Non-enzymatic transformations

An interesting combination of enzymatic with non-enzymatic transformation in a one-pot three-step multiple sequence was reported by Waldmann and coworkers [82]. Phenols 125 in the presence of oxygen and enzyme tyrosinase are hydroxylated to catechols 126 which are then oxidized in situ to ortho quinones 127. These intermediates subsequently undergo a Diels-Alder reaction with inverse electron demand by reaction with different dienophiles (Table 4.19) to give endo bicyclic 1,2-diketones 128 and 129 in good yields. 

Scheme 5. Proposed biosynthesis of allene oxide 64 from 8i -lipoxygenase initiated metabolism of arachidonic acid and subsequent non-enzymatic transformations to racemic cyclopenteone 30 [86]...

The tetrapyrroles 31 and epi-31 were suggested to arise from further endogenous (yet possibly non-enzymatic) transformation of the NCCs in the tissue of the senescent barley leaves. Oxidative loss of the formyl group from related linear tetrapyrroles has been noted (101). The original characterization for //v-NCC-1 (2) as a rusty pigment also pointed to the readiness of these reduced linear tetrapyrroles to undergo spontaneous reactions, which become manifest by the appearance of the rust colour (3, 4, 25). Clearly, these and other transformations, such as the one of //v-NCC-1 (2) to the two tetrapyrroles 31/epi-31, may reflect further degradation of the NCCs in the senescent tissue. 

The biosynthesis of these compounds seems to occur in two phases (1) coupling of two steroids via a pyrazine linker, and (2) relatively unselective oxidation at various positions. Some of these compounds are related to others by simple processes the hydration of cephalostatin 1 to its hemiketal form cephalostatin 9 the dehydration of cephalostatin 2 to an enone, which in turn may be an intermediate to cephalostatin 6 the skeletal rearrangement of ritterazine B to ritterazine A, which may be acid catalyzed and the pairs of ritterazines epimeric at C-22. One can speculate whether such reactions are non-enzymatic transformations occurring in the organism or even during the isolation procedure. 

An obstacle in the study of the enzymatic oxygenation of polyunsaturated fatty acids is the fact that these acids can be non-enzymatically transformed to hydroperoxides and many other products [51], Hematin and hematin-containing compounds, e.g. hemoglobin, myoglobin or cytochromes, catalyse the non-enzymatic formation of lipid hydroperoxides. Hydroperoxides may also be formed when unsaturated fatty acids are exposed to air. This autooxidation of polyunsaturated fatty acids is stimulated by light and heat and may eventually lead to complete eonsumption of the fatty acids. 

A reasonable route for the formation of this racemic cyclopentenone (30) was proposed from 8.R-HPETE (29), which involves the non-enzymatic hydrolysis of an allene oxide (64) intermediate (Scheme 5 ) [86]. Biochemical precedence for these transformations was provided by earlier work with plants [90] and C. 

As is apparent from a recent review there are many examples of this lype of reaction known see R. S. Ward, Client. Soe. Rev. 19, 1 (1990). Concerning terminology, the title of this article is interesting "Non-Enzymatic Asymmetric Transformations Involving Symmetrical Bifunctional Compounds". Using the Izumi-Tai system the title could have been much shorter and precise Non-Enzy-matic Enantiotopos-Differentiating Reactions. 

Glucose reacts non-enzymatically with amino acids and proteins, including hemoglobin, egg-white proteins and serum albumin. For example, if glucose is not removed prior to drying, dried egg whites slowly turn brown and develop off-flavors and odors. What do you propose as the most likely first step in the non-enzymatic glucose-protein chemical reaction How can the first product transform spontaneously into a ketose derivative ... 

Desymmetrization of an achiral, symmetrical molecule through a catalytic process is a potentially powerful but relatively unexplored concept for asymmetric synthesis. Whereas the ability of enzymes to differentiate enantiotopic functional groups is well-known [27], little has been explored on a similar ability of non-enzymatic catalysts, particularly for C-C bond-forming processes. The asymmetric desymmetrization through the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides an efficient access to remote [28] and internal [29] asymmetric induction (Scheme 8C.10) [30]. The (2/ ,5S)-s> i-product is obtained with >99% ee and >99% diastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound in a regioselective and diastereoselective manner. 

Enantiopure propargylic sec-alcohols are valuable synthetic intermediates that can be prepared by a number of efficient asymmetric transformations [131]. KR of the racemic propargylic sec-alcohols is a valuable approach, particularly as subsequent exhaustive hydrogenation of the alkyne provides an indirect approach to enantio-enriched alkyl alkyl sec-alcohols which themselves are challenging substrates for both enzymatic and non-enzymatic KR. 

Glycation reactions. Glucose or other sugars may react non-enzymatically with proteins to form glycation products. Early glycation products such as fructosamine-protein adducts may later be transformed to the more complex advanced glycation end products (AGE products). 

The 5(2H)-oxazolones (213) present two sites, C(4) and C(5), to nucleophilic attack they usually react at the latter. The benzylidene derivative (214), the most thoroughly studied member of this class, possesses an additional electrophilic centre at the exocyclic carbon atom. However, alkaline hydrolysis of this compound affords phenylacetamide and benzoylformic acid by acyl-oxygen fission (equation 50). a-Keto acids are also obtained when 2-trifluoromethyl-5(4//)-oxazolones are hydrolyzed, the reaction involving preliminary isomerization to a 5(2//)-oxazolone. The example shown in equation (51) represents the first non-enzymatic synthesis of an optically active a-keto acid. An instance of nucleophilic attack at C(4) of a 5(2//)-oxazolone is the formation of the oxazolidinone (215) in a Grignard reaction (equation 52). However, the typical behaviour of unsaturated pseudooxazolones like (214) is conjugate addition of a nucleophile, followed by further transformations of the resulting 5(4F/)-oxazoIones. This is illustrated by the reaction of compound (214) with benzene in the presence of aluminum chloride to yield, after aqueous work-up, the acylamino acid (216 equation 53). 

The deracemization of a number of pharmaceutically valuable building blocks has been carried out by biocatalytic processes. This includes epoxides, alcohols, amines and acids. DKR involves the combination of an enantioselective transformation with an in situ racemisation process such that, in principle, both enantiomers of the starting material can be converted to the product in high yield and ee. The racemization step can be catalysed either enzymatically by racemases, or non-enzymatically by transition metals. 

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