Hydroxy ketones oxidative cleavage

Oxidative cleavage of the terminal double bond of 49 by ozonolysis to the aldehyde followed by permanganate oxidation to the acid and esterification with diazomethane produced the methyl ester 50. Dieckmann cyclisation of 50, following the procedure developed in Holton s laboratory (LDA, THF, -78 °C, 0.5 h, then HOAc, THF), gave the enol ester 5J in 93% yield (90% conversion). Decarbomethoxylation of 5J. was carried out by temporarily protection of the secondary alcohol (p-TsOH, 2-methoxypropene, 100%), and heating the resulting compound 52 with PhSK in DMF, at 86 °C (3 h) to provide 53a or, after an acidic workup, the hydroxy ketone 53b. 92% yield. 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

An alternative approach to the synthesis of isocoumarins which probably proceeds through the intermediacy of 2-carboxybenzyl ketones is based on the oxidative cleavage of indan-1-ones (76JCS(P1)1438). Although ozonolysis of the silyl enol ether (505) leads to the 2-hydroxy-2-methylindan-l-one (506), periodate oxidation of which gives the isocoumarin, a more convenient and direct route involves ozonolysis of the enol trifluoroacetate (Scheme 182). This synthesis is especially attractive for the preparation of isotopically labelled isocoumarins, since the precursors of the indanones, arylpropanoic acids or acrylophenones, are readily available bearing labels at specific sites. 

The reagent is effective for oxidative cleavage of a-glycols to aldehydes, of a-hydroxy ketones to an aldehyde and a carboxylic acid, and of a-diketones and a-keto iicids to acids.3... 

Novel nor-seco baccatin 99 was synthesized in 92% yield through oxidative cleavage of the A ring of 14-OH-DAB (75) with periodic acid via the hydroxy ketone intermediate 100 (Scheme 19). Protection of the 7-hydroxyl of 99 as TES ether followed by reduction of the aldehyde with sodium borohydride yielded nor-seco baccatin alcohol 101 in 80% yield. Nor-seco 13-amino-baccatins 102 and 103 were synthesized from 101 and 99a via the Mitsunobu reaction and reductive amination, respectively, in high yields (Scheme 20). 

Aside from oxidative dimerizations [175-186] vanadium catalysts are able to induce C-C and C-0 bond cleavages. Momose and coworkers developed a catalytic system to fragment a-hydroxy ketones 101 to diesters or ketoesters 102 (Fig. 31) [190]. Using 1 mol% of EtOVOCl2 as a catalyst and oxygen as the terminal oxidant, 55-87% of 102 was obtained. The reaction mechanism is not known, but the reaction is inhibited by 2,6-di-tert-butylcresol (BHT) pointing to the involvement of a radical process. 

Fig. 31 Oxidative cleavage of a-hydroxy ketones catalyzed by EtOVOCl2...

Cleavage of isoxazolines to fi-hydroxy ketones.1 This cleavage can be effected with either 3,5-dinitroperbenzoic acid (1) or trifluoroperacetic acid using about 5 equiv. of the peracid at 25°. Use of more drastic conditions results in Baeyer-Villigar oxidation of the p-hydroxy ketones to acylated diols. 

Conagenin (39) is a promising anticancer natural product isolated in 1991 from the culture broths of Streptomyces roseosporus20 (Scheme 4.1n). The chelation-controlled Zn(B 114)2 reduction of the p-hydroxy ketone 40 produced the 1,3-syn-diol 41 in 30 1 diastereoselectivity. Protection of the hydroxyl groups gave the bis-acetate 42, which was then subjected to oxidative cleavage to afford the acid 43. 

---