Alcohol epimers, formation

Energetic reduction with lithium aluminum hydride led to the reduction of the carbonyl group with the formation of the correct alcohol epimer, as expected from the steric hindrance presented by the benzene ring, and to removal of the aromatic bromine. This last reaction is a noteworthy example of the removal of aromatically bound halogen without reduction of either an allyhc hydroxyl or a double bond. The codeine so produced (CCCLXXXIII) was then demethylated to morphine (CCCLXXXIV) by short heating to 220° with pyridine hydrochloride. 

The same basic strategy was applied to the synthesis of the smaller fragment benzyl ester 28 as well (Scheme 4). In this case, aldehyde 22 prepared from (S)-2-hydroxypentanoic acid [9] was allylated with ent-10 and tin(IV) chloride, and the resulting alcohol 23 was converted to epimer 24 via Mitsunobu inversion prior to phenylselenenyl-induced tetrahydrofuran formation. Reductive cleavage of the phenylselanyl group, hydrogenolysis of the benzyl ether, oxidation, carboxylate benzylation, and desilylation then furnished ester 28. 

The dehydration of cis,alumina surfaces, could readily explain the observed data ... 

The carbonyl group (and adjacent alcohol) oxidizes with excess phenyl hydrazine (PhNHNH2) to form an osazone (see Figure 16-15). Osazone formation is very important in determining the relationship between various monosaccharides. For example, both D-glucose and D-mannose produce the same osazone, so they re epimers. Epimers differ by only one chiral center, which osazone formation destroys. 

The synthesis was initiated with the stereoselective introduction of two methyl groups onto the tritylated butenolide 1 to give the dimethylated lactone 2 (67%) along with the C-2 epimer (13%). As this stereocenter will be lost in the Stork annulation vide post), both epimers could be used in the total synthesis of 12. Their structures were confirmed by the NOE enhancement in 2. After detritylation, the resulting alcohol was transformed to the dimethyl acetal 3. Reaction with the lithiated MeS02Ph gave the lactol 4, which was silylated to the open chain having the enol silyl ether 5 (91%). These reactions seem to depend on the readiness of the enol silyl ether formation. 

The second inherent problem is encountered in the reduction of ketones with a proton-bearing chiral center adjacent to the carbonyl group. In this case, enolate formation may lead to equilibration before reduction. For example, reduction of a 98.6 1.4 mixture of menthone (4) and its epimer isomenthone (5) with Na or K in ethanol gave approximately 15% of a mixture of alcohols (8) and (9), in addition to 82% of menthol (6) and a small amount of neomenthol (7), because of partial isomerization. 

Union of the two segments was now effected via formation of the dianion of 208 and subsequent addition to ketone 202 to afford 209 in 80% yield. Although contaminated with a small amount of the C-6 epimer (ratio 5 1), the major component 209 contained all the necessary carbon atoms and possessed the required stereochemistry (except the C-13 alcohol) for the completion of erythronolide A. To this end, the methylene group was ozonolyzed, and the sulfoxide reductively cleaved, providing ketone 210 (84%). Stereoselective reduction of the ketone concomitant with cleavage of the silyl ether gave an 85% yield of 211 as a 20 1 mixture of C-13 Isomers. Intermediate 211 contains all the stereochemical centers present in erythronolide A. 

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