Hydroxy group, oxidation

Isomers of ketone (67) have also been obtained, opening up the route to the synthesis of isomers of cortisone. The oxidation of (67) yielded the anti-trans-diketone (71) and its reduction the corresponding diol (70). The anti-c is-diketone (72) was obtained from the diol (64) by acelyl protection of the 14-hydroxy group, oxidation at C, deacelylation to the ketol (68), and oxidation of the latter at 0 4. By isomerizing compound (72), the anti-trans-diketone (71) was obtained. By isomerization at Cg and oxidation, the ketol (68) gave a third isomer, the syn-trans-diketone (69) [659]. An unsuccessful attempt has been made to obtain the last of the theoretically possible isomers, the syn-cis compound, by means of a diene synthesis [660]. 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

Six protective groups for alcohols, which may be removed successively and selectively, have been listed by E.J. Corey (1972B). A hypothetical hexahydroxy compound with hydroxy groups 1 to 6 protected as (1) acetate, (2) 2,2,2-trichloroethyl carbonate, (3) benzyl ether, (4) dimethyl-t-butylsilyl ether, (5) 2-tetrahydropyranyl ether, and (6) methyl ether may be unmasked in that order by the reagents (1) KjCO, or NH, in CHjOH, (2) Zn in CHjOH or AcOH, (3) over Pd, (4) F", (5) wet acetic acid, and (6) BBrj. The groups may also be exposed to the same reagents in the order A 5, 2, 1, 3, 6. The (4-methoxyphenyl)methyl group (=MPM = p-methoxybenzyl, PMB) can be oxidized to a benzaldehyde derivative and thereby be removed at room temperature under neutral conditions (Y- Oikawa, 1982 R. Johansson, 1984 T. Fukuyama, 1985). 

The benzylidene derivative above is used, if both hydroxyl groups on C-2 and C-3 are needed in synthesis. This r/vzns-2,3-diol can be converted to the sterically more hindered a-cpoxide by tosylation of both hydroxy groups and subsequent treatment with base (N.R. Williams, 1970 J.G. Buchanan, 1976). An oxide anion is formed and displaces the sulfonyloxy group by a rearside attack. The oxirane may then be re-opened with nucleophiles, e.g. methyl lithium, and the less hindered carbon atom will react selectively. In the following sequence starting with an a-glucoside only the 2-methyl-2-deoxyaltrose is obtained (S. Hanessian, 1977). 

Higher alkoxylated products, ie, oligomers, are formed by secondary reaction of oxide and the hydroxy group of the previous product. 

This is a particularly troublesome competing reaction when the olefin oxide, eg, ethylene oxide, produces the more reactive terminal primary hydroxy group. Glycol ethers are used as solvents ia lacquers, enamels, and waterborne coatings to improve gloss and flow. 

Methylation of avermectins B and B2 leads to the corresponding derivatives of the A series (49). A procedure involving the oxidation of the 5-methoxy group with mercuric acetate and NaBH reduction of the 5-keto-intermediate allows the conversion of the A to the B components (50). The 23-hydroxy group of the "2" components, after selective protection of the other secondary hydroxy groups, is converted to a thionocarbonate, which can be elirninated to give the 22,23-double bond of the "1" components alternatively it can be reduced with tributyltin hydride to the 22,23-dihydro derivatives (= ivermectins) (51). 

Amino groups in pyridazine A-oxides can be diazotized and the diazonium group further replaced by halogens, hydroxy group or hydrogen. So, 3-, 4-, 5- and 6-bromopyridazine 1-oxides can be prepared from the corresponding amino A-oxides. 

N-Amino and N-nitro groups N-Hydroxy groups and N-oxides N-Hatogeno groups... 

V-Hydroxy groups can be acetylated (AC2O) and O-alkylated in basic media by methyl iodide. 1-Hydroxypyrazole 2-oxides are quite strong acids. 

The chemical inertness of the three-membered ring permitted many conversions of functional groups in diazirines. Esterifications, cleavage of esters and acetals, synthesis of acid chlorides, oxidation of hydroxy groups to carboxyl groups as well as Hofmann alkenation all left the three-membered ring intact (79AHC(24)63). 

Iodine azide is a highly selective reagent addition to the 16-double bond of androsta-4,16-diene-3-ones is possible and some selectivity in addition to the 16-double bond of A -dienes has been observed.Hydroxy groups in the steroid should be protected, e.g., by acetylation, since in some instances oxidized side products are formed. 

Oxidation of the hydroxy group in (10) to the ketone followed by isomerization affords the 10oc-methyl-A -3-ketone (11). In contrast, methylenation of 3)5-hydroxy-A ° -compounds proceeds in refluxing ether solution to give, after oxidation and acid rearrangement, the natural 10/5-methyl-A -3-keto steroids. With an epimeric mixture of 3fi- and 3a-A ° -alcohols only the )5-alcohol reacts under these imild conditions. ... 

Note 1. An alternative procedure proceeds by oxidation of the 3/5-hydroxy group with chromic acid-sulfuric acid and subsequent elimination of hydrogen chloride by treatment of the intermediate chloroketone with potassium acetate in methanol. Good overall yields are obtained with this reaction sequence in the androstane series. 

As reagents concentrated sulfuric acid, hydrochloric acid, liquid sulfur dioxide, thionyl chloride, phosphorus pentachloride, zinc oxide" and even silica gel can be used. Reagents like phosphorus pentachloride (as well as thionyl chloride and others) first convert the hydroxy group of the oxime 1 into a good leaving group ... 

Viprostol (81) also incorporates a hydroxy group moved to C-16 and protects this from facile metabolic oxidation by vinylation. It is a potent hypotensive and vasodilatory agent both orally and transdermally. The methyl ester moiety is rapidly hydrolyzed in skin and in the liver so it is essentially a prodrug. It is synthesized from protected E-iodo olefin 78 (compare with 75) by conversion to the mixed organocuprate and this added in a 1,4-sense to olefin 79 to produce protected intermediate 80. The synthesis of viprostol concludes by deblocking with acetic acid and then reesterification with diazomethane to give 81 [19]. 

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