Enzyme-mediated asymmetric

The catalytic, asymmetric hydrogenations of alkenes, ketones and imines are important transformations for the synthesis of chiral substrates. Organic dihydropyridine cofactors such as dihydronicotinamide adenine dinucleotide (NADH) are responsible for the enzyme-mediated asymmetric reductions of imines in living systems [86]. A biomimetic alternative to NADH is the Hantzsch dihydropyridine, 97. This simple compound has been an effective hydrogen source for the reductions of ketones and alkenes. A suitable catalyst is required to activate the substrate to hydride addition [87-89]. Recently, two groups have reported, independently, the use of 97 in the presence of a chiral phosphoric acid (68 or 98) catalyst for the asymmetric transfer hydrogenation of imines. 

K. Miyamoto and H. Ohta, "Enzyme-mediated asymmetric decarboxylation of disubsti-tuted malonic acids". Journal of the American Chemical Society 112,4077—4078 (1990). 

Miyamoto K, Ohta H. Enzyme-mediated asymmetric decarboxylation of disubstituted malonic acids. J. Am. Chem. Soc. 1990 112 4077 78. 

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

The oxidation of heteroatoms and, in particular, the conversion of sulfides to asymmetric sulfoxides has continued to be a highly active field in biocatalysis. In particular, the diverse biotransformations at sulfur have received the majority of attention in the area of enzyme-mediated heteroatom oxidation. This is particularly due to the versatile applicability of sulfoxides as chiral auxiliaries in a variety of transformations coupled with facile protocols for the ultimate removal [187]. 

A successful case study for asymmetric nitrogen oxidation was reported for a series of (hetero)aromatic tertiary amines. High diastereoselectivity was observed for the enzyme-mediated oxidation of S-(—)-nicotine by isolated CHMOAdneto to give the corresponding ds-N-oxide [215]. The stereoselectivity of this biooxidation was complementary to the product obtained by flavin M O (FM O) from human li ver (trows-selective [216]) as well as unspecific oxidations by FMOs from porcine and guinea pig liver. 

A patent procedure for formation of compounds 19 from simple tartaric acid derivatives has appeared <06USP047129> and various new routes to chiral dioxolanones include synthesis of dioxolan-2-ones either by transition metal-mediated asymmetric synthesis <06T1864> or enzyme-mediated kinetic resolution <06H(68)1329> and a new synthesis of the chiral dioxolan-4-ones 21 from lactic or mandelic acid involving initial formation of intermediates 20 with trimethyl orthoformate in cyclohexane followed by reaction with pivalaldehyde <06S3915>. 

Efficient kinetic resolution of chiral unsaturated secondary alcohols by irreversible enzyme-mediated acylation (with vinyl acetate as acylating agent, a crude preparation of Pseudomonas AK, and hexane as solvent) is possible, provided one relatively large and one small substituent are attached to the carbinol carbon. However, the method can be used to resolve substrates that are not amenable to asymmetric epoxidation (see examples 23, 25, 27, 29, where the double bond is either deactivated by an electron-withdrawing substituent, or is of the propargyl alcohol type). Acylation of the / -enantiomer consistently proceeds faster than that of the 5-enantiomer. An example of an allenic alcohol was also reported248. 

Colonna S, Del Sordo S, Gaggero N, Carrea G, Pasta P (2002) Enzyme-Mediated Catalytic Asymmetric Oxidations. Heteroatom Chem 13 467... 

Previously, a wide variety of metal-mediated asymmetric two-center catalyses based on a multifunctional catalyst concept was developed [5]. Similar to an enzyme reaction, the synergistic functions of two or more active sites in multimetallic catalysts make substrates more reactive, and control their position in the transition state so that the functional groups are proximal to each other. In order to extend this concept to asymmetric organocatalysis, two ammonium salt moieties were... 

Colonna, S., Del Sordo, S., Gaggero, N., Carrea, G. and Pasta, P. (2002) Enzyme-mediated catalytic asymmetric oxidations. Heteroatom Chemistry, 13, 467 73. 

Unless specified otherwise, all reductions included in this chapter gave good yields of >90% enantiomeric excess (ee) products. Not all products of enzyme-catalyzed reactions meet the minimum % ee levels normally required for asymmetric synthetic applications. However, protocols exist for improving ee s of imperfectly specific enzyme-mediated transformations. 

While discussing asymmetric synthesis in Chapter 9 we noted that enzymes are among the best candidates for producing a desired enantiomer with remarkable selectivity. A few specific examples of microbiological y mediated asymmetric synthesis were given to emphasize the attractiveness of this route. 

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