Stereochemistry using chiral methyl groups

The amino acid methionine is formed by a melhylation reaction of homo cysteine with iV-methyltetrahydrofolate. The stereochemistry of the reactior has been probed by carrying out the transformation using a donor with a "chiral methyl group" that contains protium (H), deuterium (D), and tritium (T isotopes of hydrogen. Does the methylation reaction occur with inversion oi retention of configuration ... 

A second example is isomerization of isopentenyl diphosphate to dimethylallyl diphosphate (Eq. 13-56) 304-307 The stereochemistry has been investigated using the 3H-labeled compound shown in Eq. 13-56. The pro-R proton is lost from C-2 and a proton is added to the re face at C-4. When the reaction was carried out in 2H20 a chiral methyl group was produced as shown.304 A concerted proton addition and abstraction is also possible, the observed trans stereochemistry being expected for such a mechanism. However, the... 

A second type of reaction whose stereochemistry was elucidated by the use of chiral methyl groups is of the CDTXY->CHDTX type, exemplified by the citrate lyase reaction (Fig. 69). The stereochemical outcome of a number of these reactions has also been tabulated 149). 

Another interesting development is the recent use of tritium NMR spectroscopy to study the removal of hydrogen from a chiral methyl group. In the degradation of L-valine, isobutyryl-CoA, 163, is an intermediate this metabolite is then oxidized to metacrylyl-CoA, 164. In the oxidation, one hydrogen is removed from C-2, and one from the pro-S methyl group on the same carbon. To determine the stereochemistry... 

The isomerization of the double bond in the synthesis of (-)-menthol is stereospecific. Evidence obtained using vinyl amine specifically deuterated at C-l indicates that the transfer of a proton from C-l to C-3 is suprafacial,118 as indicated by equation 9.46. Equation 9.47 illustrates how the chirality of the BINAP ligand and the stereochemistry of the trisubstituted double bond in 86 control the stereochemistry of the methyl group at C-3 in 87 upon double bond migration. 

Retey et al. (72) used this same principle in their work on the stereochemistry of citrate formation from chiral acetyl-CoA with Si-citrate synthase (Scheme 15). The chiral methyl group was converted into one of the methylene groups of succinate and the distinction between sets (I, 2, 3) and (4, 5, 6) was then based on the known different isotope effects for the removal of pro-/ ( hMd = 5.3 kH/kT = 12) vs. pro-5 (kH/kD = 1.35 kH/kj = 1.5) hydrogens of succinate in the succinate dehydrogenase reaction (73). However, the malate synthase/fumarase procedure is clearly the most commonly used method to analyze the configuration and chiral purity of chiral methyl groups. 

Tanaka and co-workers in their work on helical aromatic compounds were able to decrease reaction time and control racemization when heated in a commercial microwave oven. When (5)-2-methylglutaric acid was reacted under classic heating conditions complete epimerization of the chiral methyl groups was observed. Using microwave heating a 50% enantiomeric excess was observed. The retention of stereochemistry was attributed by the authors to the markedly decreased reaction times. 

Use of the three isotopes of hydrogen to fabricate chiral methyl groups for study of the stereochemistry of enzyme-catalysed reactions involving methyl groups is to be noted (Sections 1.2.2, 4.2 and 4.4). 

Of interest from the mechanistic point of view is the formation of only one diastereoisomer in the methylation step VII/119 — VII/124. Two possible explanations are discussed in the literature [3]. First, a stereoselective methylation of the aldehyde group takes place under the influence of the nitro group leading to the correct stereochemistry in VII/124. The second possibility involves the titanium reagent. An equilibrium can exist between the diastereoisomeric mixture VII/121 and the pure VII/123 via the isomer VII/122. By quenching the equilibrium mixture, only the thermodynamically most stable isomer would be obtained [3]. A differentiation of the two mechanisms seems possible using chiral reaction conditions. Treatment of the chiral (-)-VII/119 (50 % ee), prepared by an asymmetric Michael addition of acrylaldehyde and 2-nitrocyclohexa-none in the presence of cinchonine [84], with achiral dimethyltitaniumdiisopro-poxide yields only achiral methylation products. This experiment shows that no stereoselective methylation takes place. The second consideration, then seems to be more likely (Scheme VII/24)7). 

Undoubtedly one of the major sesquiterpenoid synthetic achievements of the year has been the synthesis of hirsutic acid C (288) (Scheme 42). Intramolecular Michael reactions were used to generate the key tricyclic ketone (287) with the correct relative stereochemistry at four of the chiral centres. The ethylene bridge was then cleaved to create the two requisite methyl groups. Interestingly the first intramolecular Michael reaction [(285) (286)] could be achieved with (-)-... 

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