Hydroxyketones isomerization

It is of interest to note that attachment of a basic side chain on carbon of an isomeric dibenzazepine affords a compound in which anticholinergic activity predominates, elantrine (50). Reaction of anthra-quinone (45) with the Grignard reagent from 3-chloro-N,N-dimethylaminopropane in THF in the cold results in addition to but one of the carbonyl groups to yield hydroxyketone 46. This is then converted to oxime 47 in a straightforward manner. Treatment of that intermediate with a mixture of phosphoric and polyphosphoric acids results in net dehydration of... 

The well established chemistry of acyclic secondary-alkyl peroxides 12> suggested that bases should catalyse the isomerization of related bicyclic peroxides to cyclic hydroxyketones 62 via abstraction of bridgehead hydrogen and heterolysis of the peroxide bond (Eq. 48). 

Synthesis of 31 by Method I (107,108) and its conversion to the related anti and syn diol epoxide derivatives (32,33) has been reported (108). The isomeric trans-1,lOb-dihydrodiot 37) and the corresponding anti and syn diol epoxide isomers (38,39) have also been prepared (108) (Figure 19). Synthesis of 37 from 2,3-dihydro-fluoranthene (109) could not be accomplished by Prevost oxidation. An alternative route involving conversion of 2,3-dihydrofluoranthene to the i8-tetrahydrodiol (3-J) with OsO followed by dehydration, silylation, and oxidation with peracid gave the Ot-hydroxyketone 35. The trimethylsilyl ether derivative of the latter underwent stereoselective phenylselenylation to yield 36. Reduction of 3 with LiAlH, followed by oxidative elimination of the selenide function afforded 3J. Epoxidation of 37 with t-BuOOH/VO(acac) and de-silylation gave 38, while epoxidation of the acetate of JJ and deacetylation furnished 39. 

Alkenylbenzotriazoles 865 are readily prepared by isomerization of the corresponding allyl derivatives catalyzed by Bu OK. Lithiated compounds 865 are treated with electrophiles to provide a-substituted derivatives 866. Epoxidation of the double bond with ///-chloroperbenzoic acid converts intermediates 866 into oxiranes 867 that can be hydrolyzed to furnish a-hydroxyketones 868 in good yields (Scheme 140) <1996SC2657>. 

Although allyl-arenes are prone to olefin isomerization, several successful reactions have been performed, for example in the chemoselective oxygenation of 22 to aryl-acetone 23 (Table 2) [38]. Allyl alcohols sometimes react sluggishly, but examples with high ketone selectivity are known, for example the oxidation of tertiary alcohol 24 to a-hydroxyketone 25 [39]. 

As already mentioned, <5-hydroxyfeto s may be present in the open-chain form or as an isomeric cyclic hemiketal, depending on their substitution pattern. For example, a polyhy-droxylated 5-hydroxyketone, D-fructose, is present exclusively in the form of hemiketals (Figure 9.7). Responsible for this equilibrium position is the fact that the carbonyl group involved contains an electron-withdrawing group in both a-positions, which favors the addition of nucleophiles (see Section 9.1.1). 

The bicyclohexenone-dienone isomerization 33a - -34a + 35a (Chart 5) has also been observed in the dark by acetic and formic acid catalysis and clearly involves the cationic intermediate 110 (Chart 16)." Further, under more drastic acidic nonphotolytic conditions, photoketones of the general formula 111 (R = H or alkyl) give hydroxy-ketones 113 (R = alkyl) and 114 (R = H), respectively. In these transformations, cationic intermediates of type 112 are obviously formed. Mixtures of hydroxyketones such as 113 and 114 are also produced upon irradiating the corresponding dienones (cf. Chart 7) in aqueous acetic acid. Av, is, 27,30 Here, participation of intermediates that are either identical with or structurally related to the ground-state species 112 seems indicated Ai Both intermediates, 112 and 110, represent conjugate acids of the proposed mesoionic intermediates (general formula 102 and 106, respectively) in the photoisomerizations. 

While scheme 99 - 103 accounts for the majority of structural changes in dienone isomerizations, a few cases require modification of this general mechanistic pathway. On irradiation in dioxane solution, the B-nor steroid 135 was transformed exclusively to the isomer 137 (Chart 23). The hydroxyketone 59 furnished a mixture of the isomer... 

The carbethoxy dienone 158 is isomerized smoothly to the bicyclo-hexenone product 160 in either dioxane or aqueous acetic acid, and no hydroxyketone formation could be detected. The noteworthy reluctance to incorporate solvent under acidic conditions in which hydroxyketone formation normally predominates has been ascribed to additional stabihzation of the cyclopropane bonds in the intermediate 159 towards hydrolytic cleavage (see Chart 26). 

The use of 1,2-epoxybutane in these reactions is superior in some respects to the use of alkali metal alcoholates as bases. Thus, for example, in the synthesis of the a-hydroxyketone (3i 5,3 / 5)-astaxanthin [(3RS,yRS)-403] from the Cis-phosphonium salt 3RS)-49 the yields achieved, after thermal isomerization and recrystallization, were 77% with NaOMe as proton acceptor and 83% in boiling 1,2-epoxybutane, based on the dialdehyde 34 used [69] (Scheme 12). 

