Enantiotopic hydroxyl groups

Miller et al. achieved selective functionalization of the enantiotopic hydroxyl groups of meso-inositols. In particular, they were able to convert myo-inositol 49 to either mono-phosphorylated D-myo-inositol-l-phosphate 50 or D-myo-inositol-3-phosphate mt-50 in high yield and with excellent ee (98%) (Scheme 13.25) [40, 41], This remarkable result was achieved by using the pentapeptides 51 or 52 as catalyst. These catalysts were identified from peptide libraries by a combinatorial approach. The peptides 51 and 52 are highly selective and complementary low-molecular-weight kinase mimics. It is also interesting to note that the opposite enantioselectivity of catalysts 51 and 52 could hardly have been predicted on the basis of the type and sequence of the amino acids involved. (Application of the Miller peptide catalysts to the kinetic resolution of racemic alcohols is discussed in Section 12.1.)... 

Horse liver alcohol dehydrogenase (HLADH) catalyzes the oxidoreduction of a variety of compounds [56,57], It has been demonstrated that HLADH catalyzes the stereospecihc oxidation of only one of the enantiotopic hydroxyl groups of acyclic and monocyclic meso-diols [58,59], The authors demonstrated the oxidation of meso exo- and endo-7-oxabicyclo [2.2. l]heptane-2,3-dimethanol to the corresponding enantiomerically pure y-lactones by HLADH. NAD+ and flavin adenine dinucleotide (FAD) at concentrations of 1 and 20 mmol, respectively,... 

Hydrolytic enzymes such as esterases and Upases have proven particularly useful for asymmetric synthesis because of their abiUties to discriminate between enantiotopic ester and hydroxyl groups. A large number of esterases and Upases are commercially available in large quantities many are inexpensive and accept a broad range of substrates. 

For Rh(I)/BINAP-catalyzed isomerizations of allylic amines, the mechanistic scheme outlined in Eq. (2) has been proposed. The available data are consistent with the notion that Rh(I)/PF-P(o-Tol)2-catalyzed isomerizations of allylic alcohols follow a related pathway [11]. For example, the only deuterium-containing product of the reaction depicted in Eq. (9) is the l,3-dideuterated aldehyde, which estabhshes that the isomerization involves a clean intramolecular 1,3-migration. The data illustrated in Eqs. (10) and (11) reveal that the catalyst selectively abstracts one of the enantiotopic hydrogens/ deuteriums alpha to the hydroxyl group. 

Fig. 18. The expected percentages of various labelled products of the dioldehydratase reaction using 25 as substrate. The calculation was based on the following facts and assumptions (1) The enzyme does not differentiate between the enantiotopic hydrogen positions (conclusion from experiments with species 17 and 18 shown in Fig. 14) (2) in the competition between vicinal hydrogen atoms there is an intramolecular kinetic deuterium isotope effect of 2.6 (Fig. 15) (3) this effect is 10 for geminal hydrogen atoms (4) the migrating hydroxyl group substitutes one of the hydrogen atoms in the vicinal position stereospecifi-cally (i.e., with inversion).

Finally, for the other molecules, mentally replace each of the two hydrogens in the indicated set with X, a different group. In (a), the resulting products are enantiomers, and the protons are enantiotopic. Replacement of the protons in (b) produces two chirality centers (the carbon bearing the hydroxyl group is now chiral) and the indicated protons are diastereotopic. Replacement of one of the methyl protons in each of the groups in (c) produces a pair of double-bond isomers that are diastereomers these protons are diastereotopic. The protons in (f) are homotopic. 

Another example of stereospecific oxidation of an enantiotopic methyl group is the hydroxylation of 3 by Sporotrichum sulfurescens353. 

This lack of stereochemistry is typical of substituents that lie on a pseudo- C2 axis and compound 60 was drawn correctly without stereochemistry to the central phenyl group. However, the central substuent does disrupt the C2 axis that would otherwise be there. Consider the two hydroxyl groups on the left and right of the molecule. One of them will be on the same side of the molecule as the central hydroxyl and one will not. The hydroxyl groups on the left and right of the molecule are diastereotopic whereas they would be enantiotopic if the central hydroxyl were not there (because they would be related by the C2 axis)... 

Methylation of amines in nucleotides and proteins plays important roles in biological function. Methyl transferases accept a wide range of nucleophiles such as halides, amines, hydroxyls, and enolates [reactions (a) and (b), Scheme 8.6] [42-44], For example, in the biosynthesis of novobiocin, methylation takes place at only one phenolic carbon and not the remaining three hydroxyl groups [45, 46]. On the other hand, methyl transfer to electron-deficient substrates often occurs under radical mechanisms requiring methylcobalamin as the cofactor, as shown in the biosynthesis of fosfomycin, where only one of the two enantiotopic hydrogen was replaced by the methyl group [reaction (c), Scheme 8.6] [47]. 

Selective hydroxylation of one enantiotopic methyl group as an approach to optically pure... 

Finally, reaction E in Fig. 4 illustrates a stereoselective synthesis that proceeds by differentiation of two enantiotopically related groups of a meso compound. Here, one hydroxyl group of d.s-1,2-cyclohexanediol is preferentially benzoylated in the presence of one molar equivalent of an enantiomerically pure diamine [26]. These desymmetrization reactions (that have many biological versions) are also called meso-tricks , and are currently receiving a great deal of attention for the preparation of new chiral building blocks [27]. 

The enzyme (aconitase), being itself chiral, can distinguish between the two enantiotopic carboxymethylene groups (one pro-R and the other pro-S) of citrate (Figure 8.20). Then, as shown in Scheme 8.86, the pro-R proton from the pro-R carboxymethylene is abstracted and the hydroxyl is lost in an antiperiplanar... 

D-Xylose derivative 7 has a latent plane of symmetry, the terminal hydroxyl and carbonyl groups being virtually enantiotopic. With adapted reactions and a judicious order of performing them (Scheme 4), the two enantiomeric intermediates 8 and ent-S were prepared [45], They are interesting starting materials for further diastereodivergent synthesis of conduritol and inositol derivatives [46],... 

Microbial hydroxylation of a methyl group has the potential to be stereoselective in cases where the substrate possesses enantiotopic CH3 substituents. A classic example of such a process is the conversion of isobutyric acid to P-hydroxyisobutyric acid (Fig. 4), where the use of Candida rugosa IFO 0750 leads to formation of the D-(—) (R) isomer [9], and the L-(+) (S) product is obtained from oxidation using Bullera alba IFO 1030 [10]. Similar stereoselectivity is also observed in the oxidation of homologous acids and hydrocarbons by Rhodococcus species [11], and in the oxidation of cumene (1) to (jR)-2-phenylpropionic acid (2) by Pseudomonas oleovorans NRRL B-3429 (Fig. 5) [12]. 

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