NHI, OPPE-NH2-oxypropylated pentaerythri-tols) in bulk and in nitrobenzene solution at 80°C, with cMt = cao + ecosystems 1 and 2, HDI and POP triols 3, MDl and POP triol 4 and 5, HDI and POP tetrols. Key 1, HDI and LHT240, is 33 2, HDI and LHTII2, v is 61 3, MDl and LHT240, v is 30 4, HDI and OPPE-NHI, v is 29 S, HDI and OPPE-NH2, v is 33.

Let us now discuss heterocyclic propellanes and dispirans. 8,1 l-Dioxa[4.3.3]propell-3-ene 34 was prepared (in 73% yield) by heating the tetrol 33 with KHS04 at 190-200 °C4e). This was accompanied by the bicyclic ether 35 (10% yield) but no... 

Again, only oxa-propellanes, not dispirans, were formed when 1,1,2,2-cyclobutane derivatives were used as starting materials 4d). The tetratosylate 37 was formed by esterification of the corresponding tetrol 36 with p-TsOH accompanied by the bicyclic... 

There are many more syntheses of heterocyclic propellanes from 1,1,2,2-substituted carbocyclic starting materials. The tetrol discussed above, when treated with KHS04 at 170-190 °C affords the dioxa[3.3.2]propellane shown no isomeric spiran is mentioned. Although the yield is only 50% perhaps some dispiran is hiding in the brauner Ruckstand from which the propellane diether is either crystallized at low... 

To the Buchta heterocycles the higher homologs must also be added. The cyclopentane-1,1,2,2-substituted tetrol 54 was cyclized, in this case heated rapidly with H2S04 at 160-170°, to give the dioxa[3.3.3]propellane 55 in 74 % yield, no dispiran by-product being mentioned here either13). 

A somewhat different method than those described above led to dithia[3.3.3]pro-pellane. When the same tetrol 54 was treated with p-TsCl in pyridine, the ditosylate 56 was formed at room temperature. At —5 °C the tetratosylate 57 was formed without formation of the five-membered ether ring 13). 

The 3,4-dihydrodiol is a major component of the free dihydrodiols formed in mouse skin maintained in short-term culture (28). The optical purities of these dihydrodiols were determined by a CSP-HPLC method (43). The metabolic fates of the enantiomeric DMBA 3,4-dihydrodiols are not yet known. Studies in our laboratory indicate that the products formed in liver microsomal metabolism of DMBA 3,4-dihydrodiol bind extensively to the components of liver microsomes and the expected 1,2,3,4-tetrols of DMBA were not detected in the acetone/ethyl acetate extract of the incubation mixture (unpublished results). It is known that these products bind extensively to DNA... 

In vitro studies of DNA interactions with the reactive ben-zo[a]pyrene epoxide BPDE indicate that physical binding of BPDE occurs rapidly on a millisecond time scale forming a complex that then reacts much more slowly on a time scale of minutes (17). Several reactive events follow formation of the physical complex. The most favorable reaction is the DNA catalyzed hydrolysis of BPDE to the tetrol, BPT (3,5,6,8,17). At 25°C and pH=7.0, the hydrolysis of BPDE to BPT in DNA is as much as 80 times faster than hydrolysis without DNA (8). Other reactions which follow formation of physical complexes include those involving the nucleotide bases and possibly the phosphodiester backbone. These can lead to DNA strand scission (9 34, 54-56) and to the formation of stable BPDE-DNA adducts. Adduct formation occurs at the exocyclic amino groups on the nucleotide bases and at other sites (1,2,9,17,20, 28,33,34,57,58). The pathway which leads to hydrocarbon adducts covalently bound to the 2-amino group of guanine has been the most widely studied. 

Table IV also contains results of UV absorption studies of hydroxylation effects on the DNA intercalative binding of ben-zo[a]pyrene metabolites and metabolite model compounds. The most important feature of these results is that hydrolysis of BPDE to BPT causes a four-fold reduction in the intercalation association constant. Of all the BP derivatives studied, the tetrol has the lowest binding constant for intercalation. The small binding constant of the tetrol compared with BPDE, coupled with the DNA catalyzed hydrolysis of BPDE to the tetrol may provide a detoxification pathway for removal of a portion of unreacted intercalated BPDE.

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