Substrate tolerance

Although an efficient reaction, the Rees-Atkinson aziridination method suffers from two drawbacks the necessity for an N-phthalimido or N-quinazolinonyl substituent and the use of a highly toxic oxidant. Thus, recent efforts (especially in these green times) have focussed upon more benign methods for generation of the key nitrenoids. Yudin demonstrated the power of electrochemistry with a novel method that removes the need for an added metal oxidant, demonstrating an unusually and impressively broad substrate tolerance compared to many alkene aziridination reactions (Scheme 4.14) [10]. 

The most widely employed methods for the synthesis of nitrones are the condensation of carbonyl compounds with A-hydroxylamines5 and the oxidation of A+V-di substituted hydroxylamines.5 9 Practical and reliable methods for the oxidation of more easily available secondary amines have become available only recently.10 11 12 13. These include reactions with stoichiometric oxidants not readily available, such as dimethyldioxirane10 or A-phenylsulfonyl-C-phenyloxaziridine,11 and oxidations with hydrogen peroxide catalyzed by Na2W044 12 or Se02.13 All these methods suffer from limitations in scope and substrate tolerance. For example, oxidations with dimethyldioxirane seem to be limited to arylmethanamines and the above mentioned catalytic oxidations have been reported (and we have experienced as well) to give... 

Likewise, C. parapsilosis was investigated for substrate tolerance in the deracemization reactions with aryl a-hydroxy esters (23) (Figure 5.16) [29]. A range of... 

The wide substrate tolerance of lipases is demonstrated by the resolution of organometallic substrates [129-131]. The presence of tin, selenium, or tellurium in the structure of secondary alcohols does not inhibit the lipase activity and enantiopure organometallic alcohols were obtained by acylation in organic media (Figure 6.48). 

Styrene was successfully oxidized to the S-product both by xylene monooxygenase from P. putida mt-2 [113] and styrene monooxygenase from Pseudomonas sp.VLB120 [114] (Scheme 9.13), with the latter enzyme displaying a particularly large substrate tolerance with excellent stereoselectivity (>99% ee). In this context it is interesting to note that both xylene monooxygenase as well as chloroperoxidase are very selective for mono-epoxidation in case of presence of multiple alkene functionalities [115]. 

Catalytic C—C coupling is particularly valuable in asymmetric synthesis because of its potential for stereodivergent product generation [13], by which multiple stereoisomeric products can be derived from common synthetic building blocks (Eigure 10.1). Obviously, such a synthetic strategy depends on the prevalence of related stereocomplementary enzymes that must have a similarly broad substrate tolerance. 

Enzyme preparations from liver or microbial sources were reported to show rather high substrate specificity [76] for the natural phosphorylated acceptor d-(18) but, at much reduced reaction rates, offer a rather broad substrate tolerance for polar, short-chain aldehydes [77-79]. Simple aliphatic or aromatic aldehydes are not converted. Therefore, the aldolase from Escherichia coli has been mutated for improved acceptance of nonphosphorylated and enantiomeric substrates toward facilitated enzymatic syntheses ofboth d- and t-sugars [80,81]. High stereoselectivity of the wild-type enzyme has been utilized in the preparation of compounds (23) / (24) and in a two-step enzymatic synthesis of (22), the N-terminal amino acid portion of nikkomycin antibiotics (Figure 10.12) [82]. 

A more general access to biologically important and structurally more diverse aldose isomers makes use of ketol isomerases for the enzymatic interconversion of ketoses to aldoses. For a full realization of the concept of enzymatic stereodivergent carbohydrate synthesis, the stereochemically complementary i-rhamnose (Rhal EC 5.3.1.14) and i-fucose isomerases (Fuel EC 5.3.1.3) from E. coli have been shown to display a relaxed substrate tolerance [16,99,113,131]. Both enzymes convert sugars and their derivatives that have a common (3 J )-OH configuration, but may deviate in... 

A biochemically related benzaldehyde lyase (BAL) (EC 4.1.2.38) catalyzes the same carboligation reactions, but with opposite (J )-selectivity (mf-110) [178]. All these enzymes seem to display a rather useful substrate tolerance for variously substituted aldehyde precursors. 

Whereas SHMT in vivo has a biosynthetic function, threonine aldolase catalyzes the degradation of threonine both l- and D-spedfic ThrA enzymes are known [16,192]. Typically, ThrA enzymes show complete enantiopreference for their natural a-D- or a-t-amino configuration but, with few exceptions, have only low specificity for the relative threo/erythro-configuration (e.g. (122)/(123)) [193]. Likewise, SHMT is highly selective for the L-configuration, but has poor threo/erythro selectivity [194]. For biocatalytic applications, the knovm SHMT, d- and t-ThrA show broad substrate tolerance for various acceptor aldehydes, notably induding aromatic aldehydes [193-196] however, a,P-unsaturated aldehydes are not accepted [197]. For preparative reactions, excess of (120) must compensate for the unfavorable equilibrium constant [34] to achieve economical yields. 

Baranton S, Coutanceau C, Roux C, Hahn F, Leger JM. 2005. Oxygen reduction reaction in acid medium at iron phthalocyanine dispersed on high surface area carbon substrate tolerance to methanol, stability and kinetics. J Electroanal Chem 577 223-234. 

Broad Substrate Tolerance of Wild-Type Aldolases 116... 

Directed evolution methods, as well as rational structure-based mutagenesis approaches, have been successful in broadening the substrate tolerance of aldolases. A common goal is to... 

Figure 6.9 Broad acceptor substrate tolerance of sialic acid aldolase in synthesis of nonnatural disaccharides...

Efforts to tune the reactivity of rhodium catalysts by altering structure, solvent, and other factors have been pursued.49,493 50 Although there is (justifiably) much attention given to catalysts which provide /raor-addition processes, it is probably underappreciated that appropriate rhodium complexes, especially cationic phosphine complexes, can be very good and reliable catalysts for the formation of ( )-/3-silane products from a air-addition process. The possibilities and range of substrate tolerance are demonstrated by the two examples in Scheme 9. A very bulky tertiary propargylic alcohol as well as a simple linear alkyne provide excellent access to the CE)-/3-vinylsilane products.4 a 1 In order to achieve clean air-addition, cationic complexes have provided consistent results, since vinylmetal isomerization becomes less competitive for a cationic intermediate. Thus, halide-free systems with... 

Recently, the purification of recombinant protein acyl transferases was published. Future investigations will show whether these biocatalysts may also serve as tools for acylating proteins. Depending on their substrate tolerance the incorporation of non-natural acyl analogues could also be possible. 

Section 11.06.4 of this chapter highlights the substrate scope of olefin CM reactions. Based on this survey of the literature, olefins will then be placed into their appropriate category based upon catalyst activity and substrate tolerance, citing specific examples (Section 11.06.4.6). It is important to note that olefin-type characterization can change in response to catalyst reactivity. For example, an olefin may be characterized as a type III olefin in CM... 

Figure 3.2. The chemical diversity that is characteristic of NPs can be considered to arise in two phases. In the first phase, a few precursors are joined together in a few similar ways (using a modular or iterative processes) to produce families of structures that provide the basic carbon skeletons that characterise the group. In the second phase, enzymes with broad substrate tolerances tailor the skeletons in versatile ways to generate even greater diversity.

Evidence to support this proposition that enzymes involved in NP metabolism would possess broad substrate tolerance... 

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