Chiral flavins

Enzyme-mediated chiral sulfoxidation has been reviewed comprehensively in historical context [188-191]. The biotransformation can be mediated by cytochrome P-450 and flavin-dependent MOs, peroxidases, and haloperoxidases. Owing to limited stability and troublesome protein isolation, a majority of biotransformations were reported using whole-cells or crude preparations. In particular, fungi have been identified as valuable sources of such biocatalysts and the catalytic entities have not been fully identified in all cases. 

Walsh and coworkers oxidized ethyl p-tolyl sulfide on an analytical scale to the S-sulfoxide of 64% enantiomeric purity using a bacterial flavoenzyme cyclohexanone monooxygenase derived from Adnetobacter . Using a flavin adenine dinucleotide containing monooxygenase purified from hog liver microsomes yielded the R-sulfoxide of 90% enantiomeric purity. HPLC on a column containing a 3,5-dinitrobenzoyl-D-phenylglycine chiral stationary phase was used to determine the optical purity of the sulfoxides. 

Light DR, Waxman DJ, Walsh C. 1982. Studies on the chirality of sulfoxidation catalyzed by bacterial flavoenzyme cyclohexanone monooxygenase and hog liver flavin adenine dinucleotide containing monooxygenase. Biochemistry 21 2490-2498. 

The one-electron oxidation of iV-benzylphenothiazine by nitric acid occurs in the presence of /i-cyclodextrin, which stabilizes the radical cation by incorporation into its cavity. The reaction is inhibited by adamantane, which preferentially occupies the cavity. Novel Pummerer-type rearrangements of / -sulfinylphenyl derivatives, yielding /7-quinones and protected dihydroquinones, and highly enantioselective Pummerer-type rearrangements of chiral, non-racemic sulfoxides have been reviewed. A comprehensive study has demonstrated that the redox potential for 7- and 8-substituted flavins is linearly correlated with Hammett a values. DFT calculations in [3.3.n]pro-pellanes highlight low ionization potentials that favour SET oxidative cleavage of the strained central C-C bond rather than direct C-H or C-C bond attack. Oxidations and reductions in water have been reviewed. ... 

Cytochrome c552 from Euglena gracilis (also known as cytochrome / or c6) contains 87 amino acid residues, two hemes and one flavin per molecule.693 NMR studies706 indicate that the chirality of the axial methionine is similar to that of cytochrome c but different from cytochrome c5Sl. Rapid intramolecular transport has been demonstrated by the use of pulsed laser excitation, and the measurement of reduction kinetics. Both flavin and heme groups are reduced simultaneously on a multisecond time scale, with the transient formation of a protein-bound flavin anion radical.707... 

Biological oxidation of sulfides involves cytochromes P-450 or flavin-dependent oxygenases. A chiral flavin model was prepared by Shinkai etal. and used as the catalyst in the oxidation of aryl methyl sulfides [87]. Flavinophane 30 (Scheme 6C.10) is a compound with planar chirality. It catalyzes the oxidation of sulfides with 35% H202 in aqueous methanol at -20°C in the dark. 

The hydroxynitrile lyase (HNL) class of enzymes, also referred to as oxynitrilases, consists of enzymes that catalyze the formation of chiral cyanohydrins by the stereospecific addition of hydrogen cyanide (HCN) to aldehydes and ketones (Scheme 19.36).275 279 These chiral cyanohydrins are versatile synthons, which can be further modified to prepare chiral a-hydroxy acids, a-hydroxy aldehydes and ketones, acyloins, vicinal diols, ethanolamines, and a- and P-amino acids, to name a few.280 Both (R)- and (.S )-selective HNLs have been isolated, usually from plant sources, where their natural substrates play a role in defense mechanisms of the plant through the release of HCN. In addition to there being HNLs with different stereo-preferences, two different classifications have been defined, based on whether the HNL contains a flavin adenine dinucleotide (FAD) co-factor. 

The stereochemical data discussed for the protonation/deprotonation at C-fi catalyzed by the above enzymes are consistent with the results of trapping experiments with JV-ethylmaleimide carried out by Flavin and Slaughter [160]. This reagent will react with enamines, like the PLP-aminocrotonate intermediate, with formation of an adduct, a-keto-3-[3 -(A"-ethyl-2, 5 -diketopyrrolidyl)]butyric add (KEDB) This compound has two chiral centers which are generated during the reaction. 

Flavin-dependent monooxygenase-mediated Baeyer-Villiger oxidations leading to chiral lactones 02EJO3711. 

Apart from the asymmetric metal catalysis, enantioselective Baeyer-Villiger oxidations mediated by enzymes have been known for some time [32,33,34]. Both whole-cell cultures and isolated enzymes, usually flavin-dependent monooxygenases, can be used to oxidize ketones enantioselectively. For future improvements in the asymmetric Baeyer-VilHger oxidation the use of chiral Lewis acids in combination with an appropriate oxidant seems worthy of intensive investigation. 

NADH directly transfers a hydride ion to flavins and analogs (e.g., deazaflavin), indicating hydrogen transfer within a molecular complex (Scheme 7.2.27). Hydrophobic NADH derivatives with an ammonium side chain have been bound to a PEG substituent of a flavin and are then oxidized much faster to NAD than without complex formation. Chiral deazaflavino-... 

All mechanistic studies on enzymatic Baeyer-Villiger reactions support the hypothesis that conventional and enzymatic reactions are closely related [1063, 1204]. The oxidized flavin cofactor (FAD-4a-OOH, see Scheme 2.147) plays the role of a nucleophile similar to the peracid. The strength of enzyme-catalyzed Baeyer-Villiger reactions resides in the recognition of chirality [1205-1207], which has been accomplished by conventional means only recently, albeit in reactions exhibiting moderate selectivities [1208]. 

Asymmetric hydrogen transfer from NADH or chiral 1,4-dihydro-pyridine derivatives to flavin in mimetic systems has been attempted. Levine and Kaiser (1980) found that flavin attached to the Cys-25 in papain (flavopapain) discriminates between the prochiral hydrogens on NADH. Flavopapain, in which the active site of the hydrolytic... 

By using a chiral Sharpless ligand, high enantioselectivities were obtained. In the flavin system, an increase in the addition time for alkene and H2O2 has a positive... 

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