The (15Z)-isomers of rubixanthin (72) [29] and of optically inactive zeaxanthin (119 120 121=1 2 1) [30] have been synthesized. Five geometrical isomers of (3/ ,3 / )-zeaxanthin (119) have been obtained by specific synthesis and fully characterized, namely the (7Z)-, (7Z,7 Z)-, (9Z,9 Z)-, (7Z,9Z,7 Z)- and (7Z,9Z,7 Z,9 Z)-isomers [31]. Six additional geometrical isomers were isolated in small quantities from the reaction mixtures and partially characterized [31]. A Ci5 + Cio + Ci5 = C4o approach was employed, with the Cio-dial 13 as the C 10-component. The Ci5-phosphonium salts containing the preformed (7Z)- and/or (9Z)-double bonds were obtained from the hydroxyketone 27 [32], which was converted, in several steps, into the acetylenic Ci5-phosphonium salts 28 and 29 (Scheme 14). Partial hydrogenation of 28 with Raney-Ni, followed by Pd(II)-catalysed isomerization, resulted in the formation of the olefinic phosphonium salts 30 (7Z,9 ) and 31 (1E,9E). The use of the phosphonium salt 29 led to the new isomers 32 (7Z,9Z) and 33 (7 ,9Z). The hydrogenation of the isomer 29 proceeded considerably more slowly than that of the (9 )-isomer 28. 

The hydroxyketone, protected with isopropenyl methyl ether, (73) is coupled to the protected C6-lithium acetylenide 80. The Cj -triol 87 is formed after removal of the protecting groups. Acid-catalysed dehydration of 87 leads to the Ci5-diol 88, which is partially produced in the (9Z)-form. The (9 )-compound must be isolated by crystallization from the ( 7Z)-mixture of the acetylenic Cis-phosphonium chloride 89 prepared in the conventional manner. Successive partial hydrogenation of (E)-89, palladium-catalysed isomerization, and crystallization, give 86 in an overall yield of 43% based on 73. 

In a related process, acyloins (a-hydroxyketones and a-hydroxyaldehydes) are transformed into isomeric acyloins with dilute alcoholic sulfuric acid (H2SO4) as shown in Scheme 9.94. 

These oxidation reactions require oxygen (O2) and tetrahydrobiopterin as a cofactor. Thus, as shown in Scheme 13.39, 7,8-dihydroneopterin 3 -triphosphate (generated from guanosine triphosphate [GTP] as seen in Scheme 12.118) is converted to 6-pyruvoyl-5,6,7,8-tetrahydropterin by an elimination reaction and two keto-enol isomerizations. The process is catalyzed by the enzyme 6-pyruvoyltetra-hydropterin synthase (EC 4.2.3.12). Then, via an intermediate, written as an equilibrium between a-hydroxyketones (named dihydrosepiapterin) linked by a common enol, reduction to tetrahydrobiopterin is effected (in two separate steps) by 2 equivalents of NADPH used by the enzyme sepiapterin reductase (EC 1.1.1.153). Tetrahydrobiopterin is the cofactor involved in the National Institutes of Health (NIH) shift (cf. Chapter 6) pathway used by the iron-containing enzyme phenylalanine 4-monooxygenase (EC 1.14.16.1) to convert phenylalanine (Phe, F) to tyrosine (Tyr, Y) and is converted to (6i )-6-(L-erythro-l,2-dihydroxypropyl)-5,6,7,8-tetrahydro-4a-hydroxypterin in the process. 

Many other potential metabolites could be fitted into this scheme. Among these there could be considered the isomeric saturated diols with the 17-hydroxyl group in the a orientation, as well as the hydroxyketones, with the carbonyl group at Cj and with the 17-hydroxyl group in either orientation. Compounds of this type may be present in urine in such minute quantities that the present methods of separation and characterization are inadequate to demonstrate their presence. 

The formation of the pyrrolo[l,2-a]quinoxaline stmcture in this reaction can be represented in one of two ways (Scheme 3.38) (a) isomerization of the 2-hydroxy-1,5-diketone 118 to the 5-hydroxy-l,4-diketone 121 with the subsequent formation of the o-aminophenylpyrrole 122 and closure of the dihydroquinoxaline structure 123 (b) reaction of the a-hydroxyketone fragment with 1,2-DAB with the formation of the hydroquinoxaline derivative 125 and subsequent closure of the dihydropyrrole ring and isomerization of the 3,3a-dihydropyrrolo[l,2-a]quinoxaline structure 124 to the more stable 4,5-dihydropyrrolo[l,2-a]quinoxaline structure 123. 

On diene condensation with butadiene, the 4-methoxy-2,5-toluquinone (307) obtained from toluquinone in three stages with a yield of 26% formed the cis adduct (308), which on alkaline isomerization and reduction gave the trans-C/D glycol (309). Treatment of this with an aqueous dioxane solution of sulfuric acid led to hydrolysis and dehydration to a hydroxyketone forming an acetate (310). The treatment of compound (310) with metallic zinc in acetic anhydride enabled a CD fragment to be obtained, the so-called "Woodward s ketone" (311) this completed the formation of the bicyclic precursor. 

Scheme 1 was uneventful, but attempted isomerization in 0.1 M NaOH gave only yyl-acetonylthymine (18) in 38% yield (Scheme 2). By contrast, reaction in 1 M NaOH gave the expected oxacyclopentene (16b) in 58 % yield, indicating possible involvement of thymallene (11b) as an intermediate. Events leading to the formation of 18 became more clear when butynol 10b was transformed to oxazole 19 (45%) after refluxing with DBN in DMF for 30 min. The latter product was hydrolyzed with 0.1 M NaOH at room temperature to give P-hydroxyketone 20 (74%). Reflux of 19 or 20 in 0.1 M NaOH afforded N -acetonylthymine (18) in 66 and 55% yield, respectively. 

Some 1,3-hydroxyketones are formed if the initial attack is at a tertiary site, in which case the oxy radical formed after the first isomerization cannot itself isomerize. Instead, oxy radical dissociation may occur, leading to a 1,3-hydroxyketone. 

Potassium tert-butoxide Isomerization of cyclic hydroxyketones Transannular 1,4-hydride transfer... 

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