Enantiotopic discrimination

The desymmetrization of l-alkylbicyclo[3.3.0]octane-2,8-diones can be achieved in a facile coenzyme-independent enzymatic reaction in buffer. Alkyl chains in the 1 -position of up to at least five carbon atoms are tolerated. The yields of the crude keto-acids are essentially quantitative, and the enantiotopic discrimination by the enzyme is usually excellent." Work remains to be done on the optimization of this biocatalyst with respect to protein stability and reaction engineering, but it remains a unique and intriguing possibility for the generation of interesting intermediates bearing multiple chiral centres. 

The enantiotopic discrimination of hydrogens during oxidation of unactivated C—H bonds by microorganisms is synthetically extremely useful, and some examples are shown in Scheme The resultant products are valuable chiral synthons. For example (/ )-3-hydroxybutanoic acid (7) a versatile homochiral synthon, can be used in the synthesis of antibacterials. > (5)-2-Methyl-3-hydn>xypropanoic acid (8) has been widely employed as a source of chirality, for example in the synthesis of maysine, macrolide antibiotics and both (/ )- and (S)-muscone. A variety of other optically active 3-hydroxy aliphatic carboxylic acids can be prepared by analogous methods. 

Enzymatic Reactions, Molecular Imprints, and Enantiotopic Discrimination... 

Stereoisomerism and Connectivity 300 Total Synthesis of an Antibiotic with a Staggering Number of Stereocenters 303 The Descriptors for the Amino Acids Can Lead to Confusion 307 Chiral Shift Reagents 308 C2 Ligands in Asymmetric Synthesis 313 Enzymatic Reactions, Molecular Imprints, and Enantiotopic Discrimination 320 Biological Knots—DNA and Proteins 325 Polypropylene Structure and the Mass of the Universe 331 Controlling Polymer Tacticity—The Metallocenes 332 CD Used to Distinguish a-Helices from [3-Sheets 335 Creating Chiral Phosphates for Use as Mechanistic Probes 335... 

Both acylation and deacylation brought about clear-cut enantiotopical discrimination of the specific enantiomers, giving rise to enantiocomplementaiity to alcohol 215 and acetate 216 as a 1 1 mixture. These two approaches were made complementary so as to... 

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. 

In contrast to the hydrolysis of prochiral esters performed in aqueous solutions, the enzymatic acylation of prochiral diols is usually carried out in an inert organic solvent such as hexane, ether, toluene, or ethyl acetate. In order to increase the reaction rate and the degree of conversion, activated esters such as vinyl carboxylates are often used as acylating agents. The vinyl alcohol formed as a result of transesterification tautomerizes to acetaldehyde, making the reaction practically irreversible. The presence of a bulky substituent in the 2-position helps the enzyme to discriminate between enantiotopic faces as a result the enzymatic acylation of prochiral 2-benzoxy-l,3-propanediol (34) proceeds with excellent selectivity (ee > 96%) (49). In the case of the 2-methyl substituted diol (33) the selectivity is only moderate (50). 

Reaction of an achiral reagent with a molecule exhibiting enantiotopic faces will produce equal quantities of enantiomers, and a racemic mixture will result. The achiral reagent sodium borodeuteride, for example, will produce racemic l-deM/eno-ethanol. Chiral reagent can discriminate between the prochiral faces, and the reaction will be enantioselective. Enzymatic reduction of acetaldehyde- -[Pg.106]

In recent years, enantioselective variants of the above transannular C-H insertions have been extensively stiidied. The enantiodetermining step involves discrimination between the enantiotopic protons of a meso-epoxide by a homochiral base, typically an organolithium in combination with a chiral diamine ligand, to generate a chiral nonracemic lithiated epoxide (e.g., 26 Scheme 5.8). Hodgson... 

It is also possible to achieve enantioselective enolate formation by using chiral bases. Enantioselective deprotonation requires discrimination between two enantiotopic hydrogens, such as in d.v-2,6-dimethylcyclohexanone or 4-(/-butyl)cyclohcxanonc. Among the bases that have been studied are chiral lithium amides such as A to D.22... 

Achiral A,A-diisopropyl-ferrocenecarboxamide (440) was deprotonated by Snieckus and coworkers by n-BuLi/(—)-sparteine (11) (equation 119) . The base discriminates well between the enantiotopic protons H(2) and H(5) in the substituted ring to form the diastereomer 441 with high selectivity. Trapping the intermediate with a couple of different electrophiles afforded the substitution products 442a-d with 85 to 99%... 

As for any desymmetrization of meso compounds, enantioselectivity comes from the ability of a homochiral base to distinguish between two enantiotopic protons, in this particular case, to discriminate between the two pseudo-axial protons of the rapidly equilibrating enantiomeric half-chair conformations 51 and 52 (Scheme 25). 

It should be noted that the vinyl and methyl proton resonances of the Z-isomer [i.e., of the achiral tetracarbonylirondimethyl (Z)-butenedioate complex] are also discriminated in the presence of Eutbfc), because the internally enantiotopic nuclei are rendered diastereotopic in the presence of the nonracemic LSR81. The vinyl protons of the. E-isomer show two lines (external diastereotopism) while the vinyl protons of the Z-isomer exhibit an AB-system (internal diastereotopism)5. 

Figure 10. 250 MIU H-NMR spectra of 2,2,4,4-ietramcthyl-3-pentanol and 4,4-dimethyl-2,2-di(methyl-<7,(pentan-1.1,1 -c/,-3-ol (in chloroform-rfat 24 C) in the presence orEu(hfc)3 (substrate/LSR 1 2)103 a) discrimination of internally enantiotopic protons rendered diastcreotopic in a chiral environment, b) discrimination of externally enantiotopic protons rendered diastereotopic in a chiral environment.

---