3- Methyl-4- -ones, formation

This point is well-illustrated by the data of Table 19, which show the effect of methyl substituents on the rate coefficients for methyl ester formation from benzoic acid. The compounds fall naturally into three classes. Those with no ortho substituent react 3-4 times as fast as those which have one orthomethyl group, while 2,6-dimethylbenzoic acid, the only compound with two orf/io-substituents, did not give the ester at a measurable rate. 

The homologous azirine (143) with a one-atom bridge gave quite different results.70 Photolysis led to the 3,5-fused bicyclic dihydropyrrole (144). The isomeric azirine (145) also led to (144), although the initial products included dihydropyrrole (146) which apparently converted to (144) as photolysis continued. Azirines (143) and (145) were shown to not interconvert and die postulated two discrete azomethine ylides were trapped with methyl trifluoroacetate. Formation of dihydropyrrole (144) was explained based on a two-step cycloaddition process involving a common diradical intermediate. The observation of (146) from photolysis of (145) but not (143) can be explained based on extinction coefficient differences. Azirine (145) has a high extinction coefficient as does (146). The initial product (146) can then be optically pumped to (144) with a low extinction coefficient. Azirine (143) also has a low extinction coefficient and any (146) that formed from it would be optically pumped to (144) before observa-... 

This S-diketone might take part in several different aldol condensations, but it is ideally suited for a favorable one formation of a six-membered ring. To form a six-membered ring, the enolate of the methyl ketone attacks the cyclohexanone carbonyl. The aldol product dehydrates to give a cyclohexenone. 

Reaction of arylhydrazones 216 of piperidin-2-ones with methyl chloro-formate, phosgene, or thiophosgene yielded (80USP4213773) the fused-ring system 217. Reaction of 2,2 -azopyridine (218) with diazoalkanes afforded [66JCS(C)78 73LA2088] the 2-(pyrid-2-yl)-l,2,4-triazolo[4,3-a]-... 

The remaining segment, C-3 to C-8, was constructed by a similar route. Optically active allylic alcohol 229, produced from lithio ethylacetate and methacrolein followed by a second Sharpless kinetic resolution, was hydrolized to the corresponding hydroxy acid. Neutralization followed by iodolactonization then gave 230 in 85% yield. This highly stereoselective cyclization produced a cis-trans ratio of 20 1 via a one-pot procedure. Deprotonation and methylation afforded the expected anti a-methyl compound, contaminated with about 10% of the syn compound but none of the methyl ether. Formation of the silyl ether then produced 231 in 66% yield. Dibal reduction to the aldehyde concomitant... 

If one of the three hydroxyl groups is replaced by a methoxyl group, complexing still occurs, but it is somewhat weaker (Section III,4). If all three hydroxyl groups are methylated, complex formation becomes n igible. ... 

Protein methylation reactions can be separated into two major classes. The first class involves methyl ester formation on carboxylic acid groups. These methylation reactions are generally reversible and at least one of their functions is similar to that of protein phosphorylation reactions in switching a modified species from one type of activity to another. However, other types of methyl esterification reactions appear to play more novel roles in the metabolism of aging proteins and in the targeting of proteins to membranes. 

Two systems have recently been described that result in methyl ester formation at the C-terminus of a protein. Both appear to be widely distributed in eucaryotic cells, but have not yet been observed in procaryotic cells. In one system, the C-terminal leucine residue of one or more 36 kDa cytosolic polypeptides is the target of methylation (Xie and Clarke, 1993). These methyl ester linkages are much more labile in cell extracts than would be predicted on the basis of their chemistry and this observation suggests the presence of a methylesterase activity (Xie and Clarke, 1994a). The protein substrate for this methyltransferase has recently been identified as the catalytic subunit of protein phosphatase 2A and its reversible methylation may modulate its activity (Xie and Clarke, 1994b). 

Many intracellular proteins can be modified after their biosynthesis by the enzymatic addition of a methyl group from S-adenosylmethionine. These posttransla-tional reactions can permanently or temporarily modify the structure and function of the target proteins. Importantly, these modifications can expand the repertoire of the cellular chemistry performed by proteins. Unmodified proteins must function with only the 20 amino acid residues incorporated in ribosomal protein synthesis, while methylation reactions can create a variety of new types of residues for specialized cellular roles. At this point, we understand best the processes that reversibly form methyl esters at carboxylic acid residues. One such reaction in bacteria methylates glutamate residues on several membrane-bound chemorecep-tors whose signaling properties are modulated by the degree of modification at multiple methylation sites. Another methylation system in higher cells leads to C-terminal methyl ester formation on a variety of proteins such as the small and... 

The resin-bound chiral auxiliary 84 was allowed to react with different vinyllith-ium reagents. The resulting alcohols 85 were treated with n-BuLi, methyl chloro-formate and different cuprate reagents. Finally, the a-alkylated adducts 86 were liberated from the polymer with ozone followed by one of three different workup conditions to provide a primary alcohol, an aldehyde or a carboxylic acid (Scheme 12.32). 

---