Other Reactions at the Carbonyl Carbon Atom

Other Reactions at the Carbonyl Carbon Atom.—The rates of oxygen-18 exchange in steroid ketones have been studied by gas chromatography-mass spectrometry, the steroid ketone and being injected together. Exchange was most 

Grignard (MeMgX) and methyl-lithium reactions with steroid ketones generally afford more of the equatorial-methyl tertiary alcohol. This is the case with 

Methylmagnesium halide reacts stereospecifically with a 19-aldehyde (269) to give the (I )-19-methyl-19-ol (270), whereas lithium aluminium hydride reduced the 19-methyl-19-oxo-compound (271) to give the 19(S)-alcohol 212) Both reactions indicate a preferred conformation for the 19-carbonyl compound, with the carbonyl oxygen atom close to C-5. 

The Reformatsky reaction of 2-bromobutyrolactone with 3-oxo-steroids is normal, giving the hydroxy- (279) and unsaturated lactones (280). 17-Oxo-steroids reacted only slightly.  

Methylene addition to 3-oxo-steroids, by use of dimethylsulphonium- or dimethyloxysulphonium-methylides, gives a preponderance of the 3a-CH2 (281) and 3 -CH2 (282) oxirans respectively. The 2,2-dimethyl-3-ketone behaves similarly, but the 2a-methyl-3-ketone gives mainly the 3)5-isomer with either 

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Other Reactions at the Carbonyl Carbon Atom.— Acetal formation from 3-oxo-steroids in anhydrous alcohols is far more effective than was previously realised. C.d. studies revealed almost quantitative conversion of 5a- or 5 -3-oxo-steroids in methanol into their 3,3-dimethoxy-derivatives, and ethanol or propan-2-ol also gave considerable proportions of the corresponding acetals. Contrary to earlier belief, even the hindered 2-oxo-group gave the 2,2-dimethoxy-derivative (73 % at equilibrium). Acetal formation was drastically reduced by traces of water, however, or by alkyl substitution adjacent to the oxo-group. 

Other Reactions at the Carbonyl Carbon Atom.—Grignard reactions of a pregnan-20-one (157) with 4-methylpentylmagnesium bromide, or of a 21-norcholestan-20-one (158) with methylmagnesium bromide, gave the (205)- and (20R )-cholestan-... 

Other Reactions at the Carbonyl Carbon Atom.—A new method for converting ketones into methylene compounds is claimed to be successful even in cases where the Wittig and related reactions fail. Treatment of the ketone (e.g. 271) with phenylthiomethyl-lithium (270) gives a derivative (272), which may be acetylated or benzoylated in situ. Reduction of the ester (273) with lithium-NH3 gives the methylene compound (274) in good yield. The conversion of cholest-5-en-3-one into 3-methylenecholest-5-ene contrasts with the lability of the 5-en-3-one to the basic conditions required for the Wittig reaction. Even many hindered ketones appear to be reactive. 

The enolates of aldehydes and ketones undergo deuterium exchange, bromination, and alkylation reactions (Sections 22.4—22.6). Carboxylic acid derivatives react similarly. However, the added possibility of a competing nucleophilic acyl substitution reaction limits some of the substitution reactions at the a-carbon atom of acid derivatives. For example, acyl halides react with most bases in substitution reactions at the carbonyl carbon atom rather than by abstraction of the a-hydrogen atom. On the other hand, the pA of the a-hydrogen atoms of amides is very large, and these derivatives would require a very strong base for formation of enolates for synthetic reactions. Esters are the most convenient acyl derivatives for enolate formation and subsequent substitution at the a-carbon atom. The substituted ester can subsequently be converted into other acyl derivatives. 

By reactions 2—4 the (+)-rotating compounds la, 2a and 3a can be converted into each other. As the reactions occur only at the carbonyl carbon atom group these (+)-rotating compounds must have the same relative configuration at the manganese atom. The (-)-rotating complexes lb, 2b and 3b are related in the same way. 

The nucleophilic addition reactions of aldehydes and ketones occurring at the carbonyl carbon atom that we have studied so far are summarized below. In Chapters 18 and 19 we shall see other examples. 

Other oxidation reactions at the same carbon atom can be induced with oxidizing agents too. For example, as shown in Equation 8.43, oxidation at the a-carbon to produce a carbonyl group can be brought about by ruthenium tetroxide (RUO4). 

As we saw m Chapter 20 thioesters are more reactive than ordinary esters toward nucleophilic acyl substitution They also contain a greater proportion of enol at equilib rmm Both properties are apparent m the properties of acetyl coenzyme A In some reactions it is the carbonyl group of acetyl coenzyme A that reacts m others it is the a carbon atom... 

Other products are formed when high concentrations of sodium methoxide are present or when magnesium methoxide is used as the base. Dimethyl 5-hydroxytoluene-2,4-dicarboxylate arises from attack at the acetyl carbon atom in an aldol-like condensation, whilst reaction at the ester carbonyl leads through a Claisen condensation to methyl 5-acetyl-2,4-dihydroxybenzoate. 

Activation reactions catalyzed by serine proteases (including kallikreins) are an example of limited proteolysis in which the hydrolysis is limited to one or two particular peptide bonds. Hydrolysis of peptide bonds starts with the oxygen atom of the hydroxyl group of the serine residue that attacks the carbonyl carbon atom of the susceptible peptide bond. At the same time, the serine transfers a proton first to the histidine residue of the catalytic triad and then to the nitrogen atom of the susceptible peptide bond, which is then cleaved and released. The other part of the substrate is now covalently bound to the serine by an ester bond. The charge that develops at this stage is partially neutralized by the third (asparate) residue of the catalytic triad. This process is followed by deacylation, in which the histidine draws a... 

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