Hydroxy Substituents

To expand the scope of the diastereoselective C-C bond formation by the ester enolate Claisen rearrangement, the rearrangement of allylic esters of )S-hydroxy acids is noted to introduce three continuous asymmetric centers. Fujisawa et al. investigated the rearrangement of E- and Z-crotylesters 205 under different reaction conditions [119]. 

Entry Ester R R Solvent Additive Yieid [%] Ratio 206a 206b 206c 206d 

As anticipated on the basis of steric bulk in the allyl moiety, the dianionic Claisen rearrangement of 207b was slightly less selective than that of207a, but much 

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One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Most xanthene dyes are classified as basic dyes by their method of appHcation acid dyes can be produced by introduction of sulfonic acid groups. The fluoresceins, which contain carboxy and hydroxy substituents, are also acid dyes for coloration of silk. Some of the fluoresceins in which the carboxy group has been esterified, are soluble in alcohol or other organic solvents and can be classified as solvent dyes. Mordant dyes can be produced by introducing o-dihydroxy or sahcyhc acid groups (2), which when metallised can have very good lightfastness. 

A 17a-hydroxyl group reduces the reactivity of the 20-ketone but direct ketalization with ethylene glycol is not impeded, Ketalization can also be effected in the presence of 17a- and/or 21-hydroxy substituents. Thus the 3,20-biscycloethyleneketal (88) is obtained from (87) in high yield by the direct procedure, or better by distillation under vacuum without a diluent. A bromine atom at C-17 and a 21-acetoxy group even in the absence of a 17a-hydroxyl group strongly hinder ketalization at C-20. ... 

Tlie presence of one or more electron-donating groups, such as the hydroxy substituent, is required to make easy nitration of the naphthyridines... 

The electron-donating hydroxy substituent is necessary in order to facilitate the migration of the aryl group otherwise a substituted benzoic acid would be obtained as reaction product. 

The reaction is strictly intramolecular the migrating group R is never completely released from the substrate. The driving force is the formation of the more stable rearranged carbenium ion 4, that is stabilized by the hydroxy substituent. The... 

The rearrangement of dimethyl 5-hydroxy-l-bcnzothiepin-3,4-dicarboxylate (9, R = OH), the first example of a thermal rearrangement of a thiepin derivative without loss of sulfur,12 is analogous to the oxepin-benzene oxide-phenol rearrangement (cf. Section D,l. Introduction and Section 1.2.5.1). This process is catalyzed by the acidic hydroxy substituent. In fact, if this functional group is modified by an in situ acetylation (R = OAc), the usual loss of sulfur occurs. 

Milner (1992) recently described a novel and versatile modification of the Balz-Schiemann reaction. The amine is diazotized with solid nitrosonium tetrafluoro-borate in CH2C12 and, without isolation, the diazonium salt is heated and yields the fluoroarene in good yield. The method is also applicable to aniline derivatives bearing carboxy and hydroxy substituents, compounds which give poor yields in the classical procedure. 

Fluoboric acid is also an efficacious promoter of cyclic oxo-carbenium ions (Scheme 4.24) bearing an activated double bond which, in the presence of open-chain and cyclic dienes, rapidly undergo a Diels-Alder reaction [91]. Chiral a, -unsaturated ketones bearing a -hydroxy substituents, protected as acetals, react with various dienes in the presence of HBF4, affording Diels-Alder adducts that were isolated as alcohols by hydrolysis of the acetal group by TsOH. Some examples of reactions with isoprene are reported in Table 4.23. The enantios-electivity of the reaction is dependent on the size of the substituent R on the of-carbon high levels of asymmetric induction were observed with R = z-Pr (90 1) and R = t-Bu (150 1) and low levels with R = Me (2.7 1) and R = Ph (3.0 1). Scheme 4.24 shows the postulated reaction mechanism. 

Polypropionate chains with alternating methyl and hydroxy substituents are structural elements of many natural products with a broad spectrum of biological activities (e.g. antibiotic, antitumor). The anti-anti stereotriad is symmetric but is the most elusive one. Harada and Oku described the synthesis and the chemical desymmetrization of meso-polypropionates [152]. More recently, the problem of enantiotopic group differentiation was solved by enzymatic transesterification. The synthesis of the acid moiety of the marine polypropionate dolabriferol (Figure 6.58a) and the elaboration of the C(19)-C(27) segment of the antibiotic rifamycin S (Figure 6.58b) involved desymmetrization of meso-polypropionates [153,154]. 

An impressive indication of the high regioselectivity of hydroxysteroid dehydrogenases (HSHDs) was reported for the oxidation of various hydroxyl groups at the steroid core ofbile acids [26] (Scheme 9.1). The hydroxy-substituents at positions 3, 7, and 12 could be selectively addressed depending on the hydroxysteroid... 

Concerning the arylbromide, the para-substituents Y play an important role as expected and as shown in the table (Fig. 13) for the arylation of 1-butanol, the electron donating substituent lowers the yield but only to 90 % for the methoxy substituent on the contrary the hydroxy substituent inhibits fully the arylation owing probably to the much higher electron donating character of this group in the basic conditions used. 

Several studies, however, conclusively showed that the intensity of the sweet taste depends strongly upon the number of hydroxyl groups in the A-ring. - - For example, compound 85 and its sodium salt, which have only one hydroxyl group in the A-ring, are less sweet than the 2,6-dihydroxy compound. Furthermore, there is also a requirement for an orrto-hydroxy ketone system in ring A, as compound 86 is tasteless, and because it had already been shown that the alkoxy-hydroxy substituents on ring B are also... 

