Methylation hemiketals

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

The force field calculations of the enthalpies (AAiT) of the four hemiketals of 6-methylpyrano[2,3-/ ]dioxane-8a-ols clearly indicate that the /3-m-fused link is the most favored, followed by the a-cis- and /3-/ra r-isomers, while the a-/ra r-compound, due to the pyranoid ring being forced into 4 conformation with an axial methyl group, is the least likely to be formed <1991MI235>. 

Since the hemiketals of cyclopropanone are in equilibrium with the parent ketone, they may be interconverted by standing in the presence of the appropriate alcohol. 4> However, in the cases of cyclopropanone ethyl and methyl hemiketals, dissociation to the ketone is slow and hemi-ketal interconversion requires about two weeks at room temperature for completion. 4>... 

The reaction of cyclopropanone with hydrogen chloride affords the chlorohydrin 90 (65%). 5 15) Acetylation of 90 with ketene gives the expected acetoxy compound 91 (34%) while the addition of methanol to a methylene chloride solution of 90 affords cyclopropanone methyl hemiketal (100%). The latter reaction illustrates the use of 91 as an in situ source of cyclopropanone. 

Cyclopropanone ethyl hemiketal is contaminated with 8-9% of the cyclopropanone methyl hemiketal as a result of exchange with the solvent.2 The calculated number of mmoles of total cyclopropanone hemiketal is based upon this composition. 

Methylmagnesium bromide Magnesium, bromomethyl- (8,9) (75-16-1) Diisopropylamine (8) 2-Propanamine, N-(l-methylethyl)- (9) (108-18-9) 2-Methyi-i-tetralone 1 (2H)-Naphthalenone, 3,4-dihydro-2-methyl- (8,9) (1590-08-5) Cyclopropanone ethyl hemiketal Cyclopropanol, 1-ethoxy- (8.9) (13837-45-1) Sodium hydride (8,9) (7646-69-7)... 

Wiseman and Lee (1986) also reached the ketone 14 by a route involving the cyclization of 1,5-cyclooctanediol (16 Scheme 7.4). This transformation involved the Jones oxidation of 16 to give the hemiketal 17, which was transformed into the 9-methyl-9-azabicycle[3.3.1]nonan-l-ol 18 by treatment with methylamine, followed by addition of sulphuric acid (Quinn et al. 1973). This skeleton was reconverted into the 9-azabicyclo[4.2.1]nonane by bromination-reorganisation with pyri-dinium bromide perbromide in hot acetic acid in one direct step (Stjernlof et al. 1989). This constitutes the key step of this synthesis, affording the ketone 14 in 56% yield. 

A variant of the mechanism shown in Figure 10 is one in which the aetive site base (instead of the the 04 atom) abstracts a methyl proton from the hemiketal adduct (Itoh et al, 1998) but this possibility is not consistent with the position of the methanol in the active site as seen in the X-ray strueture (Section 7.4.3). This orientation of methanol lends further support to the hemiketal mechanism. The hydroxyl oxygen is close to C5 (3.2 ) while the methyl group is considerably further away (3.9 ). This would favour covalent bond formation between C5 and the nearby hydrox over hydride ion transfer from the more distant methyl group of the substrate (Xia etal, 1999). 

Cyclopropanones have been used as unique sources of three-carbon units in various synthetic applications including the synthesis of natural products. In general, the sources of the ketones have been the readily available hemiketals or their derivatives as is illustrated in Scheme 49and in the formation of (-I-)-ll-deoxyprostaglandin E2 methyl ester (Scheme 58) ... 

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