Enzymes in organic synthesis

It is interesting that NADH is also required as a stoichiometric co-factor in enzymatic oxygenation processes. In a detailed study of styrene monooxygenase (StyA), Andreas Schmid of the ETH/Zurich showed (J. Am. Chem. Soc. 125 8209, 2(X)3) that Cp Rh(bpy)(HjO) in combination with sodium formate served effectively to regenerate the NADH. Using this combination, epoxidation of aryl alkenes such as 6, 8 and 10 proceeded in high enantiomeric excess. 

As the computational methods used in pharmaceutical development have improved, receptor binding analysis has led to many potential new drug candidates that are polycyclic. Such leads are often not pursued, however, because of the perception that even if it turned out to be active, an enantiomerically-pure polycyclic agent would be too expensive to manufacture. Taking this as a challenge, academic research groups continue to develop clever approaches for the efficient synthesis of complex polycarbocyclic target structures. Three recent approaches are outlined here. 

Hiroto Nagaoka of Tokyo University of Pharmacy and Life Science has reported (Tetrahedron Lett. 44 4649, 2003) the tandem reduction - Dieckmann cyclization of the esters 6 and 9. It is striking that the geometry of the starting alkene dictates the ring fusion of the product. Both 5/5 and 6/5 systems can be prepared this way. 

The furanoterpene 15-acetoxytubipofuran 12 shows cytotoxicity against B-16 melanoma cells. E. Peter Kiindig of the University of Geneva has reported (J. Am. Chem. Soc. 125 5642, 2003) a concise asymmetric synthesis of 12, based on the addition of lithio ethyl vinyl ether to the chromium tricarbonyl-activated benzaldehyde 10. In the course of the organometallic addition, five carbon-carbon bonds are formed. 

As most pharmaceuticals are heterocyclic, there is continuing interest in methods for the direct enantioselective construction of heterocycles. Greg Fu of MIT reports (J. Am. Chem. Soc. 125 10778, 2003) that the addition of the dipole 1 to alkynes is catalyzed by Cul, and that in the presence of the planar-chiral ligand 2 the reaction proceeds in high enantiomeric excess. The ee is maintained with aryl-substituted alkynes, and is higher when there are alkyl substituents on the heterocyclic ring of 1. 

Biotransformations are carried out by either whole cells (microbial, plant, or animal) or by isolated enzymes. Both methods have advantages and disadvantages. In general, multistep transformations, such as hydroxylations of steroids, or the synthesis of amino acids, riboflavin, vitamins, and alkaloids that require the presence of several enzymes and cofactors are carried out by whole cells. Simple one- or two-step transformations, on the other hand, are usually carried out by isolated enzymes. Compared to fermentations, enzymatic reactions have a number of advantages including simple instmmentation reduced side reactions, easy control, and product isolation. 

Quantitative Analysis of Selectivity. One of the principal synthetic values of enzymes stems from their unique enantioselectivity, ie, abihty to discriminate between enantiomers of a racemic pair. Detailed quantitative analysis of kinetic resolutions of enantiomers relating the extent of conversion of racemic substrate (c), enantiomeric excess (ee), and the enantiomeric ratio (E) has been described in an excellent series of articles (7,15,16). 

During a resolution process, the R- and S-enantiomers compete for the free enzyme to form the noncovalent enzyme—substrate complexes ES and ER. These proceed to form transition-state intermediates [ES] and [ER]  

Since the rates for MichaeHs-Menten kinetics at the steady state are described by 

The ratio of specificity constants and determines the enantioselectivity of the reaction. Since (see Fig. 1) 

---

TK-catalyzed synthesis [ENZYMES IN ORGANIC SYNTHESIS] (Vol 9) -fromhemicellulose fiEMICELLULOSE] (Vol 13)... 

The primary disadvantage of the conjugate addition approach is the necessity of performing two chiral operations (resolution or asymmetric synthesis) ia order to obtain exclusively the stereochemicaHy desired end product. However, the advent of enzymatic resolutions and stereoselective reduciag agents has resulted ia new methods to efficiently produce chiral enones and CO-chain synthons, respectively (see Enzymes, industrial Enzymes in ORGANIC synthesis). Eor example, treatment of the racemic hydroxy enone (70) with commercially available porciae pancreatic Hpase (PPL) ia vinyl acetate gave a separable mixture of (5)-hydroxyenone (71) and (R)-acetate (72) with enantiomeric excess (ee) of 90% or better (204). 

---