Aliphatic hydroxylations

1b Aliphatic Hydroxylations. Alkyl side chains of aromatic compounds are readily oxidized, often at more than one position, and provide good examples of this type of oxidation. In the rabbit the n-propyl side chain of n-propylbenzene can be oxidized at any of the three carbon atoms to yield 3-phenylpropan-l-ol (C6H5CH2CH2CH2OH) by co-oxidation,benzylmethylcarbinol(C6H5CFl2CHOHCH3) by co-l-oxidation, and ethylphenylcarbinol (C6H5CFIOFICFI2CFI3) by co-2-oxidation. Further oxidation of these alcohols is also possible. 

Alicyclic compounds, such as cyclohexane, are also susceptible to oxidation, in this case first to cyclohexanol and then to /rans-cyclohexane-1,2-diol, cyclohexaone, and adipic acid. 

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Table 5. Phenolic and Aliphatic Hydroxyl Contents of Milled Wood and Technical Lignins ...

The epoxidation is generally conducted in two steps (/) the polyol is added to epichlorohydrin in the presence of a Lewis acid catalyst (stannic chloride, boron triduoride) to produce the chlorohydrin intermediate, and (2) the intermediate is dehydrohalogenated with sodium hydroxide to yield the aliphatic glycidyl ether. A prominent side-reaction is the conversion of aliphatic hydroxyl groups (formed by the initial reaction) into chloromethyl groups by epichlorohydrin. The aliphatic glycidyl ether resins are used as flexibilizers for aromatic resins and as reactive diluents to reduce viscosities in resin systems. 

Hydromorphone [466-99-9] (31) and hydrocodone [125-29-1] (32) are isomers of morphine and codeine, respectively. Hydromorphone can be prepared by catalytic rearrangement of morphine (49) or by oxidation of the aliphatic hydroxyl group of dihydromorphine (50). Hydrocodone can be similarly prepared. As an antitussive, hydromorphone is several times more active than morphine and hydrocodone is slightly more active than codeine. Hydromorphone has a much higher addiction potential than hydrocodone. 

Since a few protective groups cannot satisfy all these criteria for elaborate substrates, a large number of mutually complementary protective groups are needed and, indeed, are becoming available. In early syntheses the chemist chose a standard derivative known to be stable to the subsequent reactions. In a synthesis of callistephin chloride the phenolic —OH group in 1 was selectively protected as an acetate. In the presence of silver ion the aliphatic hydroxyl group in 2 displaced... 

When phenolic nucleophiles were used, either potassium hydroxide or potassium f-butoxide was generally chosen as the base. When aliphatic hydroxyls constituted the nucleophiles, a stronger base was required and sodium hydride was generally chosen. 

The grafting reaction requires primary or secondary aliphatic hydroxyl functions as initiation sites and uses Ce4+ ions as the catalyst. This type of grafting was first developed by Mino and Kaizerman and applied to preparation of the polyacrylamide-polyvinylalcohol copolymer [102],... 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

The numerous biotransformations catalyzed by cytochrome P450 enzymes include aromatic and aliphatic hydroxylations, epoxidations of olefinic and aromatic structures, oxidations and oxidative dealkylations of heteroatoms and as well as some reductive reactions. Cytochromes P450 of higher animals may be classified into two broad categories depending on whether their substrates are primarily endogenous or xenobiotic substances. Thus, CYP enzymes of families 1-3 catalyze... 

Side reactions involving branching through a secondary hydroxyl group can also occur. The extent of these side reactions should decrease as the ratio of epoxy to phenol decreases since phenolate anions are significantly more nucleophilic titan aliphatic hydroxyl groups. 

O-acetylation of the aliphatic hydroxyl groups of the ribose moiety (or other sugar moieties) to the 2, 3, 5 -tri-0-acetates ... 

Figure 18.2 Representative receiver operator curves to demonstrate the leave n out validation of K-PLS classification models (metabolite formed or not formed) derived with approximately 300 molecules and over 60 descriptors. The diagonal line represents random. The horizontal axis represents the percentage of false positives and the vertical axis the percentage of false negatives in each case. a. Al-dealkylation. b. O-dealkylation. c. Aromatic hydroxylation. d. Aliphatic hydroxylation. e. O-glucuronidation. f. O-sulfation. Data generated in collaboration with Dr. Mark Embrechts (Rensselaer Polytechnic Institute).

