Base-catalyzed racemization

Despite the known propensity for racemization, base-catalyzed cyclization continues to be used occasionally. Thus a series of cyclodipeptides derived from 1-methyl-L- and D-tryptophans and S-methyl-L-and D-cysteine have been prepared by ammonia-catalyzed cyclization (87JMC1706), (Scheme 1). 

A completely different enzyme-catalyzed synthesis of cyanohydrins is the lipase-catalyzed dynamic kinetic resolution (see also Chapter 6). The normally undesired, racemic base-catalyzed cyanohydrin formation is used to establish a dynamic equilibrium. This is combined with an irreversible enantioselective kinetic resolution via acylation. For the acylation, lipases are the catalysts of choice. The overall combination of a dynamic carbon-carbon bond forming equilibrium and a kinetic resolution in one pot gives the desired cyanohydrins protected as esters with 100% yield [19-22]. 

Solvent for Base-Catalyzed Reactions. The abihty of hydroxide or alkoxide ions to remove protons is enhanced by DMSO instead of water or alcohols (91). The equiUbrium change is also accompanied by a rate increase of 10 or more (92). Thus, reactions in which proton removal is rate-determining are favorably accompHshed in DMSO. These include olefin isomerizations, elimination reactions to produce olefins, racemizations, and H—D exchange reactions. 

To minimize racemization, the use of nonpolar solvents, a minimum of base, low reaction temperatures, and carbamate protective groups (R = O-alkyl or O-aryl) is effective. (A carbamate, R = O-r-Bu, has been reported to form an oxazolone that appears not to racemize during base-catalyzed coupling.) ... 

Carbamates can be used as protective groups for amino acids to minimize racem-ization in peptide synthesis. Racemization occurs during the base-catalyzed coupling reaction of an A-protected, carboxyl-activated amino acid and takes place in the intermediate oxazolone that forms readily from an A-acyl-protected amino acid (R = alkyl, aryl) ... 

One commonly used procedure for studying the steric stability of the carbanion is comparison of the rate of base-catalyzed H/D exchange reaction (kel) on the chiral carbon with the rate of racemization (fcrac). By this comparison, inversion, racemization or... 

In the base-catalyzed H/D exchange of the four-membered cyclic sulfone 85, the rate of exchange is slightly higher than that of racemization and the carbanion formed was also considered to be planar101. 

In contrast to oxoesters, the a-protons of thioesters are sufficiently acidic to permit continuous racemization of the substrate by base-catalyzed deprotonation at the a-carbon. Drueckhammer et al. first demonstrated the feasibility of this approach by performing DKR of a propionate thioester bearing a phenylthiogroup, which also contributes to the acidity of the a-proton (Figure 4.14) [39a]. The enzymatic hydrolysis of the thioester was coupled with a racemization catalyzed by trioctylamine. Owing to the insolubility of the substrate and base in water, they employed a biphasic system (toluene/H2O). Using P. cepacia (Amano PS-30) as the enzyme and a catalytic amount of trioctylamine, they obtained a quantitative yield of the corresponding... 

Racemization of some substrates can take place through reversible formation of the substrate via an addition/elimination process. The racemization can be acid or base catalyzed. In this section we vill discuss DKR of cyanohydrins and hemithioacetals. 

In 1992, Oda et al. reported a one-pot synthesis of optically active cyanohydrin acetates from aldehydes, which were converted to the corresponding racemic cyanohydrins through transhydrocyanation with acetone cyanohydrin, catalyzed by a a strongly basic anion-exchange resin [46]. The racemic cyanohydrins were acetylated by a lipase from P. cepacia (Amano) with isopropenyl acetate as the acyl donor. The reversible nature of the base-catalyzed transhydrocyanation enabled continuous racemization of the unreacted cyanohydrins, thereby effecting a total conversion (Figure 4.21). 

M Goodman, KC Stueben. Amino acid active esters. III. Base-catalyzed racemization of peptide active esters. J Org Chem 27, 3409, 1962. 

B Liberek. Racemization during peptide synthetic work. II. Base catalyzed racemization of active derivatives of phthaloyl amino acids. Tetrahedron Lett 1103, 1963. 

Indeed, it was shown that aposcopolamine was not formed by direct dehydration of scopolamine, but via the conjugate scopolamine O-sulfate generated by a sulfotransferase [127]. This explains the species differences observed, and indicates a mechanism of heterolytic C-0 bond cleavage made possible by the electron-withdrawing capacity of the sulfate moiety. The reaction is also facilitated by the acidity of the departing proton carried by the vicinal, stereogenic C-atom. This acidity also accounts for the facile base-catalyzed racemization of scopolamine and hyoscyamine [128]. 

Dynamic kinetic resolution (DKR) is an attractive protocol for the production of enantiopure compounds from racemic mixtures [45]. The concept of DKR is illustrated in Scheme 5.13. In many cases, DKRs are accomplished by the combination of enzymatic resolution and transition-metal-catalyzed racemization based on hydrogen transfer. Thus, the use of Cp Ir complexes as catalysts for racemization in DKR can be anticipated. 

Tautomerization can be induced through the addition of an acid or base. (See the previous section for details on tautomerism.) We begin here by investigating the racemization (the formation of both enantiomers) of the compound shown in Figure 11-5, and we use this reaction to investigate both the acid and base mechanisms. The acid-catalyzed mechanism is shown in Figure 11-6 and the base-catalyzed mechanism is shown in Figure 11-7. 

In the base-catalyzed racemization (Figure 11-7), the carbon is also vulnerable to attack from either side. Attack from one side gives one enantiomer, while attack from the other side gives the other enantiomer. (The attack results in deprotonation.) Since the probability for attack from either side is equal, a racemic mixture again results. 

The beginning of the mechanism forthe base catalyzed racemization. 

Scheme 35 Acid/Base-Catalyzed Racemization of 2-(Aminoalkyl)dihydrothiazole-4-carboxylic Acids1513 ...

Figure C shows an extreme case of the dependence of a substitution reaction rate on the nature of the incoming group. This happens to be the hydrolysis of the trisacetylacetonate complex of silicon (IV), cationic species, which Kirchner studied first—the rate of racemization or rate of dissociation. We studied the base-catalyzed rate of dissociation and showed that a large number of anions and nucleophilic groups, in general, would catalyze in the dissociation process. We found that the reaction rates were actually for a second-order process, so these units are liters per mole per second. But the reaction rate did vary over an enormous range—in this case, about a factor of 109—and this is typical of the sort of variation in rates of reaction (that you can get) for processes that seem to be Sn2 bimolecular displacement processes.

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