Methyl ether ozonolysis

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

Schroder and co-workers studied the addition of formaldehyde-O-oxide, generated in situ at low temperature by ozonolysis of ketene diethylacetal, to the tropolonic ring of various colchicine analogues, Fig. (4) [80]. The intermediate ozonide E formed from 4 decomposed upon warming to give A-acetylcolchinol methyl ether 32 via the presumed intermediate F, in 81% yield. 

The carbonyl oxide, a valence-unsaturated species, is not the final product of an ozonolysis. Rather, it will react further in one of two ways. Carrying out the ozonol-ysis in methanol leads to the capture of the carbonyl oxide by methanol under formation of a hydroperoxide, which is structurally identical to the ether peroxide of isopropyl methyl ether. However, if the same carbonyl oxide is formed in the absence of methanol (e.g., if the ozonolysis is carried out in dichloromethane) the carbonyl oxide undergoes a cycloaddition. If the carbonyl oxide is formed along with a... 

The ozonolysis of alkyl, aryl or benzylheptafluoroisobutcnyl ethers produced hexa-fluoroacetone. Reaction with the methyl ether at 25 C for 16.8 hours followed by the cleavage of the ozonide gave an aqueous solution of hexafluoroacetone, corresponding to a yield of 70%. ... 

In the laboratory of T. Nakai, the asymmetric tandem Claisen-rearrangement-ene reaction sequence followed by a modified McMurry coupling was used to access (+)-9(11)-dehydroestrone methyl ether. The Claisen-ene product was subjected to ozonolysis and epimerization to the 8,14-anf/ configuration. The C-ring was constructed by treating the tricyclic diketo aldehyde with TiCl3-Zn(Ag) in DME to afford the desired final product in 56% yield. 

Acetylphenyldihydrothebaine is formed by acetylation of the phenol [1, 14], Methyl and ethyl ethers of phenyldihydrothebaine were prepared by Freund, who degraded both to nitrogen-free substances [1]. Demethylation of phenyldihydrothebaine affords norphenyldihydro-thebaine [xxxi] which can be methylated to phenyldihydrothebaine methyl ether [1, 4, 8]. The latter is stable to ozonolysis [15]. 

Ozonolysis of 6 to produce 7 was studied at temperatures ranging from -78 to -0 °C in mixtures of dichloromethane and methanol. The intermediates that formed were found to be stable below -30 °C. Diol 7 was obtained in high yields when the reaction mixture was quenched with aqueous sodium borohydride. If the reaction mixture was warmed to room temperature before the quench, a complex mixture of products formed as indicated by the NMR spectrum. Similarly, only polymeric products were formed when the ozonolysis was carried out without methanol even at -78 °C. When ozonolysis was done at -5 to 0 °C in the presence of methanol, formation of trityl methyl ether was noticed, a result similar to which has been observed before [2], Diol 7 was obtained in near quantitative crude yield when ozonolysis was carried out below -30 °C, followed by the addition of the reaction mixture to cold, aqueous sodium borohydride solution. The product was used without further purification in the next step. 

Synthesis of 7 -amino acid-oxazole fragment 68 of calyculins A and B from D-erythronol-actone 58 has been reported by conversion to 59," which was subjected to oxidation reaction to afford the hemiaminal 60 (Scheme 9) Acetylation of 60 furnished 61, which was converted to ketone 62 in 88% yield. Conversion of 62 to a silyl enol ether, ozonolysis with reductive workup and O-methylation of the resultant alcohol 63 furnished 7 -lactam 64. Treatment of 64 with CAN led to 65 (60%), which was reacted with (CHj)2 A1 derivative of 66 to provide 67 (62%), which upon removal of the silyl group provided 68. 

The (A)-glyceraldehyde derivative 61 has also been nsed for the synthesis of bengamide E (3) (Scheme 6) Silylation of enoate 61 followed by redaction with DIBAL-H afforded 62, which nnderwent Sharpless epoxidation followed by iodination of the primary hydroxyl gronp to afford 63. Reaction of 63 with rerr-bntyllithinm and dimethyl snlfate and snbseqnent in situ methylation gave the methyl ether 64 in a 95 5 mixtnre of anti and syn prodncts. Ozonolysis of 64 followed by hydrolysis of the silyl ether gave 53, which nnder similar seqnence of reactions nsed in the former scheme gave 3. 

Afterwards, G. Dominguez et al. [69] accomplished the synthesis of alcohols (80) and (89) from the methyl ether of the natural quinone royleanone (95) (Scheme 16). They investigated three different approaches for compounds (80) and (89) preparation from the quinone (95). It was found that the following ones were optimal. The quinone (95) was ozonised, and the ozonolysis products were oxidised with periodic... 

An ingenious approach to racemic estrone has used two reactions in a combined tandem Cope-Claisen rearrangement (ref. 130). 1-Bromomethyi-3,4-dihydro-6-methoxynaphthalene is used to alkylate 1-methoxycarbonyl-2-methylcyclopent-2-ene and the ester group in the product converted to a vinyloxymethyl substituent. Thermolysis afforded a mixture of diastereoisomeric aldehydes (2 1) containing a majority of the trans compound. Ozonolysis and epimerisation at the 8-position succeeded by McMurry coupling gave the required tetracyclic structure from which racemic estrone methyl ether was obtained. 

Ancistrocladus hamatus (Vahl) Gilg is a related climber, found in Sri Lanka. Chemical investigation by Govindachari s group showed that this plant also contains ancistrocladine (1) as the major alkaloid, accompanied by its atrop-isomer, called hamatine (10). Compound 10, on dehydrogenation of its methyl ether, gives an aromatic isoquinoline, enantiomeric to 4, whereas ozonolysis yields the same p-amino acid 3, as ancistrocladine (1) (20,21). 

The methoxy bicycloheptadienone (135) was obtained [142] by irradiation of a-tropolone methyl ether which, after hydrogenation of the conjugated double bond, underwent cleavage by ozonolysis of the enol ether double bond to give the dimethyl acetal (136). The latter was then alkylated with ethyl 7-... 

Methoxy-3,6-bicyclo[3,2,0]heptadien-7-one is readily available from the photo-chemically induced valence tautomerism and skeletal reorganization of the methyl ether of tropolone. The double bond of the ap-unsaturated ketone can be selectively reduced to give (375). Ozonolysis of (375) in methanol-methylene chloride at low temperature, followed by treatment of the ozonide with liquid sulphur dioxide, gives the substituted cyclopentanone (376X which has been used in yet another prostaglandin synthesis. ... 

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