A fourth important pharmacophoric element was established for the non-classical cannabinoid series in the form of a southern aliphatic hydroxyl group. Addition of this group to (192) resulted in the high-affinity CBi and CB2 receptor full agonist CP 55,940 (193) [129, 133], the tritiated form of which was used to first demonstrate specific cannabinoid binding sites in brain tissue [134]. Its enantiomer, CP 56,667 (194) has lower affinity for the CBi receptor (Table 6.17). 

An additional pharmacophore introduced in the nonclassical cannabinoid series is the southern aliphatic hydroxyl (Makriyan-nis, 1990). A variation involves the highly potent classical/non-classical cannabinoid hybrids (e.g., 4, AM919) (Drake, 1998). 

Aromatic hydroxylation Aliphatic hydroxylation AM Iydroxylalion N-, O-, 5-Dealkylation Deamination Sulfoxidation Af-Oxidation Dehalogenation... 

Aliphatic glycidyl ethers, 10 376-377 Aliphatic hydrocarbons. See also Aliphatics photochemical chlorination of, 19 113 separation of, 10 782-785 Aliphatic hydroxyl, replacement with chloride, 13 821... 

Groves JT, McClusky GA. Aliphatic hydroxylation by highly purified liver microsomal cytochrome P-450. Evidence for a carbon radical intermediate. Biochem Biophys Res Commun... 

The theory predicting the stability of the radical formed assumes that the rate-limiting step is the extraction of the hydrogen atom to form a radical, and this hypothesis is in principle valid for aliphatic hydroxylation, but it might not be the case for other reactions. Several examples in the literature show that this method is useful for the prediction of the site of metabolism for compounds undergoing metabolism by CYP3A4 [8]. Nevertheless, there is a lack of a theory that could explain all the different metabolism reactions and mechanisms that may or may not involve radical formation. 

Serine (Ser or S) ((S)-2-amino-3-hydroxypropanoic acid) is a polar, neutral, uncharged amino acid with the formula H00CCH(NH2)CH20H. It has an aliphatic hydroxyl side chain and can be seen as a hydroxylated version of Ala. Ser participates in the biosynthesis of purines and pyrimidines and is also the precursor to several amino acids including Gly, Cys, and Trp (in bacteria). In addition, it is the precursor to numerous other metabolites, including sphingolipids and is present in enzymes such as a-chymotrypsin. Ser, Asn, and aspartate disrupt a helices. 

Threonine (Thr or T) ((2S,31( )-2-amino-3-hydroxybutanoic acid) has an aliphatic hydroxyl side chain and is classified as a polar, uncharged amino acid with the formula HOOCCH(NH2)CHOHCH3. Together with Ser and Tyr, Thr is one of the three proteinogenic amino acids bearing an alcohol group. Thr can be seen as a hydroxylated version of Val. With two chiral centers, Thr can exist in four possible stereoisomers, or two possible diastereomers of L-Thr. However, the name L-Thr is used for one single enantiomer, (2S, 3if)-2-amino-3-hydroxybutanoic acid. The second diastereomer (2S,3S), which is rarely present in nature, is called L- //o-Thr. 

The predominant interaction of CYP3A4 is via hydrophobic forces and the overall lowering of lipophilicity can reduce metabolic lability to the enzyme. Figure 7.14 shows the relationship between unboimd intrinsic clearance in man and lipophilicity for a variety of CYP3A4 substrates. The substrates are cleared by a variety of metabolic routes including N-dealkylation, aromatization and aromatic and aliphatic hydroxylation. The trend for lower metabolic lability with lower lipophilicity is maintained regardless of structure or metabolic route. 

Scheme 2 Aliphatic hydroxylation in benzylic position of an ancillary ligand by a bis(/x-...

Proton-Donating Polymers Containing Aliphatic Hydroxyl. 143... 

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