The trapping of the radical intermediate in demercuration by oxygen can be exploited as a method for introduction of a hydroxy substituent (see p. 295). The example below and Entries 3 and 4 in Scheme 4.6 illustrate this reaction. 

Enantioselective D-A reactions of acrolein are also catalyzed by 3-(2-hydroxyphenyl) derivatives of BINOL in the presence of an aromatic boronic acid. The optimum boronic acid is 3,5-di-(trifluoromethyl)benzeneboronic acid, with which more than 95% e.e. can be achieved. The TS is believed to involve Lewis acid complexation of the boronic acid at the carbonyl oxygen and hydrogen bonding with the hydroxy substituent. In this TS tt-tt interactions between the dienophile and the hydroxybiphenyl substituent can also help to align the dienophile.114... 

When there is a hydroxy substituent at C(3) of the diene system, the Cope rearrangement product is an enol that is subsequently converted to the corresponding... 

The 2-azonia analog of the Cope rearrangement is estimated to be accelerated by 106, relative to the unsubstituted system.270 The product of the rearrangement is an isomeric iminium ion, which is a mild electrophile. In synthetic applications, the reaction is often designed to generate this electrophilic site in a position that can lead to a cyclization by reaction with a nucleophilic site. For example, the presence of a 4-hydroxy substituent generates an enol that can react with the iminiun ion intermediate to form a five-membered ring.271... 

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

In the absence of reversible reaction, for example when water acts as the lone nucleophile, QMP11 is consumed with a half-life of approximately 0.5 h as measured by its diminished ability to cross-link DNA (Scheme 9.18).69 Elimination of acetate to form the first of two possible QM intermediates (QM12) is likely rate-determining in this process since subsequent addition by water is estimated to occur with a half-life in the millisecond range.56 The resulting hydroxy substituent at the benzylic position does not eliminate and regenerate QM12 under ambient conditions. Thus, water... 

A hydroxyl group one or two carbons further removed, y or 5 to the fluorine substituent, does not influence the fluorine chemical shift significantly (Scheme 3.22). In the case of a secondary system, the fluorine is also unaffected by a y-hydroxy substituent. 

Substituents may play a crucial role in the conformation of quinolizidine systems. Thus, compound 49 shows a trans-conformation 50 with all three hydroxyl groups in equatorial positions. For its diastereomer 51, a -conformation 52 was initially proposed, but the H NMR data point at the /raor-conformation 53, with axial orientation of the hydroxy substituents and presumably stabilized by an intramolecular hydrogen bond <2004T3009>. 

In the case of deca-BDE, its suggested degradation process in mammals consists of a first reductive debromination where one, two or three bromine atoms can be replaced by hydrogen atoms followed by an oxidation to form hydroxylated metabolites, which are presumably formed from an intermediate epoxy [52]. This study detected traces of three nona-BDEs, which may be an indication of reductive debromination as a first step of degradation, and thirteen hydroxylated metabolites. Otherwise, the possibility of a deca-BDE oxidation as a first step to form the epoxy without an intermediate reductive debromination is also suggested [52]. The study conducted by Morck et al. [53] detected several hydroxylated products, from methoxy-hydroxy-pentabrominated to methoxy-hydroxy-heptabrominated compounds, which coincide with part of the metabolites obtained by Sandholm et al. [52]. In addition, both authors found that methoxy and hydroxy substituents are always on the same aromatic ring when both are present. Moreover,... 

Tetracycline and several related antibiotics (aureomycin = chlorotetracycline, terramycin — oxytetracycline dihydrate) are also obtained from various species of Streptomyces, but are of very different structure, being based on the fused polycyclic arene naphthacene. The presence of five hydroxy substituents (six for terramycin) and an NMe2 group, and possibilities for various conformations and tautomers, complicate the study of their... 

The one-electron reduction potentials, (E°) for the phenoxyl-phenolate and phenoxyl-phenol couples in water (pH 2-13.5) have been measured by kinetic [pulse radiolysis (41)] and electrochemical methods (cyclic voltammetry). Table I summarizes some important results (41-50). The effect of substituents in the para position relative to the OH group has been studied in some detail. Methyl, methoxy, and hydroxy substituents decrease the redox potentials making the phe-noxyls more easily accessible while acetyls and carboxyls increase these values (42). Merenyi and co-workers (49) found a linear Hammett plot of log K = E°l0.059 versus Op values of substituents (the inductive Hammett parameter) in the 4 position, where E° in volts is the one-electron reduction potential of 4-substituted phenoxyls. They also reported the bond dissociation energies, D(O-H) (and electron affinities), of these phenols that span the range 75.5 kcal mol 1 for 4-amino-... 

When partial hydrolysis occurs as in Scheme 7.8 to form the 2-chloro-4-hydroxy species (7.5), the dye does not have a further chance to achieve fixation via the remaining chlorine atom. Under the alkaline conditions of fixation, ionisation of the acidic 4-hydroxy substituent leads to a massive feedback of electronegativity into the triazine ring, causing total deactivation of the remaining 2-chloro substituent. The remaining chlorine atom in... 

If the diene has a 3-hydroxy substituent (C-3) the rearrangement is called the Oxy-Cope rearrangement. It is different from the normal Cope rearrangement, in two respects ... 

Scheme 12. Hydroxy Substituents Reactivity Strongly Changed by Lower Aromaticity...

Oxidation of the quinine C-9 hydroxy substituent to the ketone is best accomplished using the Woodward3 benzophenone/potassium t-butoxide method, now using toluene. The other oxidation methods investigated (Swern, Jones, ROCI variations) were less effective or limited because of the poor solubility of the substrate. Thermodynamic equilibration of these ketones has also been reported.3... 

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