Silyl ketones, oxidative cleavage

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. 

Fig. 17.32. Oxidative cleavage of an asymmetric ketone with complementary regiose-lectivities. Lactone A is obtained by Baeyer-Villiger oxidation of menthone [2-methyl-5-(l- methylethyl)cyclo-hexanone]. Alternatively, one may first convert menthone into the silylenol ether B and cleave its C=C double bond with ozone to obtain a silyl ester containing an a-methoxyhydroperoxide group as a second functional group (which resembles the unstable structural element of the so-called ether peroxides cf. Figure 1.38). The latter is reduced with NaBH4tothe hydroxylated silyl ester C. The hydroxycarboxylic acid is obtained by acid-catalyzed hydrolysis. It cyclizes spontaneously to give lactone D.

Heathcock has reported an anomalous case of ozonolysis of a silyl enol ether. Usually these substrates undergo facile oxidative cleavage in the same manner as alkoies. However, in this instance the a-silyloxy ketone (61) was obtained in quantitative yield. The inteimediacy of a silyloxy epoxide was suggested. A more recent leport has indicated that a similar process is competitive with the simple cleavage reaction, (63a) versus (63b), in the ozonolysis of the steroidal enol ether (62). 

An aldol condensation (selectivity 100 1) between e reagent 106a (produced from optically active mandelic acid), known to induce (f ) chirality, and propionaldehyde, followed by desilylation and oxidative cleavage of the resulting a-hydroxy ketone gave the p-hydroxy acid 107 in 85% yield. Esterification, silylation, and a reduction-oxidation sequence then afforded a 75% overall yield... 

Electrophilic oxygen is introduced at the carbon atom next to the old carbonyl group but the C—C bond linking these atoms is lost so the result is not a-hydroxylation. Oxidative cleavage of the enol alkene bond is going generally to be a problem in this section and is best illustrated by the useful ozonolysis of silyl enol ethers 198 and 199 of the same ketone 194. The regiospecihc formation of silyl enol ethers is described in chapter 3. 

This silyl hydrazone formation-oxidation sequence was originally developed as a practical alternative to the synthesis and oxidation of unsubstituted hydrazones by Myers and Furrow [31]. The formation of hydrazones directly from hydrazine and ketones is invariably complicated by azine formation. In contrast, silyl hydrazones can be formed cleanly from /V,/V -bis(7< rt-butyldimethylsilyl)hydrazine and aldehydes and ketones with nearly complete exclusion of azine formation. The resulting silylhydrazones undergo many of the reactions of conventional hydrazones (Wolff-Kishner reduction, oxidation to diazo intermediate, formation of geminal and vinyl iodides) with equal or greater efficiency. It is also noteworthy that application of hydrazine in this setting may also have led to cleavage of the acetate substituents. 

An enantioselective synthesis of (+)-estradiol has been accomplished from 1,3-dihy-drobenzo[c]thiophene 2,2-dioxide (306) by successive thermal S02-extrusion and cycloaddition (80HCA1703). Treatment of the optically active iodide (307) with two mole equivalents of the masked quinodimethane (306) in the presence of two mole equivalents of sodium hydride gave (308) as a 1 1 mixture of diastereoisomers. Thermolysis of this alkenic sulfone in 1,2,4-trichlorobenzene furnished the trans-anti-trans steroid (309) in 80% yield. Treatment of (309) with methyllithium gave the methyl ketone, which was subjected to a Baeyer-Villiger oxidation and then silyl ether-acetate cleavage to afford (-l-)-estradiol (310 Scheme 66). 

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